Cochrane Library Cochrane Database of Systematic Reviews Vaccines for the common cold (Review) Montesinos-Guevara C, Buitrago-Garcia D, Felix ML, Guerra CV, Hidalgo R, Martinez-Zapata MJ, Simancas-Racines D Montesinos-Guevara C, Buitrago-Garcia D, Felix ML, Guerra CV, Hidalgo R, Martinez-Zapata MJ, Simancas-Racines D. Vaccines for the common cold. Cochrane Database of Systematic Reviews 2022, Issue 12. Art. No.: CD002190. DOI: 10.1002/14651858.CD002190.pub6. www.cochranelibrary.com Vaccines for the common cold (Review) Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews TABLE OF CONTENTS ABSTRACT..................................................................................................................................................................................................... 1 PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2 SUMMARY OF FINDINGS.............................................................................................................................................................................. 4 BACKGROUND.............................................................................................................................................................................................. 6 OBJECTIVES.................................................................................................................................................................................................. 7 METHODS..................................................................................................................................................................................................... 7 Figure 1.................................................................................................................................................................................................. 9 RESULTS........................................................................................................................................................................................................ 11 Figure 2.................................................................................................................................................................................................. 12 Figure 3.................................................................................................................................................................................................. 13 Figure 4.................................................................................................................................................................................................. 14 DISCUSSION.................................................................................................................................................................................................. 15 AUTHORS' CONCLUSIONS........................................................................................................................................................................... 16 ACKNOWLEDGEMENTS................................................................................................................................................................................ 16 REFERENCES................................................................................................................................................................................................ 17 CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 34 DATA AND ANALYSES.................................................................................................................................................................................... 49 Analysis 1.1. Comparison 1: Adenovirus vaccines versus placebo, Outcome 1: Incidence of the common cold............................. 49 APPENDICES................................................................................................................................................................................................. 49 WHAT'S NEW................................................................................................................................................................................................. 56 HISTORY........................................................................................................................................................................................................ 57 CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 57 DECLARATIONS OF INTEREST..................................................................................................................................................................... 57 SOURCES OF SUPPORT............................................................................................................................................................................... 58 DIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 58 INDEX TERMS............................................................................................................................................................................................... 59 Vaccines for the common cold (Review) i Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews [Intervention Review] Vaccines for the common cold Camila Montesinos-Guevara1, Diana Buitrago-Garcia2, Maria L Felix3, Claudia V Guerra1, Ricardo Hidalgo1, Maria José Martinez- Zapata1,4, Daniel Simancas-Racines1 1Cochrane Ecuador, Centro de Investigación en Salud Pública y Epidemiología Clínica (CISPEC), Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador. 2Institute of Social and Preventive Medicine (ISPM), Graduate School of Health Sciences, University of Bern, Bern, Switzerland. 3Departamento de Neonatología, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador. 4Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain Contact: Daniel Simancas-Racines, danielsimancas10@gmail.com. Editorial group: Cochrane Acute Respiratory Infections Group. Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 12, 2022. Citation: Montesinos-Guevara C, Buitrago-Garcia D, Felix ML, Guerra CV, Hidalgo R, Martinez-Zapata MJ, Simancas- Racines D. Vaccines for the common cold. Cochrane Database of Systematic Reviews 2022, Issue 12. Art. No.: CD002190. DOI: 10.1002/14651858.CD002190.pub6. Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. This is an open access article under the terms of the Creative Commons Attribution-Non-Commercial Licence, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. ABSTRACT Background The common cold is a spontaneously remitting infection of the upper respiratory tract, characterised by a runny nose, nasal congestion, sneezing, cough, malaise, sore throat, and fever (usually < 37.8 ºC). Whilst the common cold is generally not harmful, it is a cause of economic burden due to school and work absenteeism. In the United States, economic loss due to the common cold is estimated at more than USD 40 billion per year, including an estimate of 70 million workdays missed by employees, 189 million school days missed by children, and 126 million workdays missed by parents caring for children with a cold. Additionally, data from Europe show that the total cost per episode may be up to EUR 1102. There is also a large expenditure due to inappropriate antimicrobial prescription. Vaccine development for the common cold has been difficult due to antigenic variability of the common cold viruses; even bacteria can act as infective agents. Uncertainty remains regarding the efficacy and safety of interventions for preventing the common cold in healthy people, thus we performed an update of this Cochrane Review, which was first published in 2011 and updated in 2013 and 2017. Objectives To assess the clinical effectiveness and safety of vaccines for preventing the common cold in healthy people. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (April 2022), MEDLINE (1948 to April 2022), Embase (1974 to April 2022), CINAHL (1981 to April 2022), and LILACS (1982 to April 2022). We also searched three trials registers for ongoing studies, and four websites for additional trials (April 2022). We did not impose any language or date restrictions. Selection criteria Randomised controlled trials (RCTs) of any virus vaccine compared with placebo to prevent the common cold in healthy people. Data collection and analysis We used Cochrane’s Screen4Me workflow to assess the initial search results. Four review authors independently performed title and abstract screening to identify potentially relevant studies. We retrieved the full-text articles for those studies deemed potentially relevant, Vaccines for the common cold (Review) 1 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews and the review authors independently screened the full-text reports for inclusion in the review, recording reasons for exclusion of the excluded studies. Any disagreements were resolved by discussion or by consulting a third review author when needed. Two review authors independently collected data on a data extraction form, resolving any disagreements by consensus or by involving a third review author. We double-checked data transferred into Review Manager 5 software. Three review authors independently assessed risk of bias using RoB 1 tool as outlined in the Cochrane Handbook for Systematic Reviews of Interventions. We carried out statistical analysis using Review Manager 5. We did not conduct a meta-analysis, and we did not assess publication bias. We used GRADEpro GDT software to assess the certainty of the evidence and to create a summary of findings table. Main results We did not identify any new RCTs for inclusion in this update. This review includes one RCT conducted in 1965 with an overall high risk of bias. The RCT included 2307 healthy young men in a military facility, all of whom were included in the analyses, and compared the effect of three adenovirus vaccines (live, inactivated type 4, and inactivated type 4 and 7) against a placebo (injection of physiological saline or gelatin capsule). There were 13 (1.14%) events in 1139 participants in the vaccine group, and 14 (1.19%) events in 1168 participants in the placebo group. Overall, we do not know if there is a difference between the adenovirus vaccine and placebo in reducing the incidence of the common cold (risk ratio 0.95, 95% confidence interval 0.45 to 2.02; very low-certainty evidence). Furthermore, no difference in adverse events when comparing live vaccine preparation with placebo was reported. We downgraded the certainty of the evidence to very low due to unclear risk of bias, indirectness because the population of this study was only young men, and imprecision because confidence intervals were wide and the number of events was low. The included study did not assess vaccine-related or all-cause mortality. Authors' conclusions This Cochrane Review was based on one study with very low-certainty evidence, which showed that there may be no difference between the adenovirus vaccine and placebo in reducing the incidence of the common cold. We identified a need for well-designed, adequately powered RCTs to investigate vaccines for the common cold in healthy people. Future trials on interventions for preventing the common cold should assess a variety of virus vaccines for this condition, and should measure such outcomes as common cold incidence, vaccine safety, and mortality (all-cause and related to the vaccine). PLAIN LANGUAGE SUMMARY Vaccines for preventing the common cold Review question Can vaccines help prevent the common cold? Background The common cold is mainly caused by a viral infection of the upper respiratory tract. People with the common cold feel unwell, have a runny nose, nasal congestion, sneezing, cough with or without sore throat, and have slightly elevated temperatures. However, people usually recover when their immune system controls the impact of the viral infection. Treatment for this condition is aimed at relieving symptoms. Globally, the common cold causes widespread illness and large economic loss. In the United States, economic loss due to the common cold is estimated at more than USD 40 billion per year, including millions of workdays and school days missed. In Europe, the total cost per episode may be up to EUR 1102. There is also a large expenditure on inappropriate antimicrobial prescriptions. It has been difficult to manufacture vaccines to prevent the common cold because it is caused by several viruses. The effect of vaccines for preventing the common cold in healthy people is still unknown. Search date The evidence is current to 26 April 2022. Study characteristics We did not identify any new trials for inclusion in this update. This review includes one previously identified randomised controlled trial (a type of study where participants are randomly assigned to one of two or more treatment groups) performed in 1965. This study involved 2307 young, healthy military men at a training facility in the United States Navy, and evaluated the effects of a live attenuated (weakened) adenovirus vaccine, an inactivated type 4, and an inactivated type 4 and 7 vaccines compared to a placebo (fake vaccine). Study funding sources The included trial was funded by a government institution. Key results There were no differences in the frequency of occurrence of the common cold between those who received a live attenuated adenovirus vaccine compared to those who received a placebo. There were no differences between groups in adverse events. However, as the trial Vaccines for the common cold (Review) 2 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews participants were not representative of the general population and there were flaws in the study design, our confidence in the results is very low. Further research is needed to find out if vaccines can prevent the common cold, as the current evidence does not support the use of the adenovirus vaccine to prevent the common cold in healthy people. Certainty of the evidence We assessed the certainty of the evidence as very low due to high risk of bias; because the study population was only young men; and due to the small number of people included in the study and low numbers of colds. Vaccines for the common cold (Review) 3 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Collaboration. Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Vaccines for the common cold (Review) SUMMARY OF FINDINGS Summary of findings 1. Virus vaccines compared to placebo for preventing the common cold in healthy people Library Cochrane Virus vaccines compared to placebo for preventing the common cold in healthy people Patient or population: young, healthy men in a military facility Settings: navy training centre Intervention: adenovirus vaccines (live, inactivated type 4, and inactivated type 4 and 7) Better health. Informed decisions. Trusted evidence. Comparison: placebo Outcomes Illustrative comparative risks* (95% CI) Relative effect No. of partici- Certainty of Comments (95% CI) pants the evidence Assumed risk Corresponding risk (studies) (GRADE) Placebo Virus vaccines for pre- venting the common cold Incidence of the common cold Study population RR 0.95 2307 ⊕⊝⊝⊝ (0.45 to 2.02) (1 study) Very lowa,b,c Number of participants with common cold 12 per 1000 11 per 1000 by group (5 to 24) Follow-up: mean 9 weeks Vaccine safety The study reported that there were no differences between groups 2307 ⊕⊝⊝⊝ in vaccine-related adverse events. (1 study) Very lowa,b,c Follow-up: mean 9 weeks Mortality: vaccine related and all cause - See comments The included not reported study did not report this out- Follow-up: mean 9 weeks come. Cochrane Database of Systematic Reviews *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. 4 Collaboration. Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Vaccines for the common cold (Review) Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. aDowngraded one level due to unclear risk of bias. Library Cochrane bDowngraded one level due to indirectness as the study population is only young men. cDowngraded one level due to imprecision as confidence intervals are wide, and the number of events is low. Better health. Informed decisions. Trusted evidence. Cochrane Database of Systematic Reviews 5 Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews BACKGROUND expenditure due to inappropriate antimicrobial prescription and use for URTI (Tsuzuki 2020). Description of the intervention Description of the condition There is no specific treatment for the common cold. Treatment is Although there is no standard definition for the common cold focused on easing the symptoms. Prevention is therefore essential (see Appendix 1), it is generally defined as a spontaneously to stop the spread of viruses that cause the common cold. In terms remitting infection of the upper respiratory tract (URT), of preventive measures, studies have shown that simple measures characterised by a runny nose, nasal congestion, and sneezing. such as handwashing and maintaining physical distance are Other symptoms associated with the common cold include cough, relevant to all respiratory infections, but difficult to apply or enforce malaise, sore throat, and fever (usually < 100 ºF/37.8 ºC) (Eccles because, as time passes, motivation and compliance may decrease 2009). A temperature of 100 ºF/37.8 ºC or higher for three to four (Allan 2014; Jefferson 2020). Consequently, another method of days is typically associated with influenza and other respiratory prevention is vaccination. The development of vaccines for the diseases (see Appendix 2) (DDCP 2010). Despite the fact that the common cold has been challenging because of the aetiological common cold is not considered to be a deadly disease, bacterial diversity of the disease and the antigenic variability of the common complications can lead to high morbidity and mortality (Giraud- cold viruses (Glanville 2013; To 2017). The case of HRV remains Gatineau 2020; Veiga 2021). a challenge for the public health and scientific communities due to technical, logistical, and fundamental biological difficulties The common cold is a disease of diverse aetiology (see Appendix (Stobart 2017). Unlike several human viruses, HRV vaccine must 3) (Heikkinen 2003). Premature babies, children, the elderly, and be able to elicit protective neutralising antibodies to potentially other populations with comorbidities such as chronic lung diseases over 150 serologically distinct types spanning three different (chronic obstructive pulmonary disease), congenital heart disease, species (Ren 2017; Stobart 2017). For this reason, it is difficult and asthma are more prone to viral infections that cause the to develop a vaccine that provides full protection (Stepanova common cold, including respiratory syncytial virus (RSV), human 2019). Despite these challenges, recent attempts using rhinovirus- rhinovirus (HRV), parainfluenza, coronavirus, and adenovirus (non- derived VP1, a surface protein that is critically involved in the polio) (Johnston 2017; Lu 2020; Rubner 2017; Shibata 2018). infection of respiratory cells, has demonstrated that with enough Additionally, in humans, coronavirus such as the HCoV-229E, HCoV- exposure and recombinant VP1 as an immunogen, cross-serotype OC43, HCoV-NL63, and HCoV-HKU1 strains are responsible for reactive antibodies can be generated (Edlmayr 2011; McLean URT infections (URTI) associated with the common cold (Zumla 2012). The future of vaccine development for the common cold 2016). It has been shown that 1% to 10% of the population seems promising, considering that studies on virus genotyping is infected with the HCoV-NL63 coronavirus annually (Szelazek such as HRV genotype are being published more frequently 2017). Even the infectious agent SARS-CoV-2 can be associated (Luka 2020; Ren 2017), and there is a rapid technological with the common cold (Zimmermann 2020). The transmission of development of vaccines that include micro-/nanoparticle material the common cold occurs through aerosols, direct contact with and recombinant technologies (Papadopoulos 2017). infected nasal secretions, or fomites (DeGeorge 2019; L'Huillier 2015; Reynolds 2016); the primary factors that contribute to the Adenovirus is a recognised pathogen of the URT (Biserni spread of this disease include poor hand hygiene, overcrowding, 2020). Adenovirus serotype 4 (Ad4) and serotype 7 (Ad7) and interactions in places such as schools, day-care centres, and vaccines were used during immunisation programmes beginning in between households (Adler 2018; Alexandrino 2016). 1971. Unfortunately, their interruption triggered the re-emergence of adenovirus-produced diseases in crowded locations. An example The common cold is one of the most frequent illnesses experienced of this reappearance was documented in US military training by humans. Children may experience up to 11 URTIs annually sites, where Ad4 accounted for 98% of all diagnoses (Russell (Lambert 2007; Tang 2019), whilst adults experience an average 2006). The development and deployment of AdV-4 and AdV-7 of two episodes per year (Tomita 2012; Visseaux 2017). For vaccines is essential in controlling AdV-4- and AdV-7-related URTI instance, HRV is responsible for 50% to 80% of common colds, (Collins 2020). Adenoviral vaccines delivered orally have been used and it is an important cause of morbidity, reduced productivity, for decades to prevent respiratory illnesses. New studies have and inappropriate use of antibiotics (Kardos 2017; Warner 2019). concluded that these vaccines are safe and have brought about a Although there are few studies on the socioeconomic costs of the large immune response in the studied populations. For instance, a common cold, and most existing studies are problematic in terms study examining the duration of the neutralising antibody response of methodology (e.g. recall bias) for mainly being cross-sectional generated from a live oral AdV-4 and AdV-7 vaccine showed that, studies on self-reported surveys performed in a small or specific regardless of pre-vaccination serostatus, participants developed a population, the impact on school and work absenteeism caused significant antibody response which persisted for at least six years by common cold and the economic burden it causes cannot be after vaccination (Collins 2020). overlooked (Dicpinigaitis 2015; Jaume 2020; Jaume 2021). In the United States, economic loss due to the common cold is estimated RSV is an important cause of respiratory infection in older adults, at more than USD 40 billion per year, including an estimate of 70 and almost all children have been infected with RSV by the million workdays missed by employees suffering from a cold, 189 age of two; due to incomplete and short-lived natural immunity, million school days missed by children, and 126 million work days repeated RSV infections occur throughout life (Williams 2020). missed by parents caring for children with a cold (Kardos 2017), The development of an RSV vaccine has been difficult due to all of which have an impact on productivity (Dicpinigaitis 2015). In antigenic variability, especially in proteins F and G. However, a Europe, the total cost per episode may be up to EUR 1102, of which first-in-human phase 1 trial has been reported to evaluate the 75% are indirect costs (Stjärne 2012). Additionally, there is a large safety and immunogenicity of an experimental RSV vaccine of Vaccines for the common cold (Review) 6 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews Ad26.RSV.preF (a replication-incompetent adenovirus-26 vector Studies suggest that vaccines that mimic natural infection and encoding the F protein), which is administered intramuscularly 12 take into account the structure of pathogens seem to be effective months apart in healthy adults aged ≥ 60 years old (Williams 2020). in inducing long-term protective immunity (Kang 2009). Different There have also been concerns of enhanced respiratory disease types of vaccines against respiratory viruses already exist, but (ERD) after vaccination with the formalin-inactivated RSV vaccines all have been focused on decreasing the incidence of lower in the 1960s, in which patients showed X-ray evidence of severe respiratory infections. Traditionally inactivated or live attenuated pneumonia and bronchiolitis, in addition to immunopotentiation viruses are used. However, there are promising approaches that use induced by a T helper (Th)-2 and Th17 T cell responses with micro-/nanoparticles material and recombinant technologies that the enrolment of T cells, neutrophils, and eosinophils causing produce a broad immunogenic, reproducible, safe, and often self- inflammation and tissue damage (Rey-Jurado 2017). Current adjuvating response (Gomes 2017; Papadopoulos 2017). vaccine candidates, especially those designed for infants and children, whose immune systems are still immature, must therefore Why it is important to do this review be safe and avoid these immunologic features of ERD (Mazur 2018). Although the common cold is self-limiting with symptoms often One RSV immunisation approach is the development of a vaccine lasting up to 10 days, it is the most common acute illness in for pregnant women, since it has been demonstrated that RSV- industrialised countries with a very high incidence, presenting neutralising antibodies are transferred from the pregnant woman several episodes per person a year, as well as being one of the to the foetus through the placenta (Chu 2014). A clinical trial in main causes of primary care consultations (DeGeorge 2019; Jaume which healthy pregnant women received either an intramuscular 2020). Despite being generally mild, the common cold can occur dose of RSV fusion (F) protein nanoparticle vaccine or placebo, with other respiratory illnesses, which can predispose susceptible showed that during the first 90 days of life, infants with RSV individuals to potentially serious complications. Vaccines could had a significantly lower number of respiratory tract infections therefore be used to reduce the prevalence of the disease around (1.5%) compared to the placebo group (2.4%). However, to tag the the world and decrease primary care consultations that might vaccine as successful in terms of efficacy, its possible benefits with saturate healthcare systems. respect to other endpoint events have to be demonstrated (Madhi The socioeconomic burden from the common cold has not been 2020). Another phase II clinical trial evaluated the tolerability and fully studied, and the few studies published in this area mainly have safety of RSV fusion (F) protein nanoparticle vaccine compared to methodological limitations. However, it has been demonstrated placebo in 50 healthy third-trimester pregnant women and their that the common cold can lead to work and school absenteeism infants (Muňoz 2019). The trial demonstrated that the vaccine was as well as having an impact on productivity and healthcare costs well tolerated with no differences on safety outcomes other than (Dicpinigaitis 2015; Jaume 2021; Kardos 2017), which could also be expected short-term reactogenicity in women who received the reduced by preventing the illness through vaccine use, if effective. active vaccine. In addition, transplacental antibody transfer ranged between 90% and 120% across assays for infants of the vaccinated Furthermore, if randomised controlled trials demonstrate that group of women (Muňoz 2019). there is an effective and safe vaccine to prevent the common cold, scientists could continue researching this field. Regarding parainfluenza, there is still no approved vaccine available. However, the intranasal administration of two doses of OBJECTIVES a live-attenuated human parainfluenza virus type 3 HPIV3-cp45 vaccine seems promising, as it has been shown to be well tolerated To assess the clinical effectiveness and safety of vaccines for and immunogenic in seronegative children over six months of age preventing the common cold in healthy people. (Karron 2011). METHODS How the intervention might work Criteria for considering studies for this review Vaccines work by inducing an immune response, such as an antibody response that interferes with a pathogenic invasion and Types of studies prevents their adherence to epithelial cells through opsonisation, Randomised controlled trials (RCTs). We did not apply limits with phagocytosis, and other mechanisms (Pichichero 2009; Wooden respect to follow-up periods. In future updates, we will consider at 2018). A correlate of protection to a pathogen is a measurable least 60 days of follow-up. We only included RCTs that reported data sign that a person is immune after vaccination, and can either about the incidence of the common cold. be absolute or relative (Plotkin 2020). There may also be more than one correlate of protection for a disease, known Types of participants as 'co-correlates' (Plotkin 2020). The immune memory is a critical correlate (effector memory for short-incubation and Healthy people aged between 6 months and 90 years. central memory for long-incubation diseases), and cell-mediated immunity can operate as a correlate or co-correlate of protection Types of interventions against a disease (Plotkin 2010). However, some vaccines only have Any vaccine that prevents the common cold, which protects surrogates for an unknown protective response, which are easy against RSV, rhinovirus, parainfluenza, or adenovirus (non-polio), measurements but not functional (Plotkin 2010). For instance, as irrespective of dose, schedule, or administration route, versus there is no correlate of protection for the development of HRV placebo. We excluded trials on the prevention of influenza A and B vaccines, serum IgA is used as a surrogate marker for studies on all because influenza and the common cold are two different diseases live attenuated HRV vaccines to demonstrate vaccine take (Armah (Jefferson 2012). See Appendix 3 for details. 2016). Vaccines for the common cold (Review) 7 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews Types of outcome measures 2. ClinicalTrials.gov (clinicaltrials.gov/); and Primary outcomes 3. World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (www.who.int/ictrp/search/en/). 1. Incidence of the common cold after vaccination, regardless of the causal agent determined by laboratory or clinical We did not restrict the results by language, search dates, examination. In future updates, we will consider the incidence or publication status (published, unpublished, in press, or in of the common cold as one of the primary outcomes, measured progress). 60 days after the last dose of the vaccine. Searching other resources 2. Vaccine safety, i.e. adverse events ("any untoward medical occurrence that may present during treatment with a We checked the reference lists of all relevant trials and identified pharmaceutical product but which does not necessarily have reviews. We searched the following websites for trials on 29 April a causal relationship with this treatment") and adverse drug 2022: reactions ("a response to a drug which is noxious, uninitiated and which occurs at doses normally used in men for prophylaxis, 1. US Food and Drug Administration (www.fda.gov); diagnosis, or therapy of disease, or for the modification of 2. European Medicines Agency (www.emea.europa.eu); physiologic functions") (Nebeker 2004). 3. Medicines & Healthcare Products Regulatory Agency 3. Mortality: vaccine related and all cause. (www.mhra.gov.uk/index.htm); and 4. Evidence in Health and Social Care (www.evidence.nhs.uk/). Secondary outcomes We did not consider any secondary outcomes. In future updates, we Data collection and analysis will consider mortality as a secondary outcome. Selection of studies Search methods for identification of studies We used Cochrane’s Screen4Me workflow to help assess the search results. Screen4Me comprises three components: known Electronic searches assessments – a service that matches records in the search results We updated the search strategies in the following databases: to records that have already been screened in Cochrane Crowd and been labelled as an RCT or as non-RCT; the RCT classifier 1. the Cochrane Central Register of Controlled Trials (CENTRAL; – a machine learning model that distinguishes RCTs from non- Issue 4, 2022), which contains the Cochrane Acute Respiratory RCTs; and if appropriate, Cochrane Crowd – Cochrane’s citizen Infections Specialised Register, searched 26 April 2022, in the science platform where the Crowd help to identify and describe Cochrane Library (Appendix 4); health evidence. For more information about Screen4Me and the 2. MEDLINE via Ovid (September 2016 to 22 April 2022) (Appendix evaluations that have been done, visit the Screen4Me web page 5); on the Cochrane Information Specialist’s portal. More detailed 3. Embase via Elsevier (September 2016 to 22 April 2022) (Appendix information regarding evaluations of the Screen4Me components 6); can be found in the following publications: Marshall 2018, Noel- Storr 2020, Noel-Storr 2021, Thomas 2021. 4. CINAHL via EBSCO (Cumulative Index to Nursing and Allied Health Literature) (September 2016 to 22 April 2022) (Appendix Following Screen4Me assessment, four review authors (CM, DB, 7); and MLF, MJMZ) independently screened the titles and abstracts 5. LILACS via BIREME (Latin American and Caribbean Health of studies identified as a result of the search for potential Science Information database) (September 2016 to 22 April relevance. We retrieved the full-text reports of those studies 2022) (Appendix 8). deemed potentially relevant, and four review authors (MJMZ, CM, DB, MLF) independently screened the full texts to identify studies We used the Cochrane Highly Sensitive Search Strategy to for inclusion in the review, and identified and recorded the reasons identify randomised trials in MEDLINE: sensitivity- and precision- for exclusion of excluded studies. Any disagreements were resolved maximising version (2008 revision); Ovid format (Lefebvre 2021). through discussion or by consulting a third review author (DSR) We adapted the search strategy to search Embase, CINAHL, and when needed. We identified and excluded duplicates and collated LILACS. multiple reports of the same study so that each study, rather than each report, was the unit of interest in the review. We recorded We searched the following trial registries on 26 April 2022: the selection process in sufficient detail to complete a PRISMA flow 1. ISRCTN registry (www.isrctn.com); diagram (Figure 1) and Characteristics of included studies table (Moher 2009). We imposed no language restrictions. Vaccines for the common cold (Review) 8 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews Figure 1. PRISMA flowchart Vaccines for the common cold (Review) 9 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews Figure 1. (Continued) Data extraction and management We graded each potential source of bias as low, high, or unclear and provided quotes from the study report together with a justification We used a data collection form for study characteristics and for our judgement in the risk of bias table. Where necessary, we outcome data that had been piloted on at least one study in the considered blinding separately for different key outcomes. review. Two review authors (DSR, CVG) extracted the following study characteristics from the included studies. Measures of treatment effect 1. Methods: study design, total duration of the study, details of We calculated the risk ratio (RR) with 95% confidence intervals any 'run in' period, number of study centres and location, study (CIs) for incidence of the common cold. We added outcome data setting, withdrawals, and date of the study. for the included study into a data table in Review Manager 5 to 2. Participants: N, mean age, age range, gender, severity of the calculate treatment effects (Review Manager 2020). We used RR for condition, diagnostic criteria, baseline lung function, smoking dichotomous outcomes. history, inclusion criteria, and exclusion criteria. Unit of analysis issues 3. Interventions: intervention, comparison, concomitant medications, and excluded medications. The unit of analysis was the participant. We collected and analysed 4. Outcomes: primary and secondary outcomes specified and a single measurement for each outcome from each participant. collected, and time points reported. Dealing with missing data 5. Notes: funding for the trial, and notable conflicts of interest of trial authors. We had planned to contact investigators or study sponsors to verify key study characteristics and to obtain missing numerical outcome Two review authors (DSR, CVG) independently extracted outcome data where possible (e.g. when a study was identified only as an data from the included studies. We described in the Characteristics abstract); however, this was not needed. of included studies table if outcome data were not reported in a usable way. Any disagreements were resolved by consensus or Assessment of heterogeneity by involving a third review author (RH). One review author (DSR) We had planned to use the I2 statistic to measure heterogeneity transferred data into the Review Manager 5 file (Review Manager amongst trials in each analysis; however, we did not conduct a 2020). We double-checked that the data had been entered correctly meta-analysis because only one trial satisfied the inclusion criteria. by comparing the data presented in the systematic review with the study report. A second review author (MJMZ) spot-checked study Assessment of reporting biases characteristics for accuracy against the trial report. We did not assess publication bias using a funnel plot because we Assessment of risk of bias in included studies included only one trial. In future updates, we will attempt to assess whether the review is subject to publication bias by using a funnel Three review authors (DSR, CVG, RH) independently assessed risk plot if 10 or more trials are included. of bias of the included studies using Cochrane's risk of bias tool RoB 1, according to the criteria in the Cochrane Handbook for Systematic Data synthesis Reviews of Interventions (Higgins 2022). Any disagreements were resolved by discussion or by involving another review author We carried out statistical analysis using Review Manager 5 software (MJMZ). We assessed the risk of bias based on the following (Review Manager 2020). In future updates, we will summarise domains. findings using a fixed-effect model following the guidance in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 1. Random sequence generation. 2022). 2. Allocation concealment. Subgroup analysis and investigation of heterogeneity 3. Blinding of participants and personnel. 4. Blinding of outcome assessment. We did not perform a subgroup analysis. In subsequent updates of this review, when sufficient data are available, we will carry out the 5. Incomplete outcome data. following subgroup analyses: 6. Selective outcome reporting. 7. Other bias. 1. children and adults; Vaccines for the common cold (Review) 10 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews 2. country of study; and mortality (all cause and vaccine related) (Summary of findings 3. different responses in relation to different viral agents. 1). We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication We will explore sources of heterogeneity in the assessment of the bias) to assess the certainty of the evidence as it relates to the study primary outcomes by subgroup analyses. Additionally, due to the that contributed data (Atkins 2004). We used the methods and limited number of included studies, we do not plan on performing recommendations described in Section 8.5 and Chapter 12 of the a meta-regression in the future. Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2022), employing GRADEpro GDT software (GRADEpro GDT). We Sensitivity analysis justified all decisions to down- or upgrade the certainty of the We did not perform a sensitivity analysis. In future updates, we plan evidence using footnotes, and made comments to aid the reader's to conduct sensitivity analyses comparing the results using all trials understanding of the review where necessary. as follows. RESULTS 1. Trials with high methodological quality (studies classified as having a 'low risk of bias' versus those identified as having a Description of studies 'high risk of bias') (Higgins 2022). See Characteristics of included studies, Characteristics of excluded 2. Trials that performed intention-to-treat versus per-protocol studies, and Characteristics of ongoing studies tables. analyses. 3. Parallel randomised clinical trials versus cluster-randomised Results of the search clinical trials. In the current update we identified a total of 4974 search results (Figure 1). We used Cochrane’s Screen4Me workflow to help identify We will also evaluate the risk of attrition bias, as estimated by the potential reports of randomised trials. The results of the Screen4Me percentage of participants lost. We will exclude trials with a total assessment process are shown in Figure 2. We assessed 6132 attrition of more than 30% or where differences between the groups records and excluded 3657 records based on title and abstract exceeded 10%, or both, from meta-analysis, but will include these screening. We assessed the full texts of 165 studies, and did not studies in the review. include any new studies in this update. We included only one trial Summary of findings and assessment of the certainty of the in the review (Griffin 1970). evidence We created a summary of findings table using the following outcomes: incidence of the common cold, vaccine safety, and Vaccines for the common cold (Review) 11 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews Figure 2. Screen4Me summary diagram. Included studies Excluded studies We included one RCT involving 2307 healthy young men (Griffin We excluded 43 studies in the previous publication of this review 1970). Griffin 1970 compared the effect of three adenovirus vaccines (Belshe 1982; Belshe 1992; Belshe 2004a; Belshe 2004b; Clements (live, inactivated type 4, and inactivated type 4 and 7) to placebo (an 1991; DeVincenzo 2010; Doggett 1963; Dudding 1972; Falsey 1996; injection of physiological saline for the parenterally administered Falsey 2008; Fulginiti 1969; Glenn 2016; Gomez 2009; Gonzalez 2000; vaccines, and an identical-appearing inert gelatin capsule for Greenberg 2005; Hamory 1975; Karron 1995a; Karron 1995b; Karron the orally administered vaccines). See Characteristics of included 1997; Karron 2003; Karron 2005; Karron 2015; Kumpu 2015; Langley studies. 2009; Lee 2001; Lee 2004; Lyons 2008; Madhi 2006; Munoz 2003; Murphy 1994; Paradiso 1994; Piedra 1995; Pierce 1968; Power 2001; Ritchie 1958; Simoes 2001; Tang 2008; Top 1971; Tristram 1993; Watt 1990; Welliver 1994; Wilson 1960; Wright 1976). Vaccines for the common cold (Review) 12 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews We excluded 109 new studies in this update (Abarca 2020; Ahmad NCT02593071; NCT02601612; NCT02624947; NCT02794870; 2022; Aliprantis 2018; Aliprantis 2020; Ascough 2019; August NCT02830932; NCT02864628; NCT02873286; NCT02890381; 2017; Beran 2018; Bourne 1946; Cicconi 2020; Cunningham 2019; NCT02926430; NCT02952339; NCT03026348; NCT03049488; DeVincenzo 2019; Domachowske 2017; Domachowske 2018; NCT03191383; NCT03303625; NCT03334695; NCT03392389; Esposito 2019; EUCTR2008-001714-24-GB; EUCTR2012-001107-20- NCT03403348; NCT03473002; NCT03572062; NCT03674177; GB; EUCTR2013-004036-30-GB; EUCTR2014-005041-41- NCT03814590; NCT04071158; NCT04086472; NCT04752644; GB; EUCTR2015-004296-77-GB; EUCTR2016-000117-76- NTR7173; Philpott 2016; Philpott 2017; Ruckwardt 2021; Sadoff ES; EUCTR2016-000117-76-PL; EUCTR2016-001135-12-FR; 2021a; Sadoff 2021b; Samy 2020; Scaggs Huang 2021; Schwarz EUCTR2016-002733-30-ES; EUCTR2018-001340-62-FI; Falloon 2019; Shakib 2019; Shaw 2019; Swamy 2019; Van Der Plas 2017a; Falloon 2017b; Fries 2019; Israel 2016; Karppinen 2019; 2020; Verdijk 2020; Williams 2020; Yu 2020). We identified 13 Karron 2020a; Karron 2020b; Langley 2016; Langley 2017; ongoing studies (NCT01893554; NCT03387137; NCT03422237; Langley 2018; Leroux-Roels 2019; Madhi 2020; McFarland 2018; NCT03596801; NCT03916185; NCT04032093; NCT04126213; McFarland 2020a; McFarland 2020b; Munoz 2019; NCT00139347; NCT04138056; NCT04681833; NCT04732871; NCT04980391; NCT00308412; NCT00345670; NCT00345956; NCT00363545; NCT05127434; NCT05238025). We contacted the authors of the NCT00366782; NCT00383903; NCT00420316; NCT00496821; ongoing trials; however, no preliminary results have been shared NCT00641017; NCT00686075; NCT00767416; NCT01021397; with us. NCT01139437; NCT01254175; NCT01290419; NCT01475305; NCT01709019; NCT01852266; NCT01905215; NCT02115815; Risk of bias in included studies NCT02266628; NCT02296463; NCT02419391; NCT02440035; Griffin 1970 had overall low methodological quality. See Figure 3 NCT02472548; NCT02479750; NCT02491463; NCT02561871; and Figure 4. Figure 3. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages. Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias): All outcomes Blinding of outcome assessment (detection bias): All outcomes Incomplete outcome data (attrition bias): All outcomes Selective reporting (reporting bias) Other bias 0% 25% 50% 75% 100% Low risk of bias Unclear risk of bias High risk of bias Vaccines for the common cold (Review) 13 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews Figure 4. Risk of bias summary: review authors' judgements about each risk of bias item for the included study. Blinding of participants and personnel (performance bias): All outcomes Blinding of outcome assessment (detection bias): All outcomes Incomplete outcome data (attrition bias): All outcomes Random sequence generation (selection bias) Allocation concealment (selection bias) Selective reporting (reporting bias) Other bias Griffin 1970 ? ? + + + ? ? Allocation Incomplete outcome data We assessed Griffin 1970 as at unclear risk of bias for random We assessed Griffin 1970 as at low risk of attrition bias as there were sequence generation and allocation concealment as inadequate no losses. information prevented a judgement for this domain. Selective reporting Blinding We assessed Griffin 1970 as at unclear risk of reporting bias. The We assessed Griffin 1970 as at low risk of bias for blinding of study protocol was not available, but it was clear that the published participants and personnel and blinding of outcome assessment. reports include all expected outcomes. However, some of the Vaccines for the common cold (Review) 14 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews outcomes were described in a narrative fashion and did not specify Overall completeness and applicability of evidence incidence for each group. The included trial did not detect statistically significant differences Other potential sources of bias between treatment groups (Griffin 1970). We assessed Griffin 1970 as at unclear risk of other bias. The When considering such neutral results, it is important to baseline characteristics of participants were not described, and keep in mind that 'absence of evidence' is not 'evidence of there was no detailed information relating to assessment of absence' (Alderson 2004; Altman 1995; Westerterp 2020). The fact selection bias, preventing an evaluation of whether both groups that this review did not detect any differences between intervention were comparable. groups does not imply that placebo and adenovirus vaccine have the same effect on preventing the common cold. Effects of interventions The first possible explanation for not detecting any differences See: Summary of findings 1 Virus vaccines compared to placebo between intervention groups could be the lack of an appropriate for preventing the common cold in healthy people sample size (Green 2002; Schulz 1995), which resulted in small Our results are based on one RCT with 2307 healthy people, which differences in the incidence of the common cold and few events we assessed as providing very low-certainty evidence (Griffin 1970). in the comparison groups. A remarkable paper from Freiman See Summary of findings 1. 1978 suggested that "many of the therapies labelled as 'no different from control' in trials using inadequate samples, have Primary outcomes not received a fair test" and that "concern for the probability of missing an important therapeutic improvement because of small 1. Incidence of the common cold sample sizes deserves more attention in the planning of clinical We do not know if there is a difference between the adenovirus trials". Moreover, most trials with negative results usually have vaccine and placebo in reducing the incidence of the common cold insufficiently large sample sizes to detect at least 50% relative (risk ratio 0.95, 95% confidence interval 0.45 to 2.02; 1 RCT, 2307 difference (Moher 1998; Sully 2014). It has also been suggested that participants, 27 events; Analysis 1.1) (Griffin 1970). We downgraded the most important therapies adopted in clinical practice have only the certainty of the evidence to very low due to unclear risk of bias; shown modest benefits (Kirby 2002). indirectness because the population of this study was only young and healthy men; and imprecision because confidence intervals Certainty of the evidence were wide, and the number of events was low. The results for the primary outcomes of incidence of the common cold and vaccine safety were based on very low-certainty evidence 2. Vaccine safety due to imprecision because confidence intervals were wide and Griffin 1970 reported that there were no differences in adverse the number of events was low; indirectness (the RCT considered in events between live vaccine preparation and placebo. We our review included only young, healthy men); and methodological downgraded the certainty of the evidence to very low due to limitations. Random sequence generation, allocation, sample size, unclear risk of bias; indirectness because the population of this and baseline characteristics of participants were not reported. study was only young men; and imprecision because confidence Adverse events were not reported individually for each group. intervals were wide, and the number of events was low. Overall, due to a lack of evidence, the balance between the benefits and harms of cold vaccines is uncertain. 3. Mortality Potential biases in the review process Griffin 1970 did not assess either vaccine-related or all-cause mortality. Whilst performing a systematic review, several biases can emerge, such as 'significance-chasing' biases (Ioannidis 2010). This group of DISCUSSION biases include publication bias, selective outcome reporting bias, selective analysis reporting bias, and fabrication bias (Ioannidis Summary of main results 2010). Publication bias represents a major threat to the validity One RCT met our inclusion criteria (Griffin 1970). The incidence of systematic reviews, particularly those reviews that include of the common cold in Griffin 1970 was very low, probably small trials. However, in this systematic review we performed an due to the fact that only cases resulting in admission to the exhaustive search and attempted to locate all studies to include medical dispensary or hospital were included. Furthermore, the new RCTs. The current evidence does not evaluate common cold trial authors stated that more common cold cases were diagnosed outcomes. incidentally when people were hospitalised for other causes, therefore mild cases of illness were not included. Agreements and disagreements with other studies or reviews Critical appraisal of Griffin 1970 did not support the use of any Most studies on vaccines for the common cold evaluate vaccine for preventing the common cold in healthy people. We did respiratory syncytial virus (RSV) vaccines, followed by studies on not find significant differences in the incidence of the common adenovirus vaccines; only a few published studies evaluate human cold in people treated with adenovirus vaccines compared with rhinovirus (HRV) and parainfluenza vaccines. In addition, these placebo. Griffin 1970 did not evaluate main clinical outcomes such studies mainly aim to reduce lower respiratory tract infections as mortality related to the vaccine. No differences in adverse events or focus on immunological outcomes. For instance, Buchholz were reported. The relative effect of any of the vaccines for viruses 2018 and McFarland 2020b are two RCTs of live-attenuated RSV that cause the common cold remains unclear. Vaccines for the common cold (Review) 15 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews vaccines that focus on upper respiratory tract infections; however, reported according to CONSORT guidelines (Moher 2012; PCORI these studies assessed immunological outcomes such as vaccine 2012), and should adhere to the Foundation of Patient-Centered shedding, serum RSV antibodies, anti-RSV F immunoglobulin G, Outcomes Research recommendations (Gabriel 2012). surveillance period, adverse events, and reactogenicity. There is no general consensus on the outcomes to be considered in evaluating ACKNOWLEDGEMENTS the efficacy of a vaccine. In this review we assessed the following outcomes: incidence of common cold after vaccination, vaccine The authors wish to thank Tom Jefferson and David Tyrell, who co- safety, and mortality (all cause and vaccine related), which were authored the first published version of this review; Anne Lyddiatt, not considered in most RCTs assessed for inclusion by full text. We Gulam Khandaker, Lisa Jackson, Mark Griffin, and Meenu Singh for focused on these outcomes due to the impact that the common commenting on the draft protocol; and Theresa Wrangham, John cold has at the population level, with a high estimated economic Jordan, Viviana Rodriguez, and Meenu Singh for commenting on loss due to missed working days (Kardos 2017; Tsuzuki 2020). Other the first draft review. The authors wish to express their thanks systematic reviews on vaccines for preventing upper respiratory to Liz Dooley, Managing Editor of the Cochrane Acute Respiratory tract infection have assessed outcomes similar to those included in Infections Group, for her comments, which improved the quality of this review (Hao 2015; Thomas 2013). this review. We excluded 11 non-RCTs that evaluated vaccines for upper For this 2022 update, we would like to acknowledge and thank respiratory tract infections (Belshe 1982; Clements 1991; Doggett the following people for their help in assessing the search 1963; Dudding 1972; Fulginiti 1969; Hamory 1975; Karron 1997; results for this review via Cochrane’s Screen4Me workflow: Ritchie 1958; Watt 1990; Wilson 1960; Wright 1976). Only one Nikolaos Sideris, Anna Noel-Storr, Shammas Mohammed, Sarah study evaluated the incidence of the common cold (Ritchie 1958), Moore, Yuan Chi, Mohammad Aloulou, Ana-Marija Ljubenković, whilst the others focused on immunologic outcomes. The study Vighnesh Devulapalli, Jens Bredbjerg Brock Thorsen, and Mykhailo conducted by Ritchie 1958 prepared an "autologous vaccine" Havrylets. developed from the nasal secretions of 125 healthy volunteers, The following people conducted the editorial process for this 2022 who were then inoculated with this product, whilst 75 healthy update. volunteers served as a control. The results showed a lower incidence of common cold in the vaccine group than in the control 1. Sign-off Editors (final editorial decision): Mark Jones (Bond group. This study was not an RCT and was thus excluded from our University, Australia); Mieke van Driel (The University of review. Queensland, Australia). 2. Managing Editors (provided editorial guidance to authors, AUTHORS' CONCLUSIONS edited the review, selected peer reviewers, and collated peer- Implications for practice reviewer comments): Liz Dooley (Bond University, Australia); Fiona Russell (Bond University, Australia). This Cochrane Review update found very limited evidence on the 3. Contact Editor (provided comments and recommended an effects of vaccines for the common cold in healthy people. We editorial decision): Meenu Singh (Post Graduate Institute of included only one randomised controlled trial, which did not report Medical Education and Research, Chandigarh, India). differences between comparison groups. Our findings were based 4. Statistical Editor (provided comments): Menelaos on only one trial with very low-certainty evidence with an unclear Konstantinidis (University of Toronto, Canada) risk of bias, indirectness, and imprecision. Griffin 1970 involved 2307 participants and assessed adenovirus vaccines compared 5. Copy Editor (copy-editing and production): Lisa Winer, Cochrane with placebo, and showed that there may be no difference between Copy Edit Support the adenovirus vaccine and placebo in reducing the incidence of the Peer reviewers (provided comments and recommended an common cold. editorial decision): Implications for research 1. Clinical/content review: Roger E Thomas (University of Calgary, This 2022 update highlights the need for well-designed, high- Canada). quality randomised clinical trials to assess the effectiveness and 2. Consumer review: Theresa Wrangham (USA). safety of vaccines to prevent the common cold in healthy people. 3. Methods review: Rachel Richardson (Associate Editor, Cochrane, Future trials should include outcomes such as common cold UK). incidence, vaccine safety, mortality, and adverse events related to 4. Search review: Justin Clark (Institute for Evidence-Based vaccine administration. Inert placebo use would also be beneficial Healthcare, Bond University, Australia). to avoid dampening adverse events following immunisation. 5. One peer reviewer preferred to remain anonymous. Future trials should be conducted by independent researchers and Vaccines for the common cold (Review) 16 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews REFERENCES References to studies included in this review Belshe 1982 {published data only} Griffin 1970 {published data only} Belshe RB, Van Voris LP, Mufson MA. Parenteral administration of live respiratory syncytial virus vaccine: results of a field Griffin JP, Greenberg BH. Live and inactivated adenovirus trial. Journal of Infectious Diseases 1982;145(3):311-9. [PMID: vaccines. Clinical evaluation of efficacy in prevention of 7037983] acute respiratory disease. Archives of Internal Medicine 1970;125(6):981-6. [PMID: 4378136] Belshe 1992 {published data only} Belshe RB, Karron RA, Newman FK, Anderson EL, Nugent SL, References to studies excluded from this review Steinhoff M, et al. Evaluation of a live attenuated, cold-adapted parainfluenza virus type 3 vaccine in children. Journal of Clinical Abarca 2020 {published data only} Microbiology 1992;30(8):2064-70. [PMID: 1323576] Abarca K, Rey-Jurado E, Muñoz-Durango N, Vázquez Y, Soto JA, Gálvez N, et al. Safety and immunogenicity evaluation of Belshe 2004a {published data only} recombinant BCG vaccine against respiratory syncytial virus Belshe RB, Newman FK, Anderson EL, Wright PF, Karron RA, in a randomized, double-blind, placebo-controlled phase I Tollefson S, et al. Evaluation of combined live, attenuated clinical trial. EClinicalMedicine 2020;27:100517. [DOI: 10.1016/ respiratory syncytial virus and parainfluenza 3 virus vaccines j.eclinm.2020.100517] [PMID: 33073219] in infants and young children. Journal of Infectious Diseases 2004;190(12):2096-103. [PMID: 15551207] Ahmad 2022 {published data only} Ahmad A, Eze K, Noulin N, Horvathova V, Murray B, Baillet M, Belshe 2004b {published data only} et al. EDP-938, a respiratory syncytial virus inhibitor, in a Belshe RB, Newman FK, Tsai TF, Karron RA, Reisinger K, human virus challenge. New England Journal of Medicine Roberton D, et al. Phase 2 evaluation of parainfluenza type 2022;386(7):655-66. [DOI: 10.1056/NEJMoa2108903] [PMID: 3 cold passage mutant 45 live attenuated vaccine in healthy 35172056] children 6-18 months old. Journal of Infectious Diseases 2004;189(3):462-70. [PMID: 14745704] Aliprantis 2018 {published data only} Aliprantis A, Wolford D, Caro L, Maas B, Ma H, Vora K, et al. A Beran 2018 {published data only} randomized, double-blind, placebo-controlled trial to assess Beran J, Lickliter JD, Schwarz TF, Johnson C, Chu L, the safety and tolerability of a respiratory syncytial virus Domachowske JB, et al. Safety and immunogenicity of 3 (RSV) neutralizing monoclonal antibody (MK-1654) in healthy formulations of an investigational respiratory syncytial virus subjects. Open Forum Infectious Diseases 2018;5(Suppl 1):572. vaccine in nonpregnant women: results from 2 phase 2 trials. [DOI: 10.1093/ofid/ofy210.1627] Journal of Infectious Diseases 2018;217(10):1616-25. [DOI: 10.1093/infdis/jiy065] Aliprantis 2020 {published data only} Aliprantis AO, Shaw CA, Griffin P, Farinola N, Railkar RA, Cao X, Bourne 1946 {published data only} et al. A phase 1, randomized, placebo-controlled study to Bourne LB. Trial of an oral vaccine against bacterial infection evaluate the safety and immunogenicity of an mRNA-based RSV accompanying the common cold. Nature 1946;157:591. 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A randomized, double-blind, placebo- of MDT-637 in healthy subjects challenged with RSV-A controlled study of an RNAi-based therapy directed against (Memphis 37b) - phase 2a trial of MDT-637 in healthy subjects respiratory syncytial virus. Proceedings of the National Academy challenged with RSV. trialsearch.who.int/Trial2.aspx? of Sciences of the United States of America 2010;107(19):8800-5. TrialID=EUCTR2012%E2%80%90001107%E2%80%9020%E2%80%90GB [PMID: 20421463] (first received 2 August 2013). DeVincenzo 2019 {published data only} EUCTR2013-004036-30-GB {published data only} DeVincenzo J, Gymnopoulou E, De Paepe E, Murray B, EUCTR2013-004036-30-GB. A randomised, phase 2a, Bastian AR, Haazen W. A randomized, double-blind, double-blind, placebo-controlled study to evaluate placebo-controlled study to evaluate the efficacy of a single the safety, pharmacokinetics and antiviral activity of immunization of AD26.RSV.Pref against RSV infection in a viral multiple doses of orally administered ALS-008176 against challenge model in healthy adults. Open Forum Infectious respiratory syncytial virus infection in the virus challenge Diseases 2019;6(Suppl):27-8. [DOI: 10.1093/ofid/ofz359.061] model - phase 2a, double blind, placebo-controlled, viral challenge study. trialsearch.who.int/Trial2.aspx? Doggett 1963 {published data only} TrialID=EUCTR2013%E2%80%90004036%E2%80%9030%E2%80%90GB Doggett JE, Bynoe ML, Tyrrell DA. Some attempts to produce an (first received 29 November 2013). experimental vaccine with rhinoviruses. British Medical Journal 1963;1(5322):34-6. [PMID: 14028369] EUCTR2014-005041-41-GB {published data only} EUCTR2014-005041-41-GB. A phase 2a, randomized, double- Domachowske 2017 {published data only} blinded, placebo-controlled study to evaluate the antiviral Domachowske JB, Khan A, Esser MT, Jensen KM, Takas T, activity, safety, and pharmacokinetics of repeated doses Villafana T, et al. A single dose monoclonal antibody (mAb) of orally administered JNJ-53718678 against respiratory immunoprophylaxis strategy to prevent RSV disease in all syncytial virus infection in the virus challenge model in infants: results of the first in infant study with MEDI8897. Open healthy adult subjects. trialsearch.who.int/Trial2.aspx? Forum Infectious Diseases 2017;4(Suppl 1):S37. [DOI: 10.1093/ TrialID=EUCTR2014%E2%80%90005041%E2%80%9041%E2%80%90GB ofid/ofx162.089] [PMID: PMC5631822] (first received 24 April 2015). Domachowske 2018 {published data only} EUCTR2015-004296-77-GB {published data only} Domachowske JB, Khan AA, Jensen K, Takas T, Villafana T, EUCTR2015-004296-77-GB. A randomised, phase 2a, double- Dubovsky F, et al. A single dose monoclonal antibody blind, placebo-controlled study to evaluate the safety and immunoprophylaxis strategy to prevent respiratory syncytial antiviral activity against respiratory syncytial virus infection, virus disease in all infants: results of the first in infant study and the pharmacokinetics of multiple oral doses of BTA-C585 with MEDI8897. Pediatrics 2018;141(1):256. [DOI: 10.1542/ in the virus challenge model. trialsearch.who.int/Trial2.aspx? peds.141.1_MeetingAbstract.256] TrialID=EUCTR2015%E2%80%90004296%E2%80%9077%E2%80%90GB (first received 8 February 2016). Dudding 1972 {published data only} Dudding BA, Bartelloni PJ, Scott RM, Top FH Jr, Russell PK, EUCTR2016-000117-76-ES {published data only} Buescher EL. Enteric immunization with live adenovirus type EUCTR2016-000117-76-ES. A study to evaluate 21 vaccine I. Tests for safety, infectivity, immunogenicity, and safety, reactogenicity and immunogenicity of GSK potency in volunteers. Infection and Immunity 1972;5(3):295-9. biologicals’ RSV investigational vaccine based on [PMID: 4564559] viral proteins encoded by chimpanzee-derived adenovector (ChAd155-RSV) (GSK3389245A) in RSV- Esposito 2019 {published data only} seropositive infants. trialsearch.who.int/Trial2.aspx? Esposito S, Bianchini S, Bosis S, Tagliabue C, Coro I, TrialID=EUCTR2016%E2%80%90000117%E2%80%9076%E2%80%90ES Argentiero A, et al. A randomized, placebo-controlled, double- (first received 5 August 2016). blinded, single-centre, phase IV trial to assess the efficacy and safety of OM-85 in children suffering from recurrent EUCTR2016-000117-76-PL {published data only} respiratory tract infections. Journal of Translational Medicine EUCTR2016-000117-76-PL. A study to evaluate 2019;17(1):284. [DOI: 10.1186/s12967-019-2040-y] safety and immunogenicity of GSK biologicals’ RSV investigational vaccine in RSV-seropositive infants EUCTR2008-001714-24-GB {published data only} aged 12 to 23 months. trialsearch.who.int/Trial2.aspx? EUCTR2008-001714-24-GB. A phase II, double-blind TrialID=EUCTR2016%E2%80%90000117%E2%80%9076%E2%80%90PL placebo-controlled study to determine the prophylactic (first received 6 June 2018). efficacy of oral BTA798 in an experimental rhinovirus Vaccines for the common cold (Review) 18 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews EUCTR2016-001135-12-FR {published data only} Fulginiti 1969 {published data only} EUCTR2016-001135-12-FR. A study to rank different dosages of Fulginiti VA, Eller JJ, Sieber OF, Joyner JW, Minamitani M, antigen of GlaxoSmithKline (GSK) biologicals’ investigational Meiklejohn G. Respiratory virus immunization I. A field trial respiratory syncytial virus (RSV) vaccine (GSK3003891A), based of two inactivated respiratory virus vaccines; an aqueous on their immune response and safety, when administered trivalent parainfluenza virus vaccine and an alum-precipitated to healthy adult women. trialsearch.who.int/Trial2.aspx? respiratory syncytial virus vaccine. American Journal of TrialID=EUCTR2016%E2%80%90001135%E2%80%9012%E2%80%90FREpidemiology 1969;89(4):435-48. [PMID: 4305199] (first received 14 December 2016). Glenn 2016 {published data only} EUCTR2016-002733-30-ES {published data only} Glenn GM, Fries LF, Thomas DN, Smith G, Kpamegan E, Lu H, et EUCTR2016-002733-30-ES. A study to evaluate the safety, al. A randomized, blinded, controlled, dose-ranging study of a reactogenicity and immunogenicity of the GSK investigational respiratory syncytial virus recombinant fusion (F) nanoparticle vaccine GSK3003891A in healthy pregnant women and infants vaccine in healthy women of childbearing age. Journal of born to vaccinated mothers. trialsearch.who.int/Trial2.aspx? Infectious Diseases 2016;213(3):411-22. [DOI: 10.1093/infdis/ TrialID=EUCTR2016%E2%80%90002733%E2%80%9030%E2%80%90ESjiv406] [PMID: 26259809] (first received 8 February 2017). Gomez 2009 {published data only} EUCTR2018-001340-62-FI {published data only} Gomez M, Mufson MA, Dubovsky F, Knightly C, Zeng W, EUCTR2018-001340-62-FI. A study to evaluate different Losonsky G. Phase-I study MEDI-534, of a live, attenuated dose levels of GlaxoSmithKline (GSK) biologicals' intranasal vaccine against respiratory syncytial virus and investigational respiratory syncytial virus (RSV) vaccine parainfluenza-3 virus in seropositive children. Pediatric (GSK3888550A), based on the safety of the vaccine and Infectious Disease Journal 2009;28(7):655-8. [PMID: 19483659] the antibodies (body defences) that the body produces following the vaccine administration, when given to healthy Gonzalez 2000 {published data only} non-pregnant women. trialsearch.who.int/Trial2.aspx? Gonzalez IM, Karron RA, Eichelberger M, Walsh EE, TrialID=EUCTR2018%E2%80%90001340%E2%80%9062%E2%80%90FIDelagarza VW, Bennett R, et al. Evaluation of the live attenuated (first received 17 October 2018). cpts 248/404 RSV vaccine in combination with a subunit RSV vaccine (PFP-2) in healthy young and older adults. Vaccine Falloon 2017a {published data only} 2000;18(17):1763-72. [PMID: 10699324] Falloon J, Talbot HK, Curtis C, Ervin J, Krieger D, Dubovsky F, et al. Dose selection for an adjuvanted respiratory syncytial Greenberg 2005 {published data only} virus F protein vaccine for older adults based on humoral and Greenberg DP, Walker RE, Lee MS, Reisinger KS, Ward JI, cellular immune responses. Clinical and Vaccine Immunology Yogev R, et al. A bovine parainfluenza virus type 3 vaccine is safe 2017;24(9):e00157-17. [DOI: 10.1128/CVI.00157-17] and immunogenic in early infancy. Journal of Infectious Diseases 2005;191(7):1116-22. [PMID: 15747247] Falloon 2017b {published data only} Falloon J, Yu J, Esser MT, Villafana T, Yu L, Dubovsky F, et al. An Hamory 1975 {published data only} adjuvanted, postfusion F protein-based vaccine did not prevent Hamory BH, Hamparian VV, Conant RM, Gwaltney JM. Human respiratory syncytial virus illness in older adults. Journal of responses to two decavalent rhinovirus vaccines. Journal of Infectious Diseases 2017;216(11):1362-70. [DOI: 10.1093/infdis/ Infectious Diseases 1975;132(6):623-9. [PMID: 172561] jix503] Israel 2016 {published data only} Falsey 1996 {published data only} Israel S, Rusch S, DeVincenzo J, Boyers A, Fok-Seang J, Falsey AR, Walsh EE. Safety and immunogenicity of a respiratory Huntjens D, et al. Effect of oral JNJ-53718678 (JNJ-678) on syncytial virus subunit vaccine (PFP-2) in ambulatory adults disease severity in healthy adult volunteers experimentally over age 60. Vaccine 1996;14(13):1214-8. [PMID: 8961507] inoculated with live respiratory syncytial virus (RSV): a placebo- controlled challenge study. Open Forum Infectious Diseases Falsey 2008 {published data only} 2016;3(Suppl 1):650. [DOI: 10.1093/ofid/ofw172.513] Falsey AR, Walsh EE, Capellan J, Gravenstein S, Zambon M, Yau E, et al. Comparison of the safety and immunogenicity of Karppinen 2019 {published data only} 2 respiratory syncytial virus (RSV) vaccines - nonadjuvanted Karppinen S, Toivonen L, Schuez-Havupalo L, Teros-Jaakkola T, vaccine or vaccine adjuvanted with alum-given concomitantly Waris M, Auranen K, et al. Effectiveness of the ten-valent with influenza vaccine to high-risk elderly individuals. Journal of pneumococcal Haemophilus influenzae protein D conjugate Infectious Diseases 2008;198(9):1317-26. [PMID: 18855558] vaccine (PHiD-CV10) against all respiratory tract infections in children under two years of age. Vaccine 2019;37(22):2935-41. Fries 2019 {published data only} [DOI: 10.1016/j.vaccine.2019.04.026] Fries LF, Cho I, Thomas DN, Wen JL, Spindler MS, Fix AB, et al. Third trimester immunization with an respiratory syncytial virus Karron 1995a {published data only} F protein vaccine for the prevention of RSV lower respiratory Karron RA, Wright PF, Hall SL, Makhene M, Thompson J, tract infection in infants. Open Forum Infectious Diseases Burns BA, et al. A live attenuated bovine parainfluenza 2019;6(Suppl):921-2. [DOI: 10.1093/ofid/ofz360.2315] virus type 3 vaccine is safe, infectious, immunogenic, and Vaccines for the common cold (Review) 19 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews phenotypically stable in infants and children. Journal of Langley 2009 {published data only} Infectious Diseases 1995;171(5):1107-14. [PMID: 7751684] Langley JM, Sales V, McGeer A, Guasparini R, Predy G, Meekison W, et al. A dose-ranging study of a subunit respiratory Karron 1995b {published data only} syncytial virus subtype A vaccine with and without aluminum Karron RA, Wright PF, Newman FK, Makhene M, Thompson J, phosphate adjuvantation in adults > or = 65 years of age. Samorodin R, et al. A live human parainfluenza type 3 virus Vaccine 2009;27(42):5913-9. [PMID: 19651171] vaccine is attenuated and immunogenic in healthy infants and children. Journal of Infectious Diseases 1995;172(6):1445-50. Langley 2016 {published data only} [PMID: 7594701] Langley J, Macdonald L, Weir G, Mackinnon-Cameron D, Ye L, McNeil S, et al. A phase I randomized, observer-blind, Karron 1997 {published data only} controlled, dose escalation trial of the safety and tolerability of Karron RA, Wright PF, Crowe JE, Clements-Mann ML, two intramuscular doses of DPXRSV (A), a respiratory syncytial Thompson J, Makhene M, et al. Evaluation of two live, cold- virus (RSV) vaccine containing RSV SH antigen and a novel passaged, temperature-sensitive respiratory syncytial virus adjuvant depovax, or SH antigen and a novel adjuvant DepoVax, vaccines in chimpanzees and in human adults, infants, and or SH antigen co-administered with aluminum hydroxide, or children. Journal of Infectious Diseases 1997;176(6):1428-36. placebo to healthy adults ≥ 50–64 years of age. Open Forum [PMID: 9395351] Infectious Diseases 2016;3:ofw172.97. [DOI: 10.1093/ofid/ ofw172.973] Karron 2003 {published data only} Karron RA, Belshe RB, Wright PF, Thumar B, Burns B, Newman F, Langley 2017 {published data only} et al. A live human parainfluenza type 3 virus vaccine is Langley JM, Aggarwal N, Toma A, Halperin SA, McNeil SA, attenuated and immunogenic in young infants. Pediatric Fissette L, et al. A randomized, controlled, observer-blinded Infectious Disease Journal 2003;22(5):394-405. [PMID: 12792378] phase 1 study of the safety and immunogenicity of a respiratory syncytial virus vaccine with or without alum adjuvant. Journal Karron 2005 {published data only} of Infectious Diseases 2017;215(1):24-33. [DOI: 10.1093/infdis/ Karron RA, Wright PF, Belshe RB, Thumar B, Casey R, Newman F, jiw453] et al. Identification of a recombinant live attenuated respiratory syncytial virus vaccine candidate that is highly attenuated in Langley 2018 {published data only} infants. Journal of Infectious Diseases 2005;191(7):1093-104. Langley J, Macdonald L, Weir G, Mackinnon-Cameron D, Ye L, [PMID: 15747245] Mcneil S, et al. A respiratory syncytial virus vaccine based on the small hydrophobic protein ectodomain presented with a Karron 2015 {published data only} novel lipid-based formulation is highly immunogenic and safe Karron RA, San Mateo J, Thumar B, Schaap-Nutt A, Buchholz UJ, in adults: a first-in-humans study. Journal of Infectious Diseases Schmidt AC, et al. Evaluation of a live-attenuated human 2018;218(3):378-87. [DOI: 10.1093/infdis/jiy177] parainfluenza type 1 vaccine in adults and children. Journal of Pediatric Infectious Diseases Society 2015;4(4):e143-6. [DOI: Lee 2001 {published data only} 10.1093/jpids/piu104] [PMID: 26582883] Lee MS, Greenberg DP, Yeh SH, Yogev R, Reisinger KS, Ward JI, et al. Antibody responses to bovine parainfluenza virus type 3 Karron 2020a {published data only} (PIV3) vaccination and human PIV3 infection in young infants. Karron RA, Atwell JE, McFarland EJ, Cunningham CK, Journal of Infectious Diseases 2001;184(7):909-13. [PMID: Muresan P, Perlowski C. Live-attenuated vaccines prevent 11509996] respiratory syncytial virus-associated illness in young children. American Journal of Respiratory and Critical Care Medicine Lee 2004 {published data only} 2021;203(5):594-603. [DOI: 10.1164/rccm.202005-1660OC] Lee FE, Walsh EE, Falsey AR, Betts RF, Treanor JJ. Experimental [PMID: 32871092] infection of humans with A2 respiratory syncytial virus. Antiviral Research 2004;63(3):191-6. [PMID: 15451187] Karron 2020b {published data only} Karron RA, Luongo C, Mateo JS, Wanionek K, Collins PL, Leroux-Roels 2019 {published data only} Buchholz UJ. Safety and immunogenicity of the respiratory Leroux-Roels G, De Boever F, Maes C, Nguyen TL-A, Baker S, syncytial virus vaccine RSV/DELTANS2/DELTA1313/I1314L Gonzalez Lopez A. Safety and immunogenicity of a respiratory in RSV-seronegative children. Journal of Infectious Diseases syncytial virus fusion glycoprotein F subunit vaccine in 2020;222(1):82-91. [DOI: 10.1093/infdis/jiz408] [PMID: 31605113] healthy adults: results of a phase 1, randomized, observer- blind, controlled, dosage-escalation study. Vaccine Kumpu 2015 {published data only} 2019;37(20):2694-703. [DOI: 10.1016/j.vaccine.2019.04.011] Kumpu M, Kekkonen RA, Korpela R, Tynkkynen S, Järvenpää S, Kautiainen H, et al. Effect of live and inactivated Lactobacillus Lyons 2008 {published data only} rhamnosus GG on experimentally induced rhinovirus Lyons A, Longfield J, Kuschner R, Straight T, Binn L, colds: randomised, double blind, placebo-controlled pilot Seriwatana J, et al. A double-blind, placebo-controlled study trial. Beneficial Microbes 2015;6(5):631-9. [DOI: 10.3920/ of the safety and immunogenicity of live, oral type 4 and type BM2014.0164] [PMID: 26322544] 7 adenovirus vaccines in adults. Vaccine 2008;26(23):2890-8. [PMID: 18448211] Vaccines for the common cold (Review) 20 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews Madhi 2006 {published data only} of GSK biologicals' oral live attenuated HRV vaccine given Madhi SA, Cutland C, Zhu Y, Hackell JG, Newman F, Blackburn N, concomitantly with routine EPI vaccinations including OPV et al. Transmissibility, infectivity and immunogenicity of a live in healthy infants. clinicaltrials.gov/show/NCT00139347 (first human parainfluenza type 3 virus vaccine (HPIV3cp45) among received 31 August 2005). susceptible infants and toddlers. Vaccine 2006;24(13):2432-9. NCT00308412 {published data only} [PMID: 16406170] NCT00308412. Safety of and immune response to a human Madhi 2020 {published data only} parainfluenza virus vaccine (rHPIV3cp45) in healthy infants Madhi SA, Polack FP, Piedra PA, Munoz FM, Trenholme AA, [Phase 1 study to determine the safety, infectivity, and Simões E, et al. Respiratory syncytial virus vaccination during tolerability of two doses of live attenuated recombinant pregnancy and effects in infants. New England Journal of cold passaged (cp) 45 parainfluenza type 3 virus vaccine, Medicine 2020;383(5):426-39. [DOI: 10.1056/NEJMoa1908380] rHPIV3cp45, lot PIV3 102A, delivered as nose drops to infants [PMID: 32726529] 6 to 12 months of age, and to HPIV3 seronegative infants and children 6 to 36 months of age]. clinicaltrials.gov/show/ McFarland 2018 {published data only} NCT00308412 (first received 29 March 2006). McFarland EJ, Karron RA, Muresan P, Cunningham CK, NCT00345670 {published data only} Valentine ME, Perlowski C, et al. Live-attenuated respiratory syncytial virus vaccine candidate with deletion of RNA synthesis NCT00345670. Study to evaluate the safety of MEDI-534 vaccine regulatory protein M2-2 is highly immunogenic in children. against respiratory syncytial virus (RSV) and parainfluenza Journal of Infectious Diseases 2018;217(9):1347-55. [DOI: virus type 3 (PIV3) in healthy children [A phase I, randomized, 10.1093/infdis/jiy040] [PMID: 29509911] double-blind, placebo-controlled, dose-escalation study to evaluate the safety, tolerability, immunogenicity, and viral McFarland 2020a {published data only} shedding of MEDI-534, a live, attenuated intranasal vaccine McFarland EJ, Karron RA, Muresan P, Cunningham CK, against respiratory syncytial virus (RSV) and parainfluenza virus Perlowski C, Libous J, et al. Live respiratory syncytial virus type 3 (PIV3), in healthy RSV and PIV3 seropositive 1-9 year-old attenuated by M2-2 deletion and stabilized temperature children]. clinicaltrials.gov/show/NCT00345670 (first received sensitivity mutation 1030s is a promising vaccine candidate 28 June 2006). in children. Journal of Infectious Diseases 2020;221(4):534-43. NCT00345956 {published data only} [DOI: 10.1093/infdis/jiz603] NCT00345956. To evaluate immunogenicity, reactogenicity McFarland 2020b {published data only} & safety of 2 doses of GSK Bio HRV liquid vaccine given to McFarland EJ, Karron RA, Muresan P, Cunningham CK, infants (Vietnam) [A placebo-controlled study to evaluate the Perlowski C, Libous J, et al. Live-attenuated respiratory immunogenicity, reactogenicity and safety of two doses of syncytial virus vaccine with M2-2 deletion and with small GSK biologicals' oral live attenuated human rotavirus (HRV) hydrophobic noncoding region is highly immunogenic in liquid vaccine, when given to healthy infants, in Vietnam]. children. Journal of Infectious Diseases 2020;221(12):2050-9. clinicaltrials.gov/show/NCT00345956 (first received 29 June [DOI: 10.1093/infdis/jiaa049] 2006). Munoz 2003 {published data only} NCT00363545 {published data only} Munoz FM, Piedra PA, Glezen WP. Safety and immunogenicity of NCT00363545. To assess immunogenicity, reactogenicity respiratory syncytial virus purified fusion protein-2 vaccine in & safety of 2 formulations of GSK's HRV vaccine as 2-dose pregnant women. Vaccine 2003;21(24):3465-7. [PMID: 12850361] vaccination (Infants) [A study to assess the immunogenicity, reactogenicity and safety of 2 different formulations of GSK Munoz 2019 {published data only} biologicals' live attenuated HRV vaccine, given as a two-dose Muňoz FM, Swamy GK, Hickman SP, Agrawal S, Piedra PA, primary vaccination, in healthy infants previously uninfected Glenn GM, et al. Safety and immunogenicity of a respiratory with HRV]. clinicaltrials.gov/ct2/show/NCT00363545 (first syncytial virus fusion (F) protein nanoparticle vaccine in healthy received 15 August 2006). third-trimester pregnant women and their infants. Journal of NCT00366782 {published data only} Infectious Diseases 2019;220(11):1802-15. [DOI: 10.1093/infdis/ jiz390] NCT00366782. Safety of and immune response to a cow/ human parainfluenza virus vaccine (rB/HPIV3) in healthy Murphy 1994 {published data only} infants, children, and adults [A phase 1 study of the safety and Murphy BR, Hall SL, Kulkarni AB, Crowe JE, Collins PL, immunogenicity of the recombinant live-attenuated chimeric Connors M, et al. An update on approaches to the development bovine/human parainfluenza type 3 virus vaccine, rB/HPIV3, lot of respiratory syncytial virus (RSV) and parainfluenza virus PIV3 #101A, delivered as nose drops to adults 18 to 49 years type 3 (PIV3) vaccines. Virus Research 1994;32(1):13-36. [PMID: of age, HPIV3-seropositive children 15 to 59 months of age, 8030364] and HPIV3-seronegative infants and children 6 to 36 months of age]. clinicaltrials.gov/ct2/show/NCT00366782 (first received 21 NCT00139347 {published data only} August 2006). NCT00139347. A multi-country & multi-center study to assess the efficacy, immunogenicity & safety of two doses Vaccines for the common cold (Review) 21 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews NCT00383903 {published data only} in healthy 1 to < 24 month-old children]. clinicaltrials.gov/ct2/ NCT00383903. Evaluate safety & immunogenicity of 2 or 3 show/NCT00767416 (first received 7 October 2008). doses of GSK HRV vaccine in healthy infants in South Africa NCT01021397 {published data only} [A phase II, randomized, double-blind, placebo-controlled study of safety, reactogenicity and immunogenicity of 2 or 3 NCT01021397. Safety of and immune response to recombinant doses of GSK biologicals' oral live attenuated human rotavirus live attenuated parainfluenza type 3 virus vaccine in healthy vaccine at 10E6.5 CCID50 viral concentration in healthy infants infants and children [Phase I study to determine the safety, (approximately 5-10 weeks old) in the Republic of South Africa]. infectivity, and tolerability of 2 doses of live attenuated clinicaltrials.gov/ct2/show/NCT00383903 (first received 4 recombinant cold-passaged (cp) 45 human parainfluenza October 2006). type 3 virus vaccine, rHPIV3cp45, lot PIV3#102A, delivered as nose drops to HPIV3-seronegative infants and children 6 to 36 NCT00420316 {unpublished data only} months of age, at a 6 month interval]. clinicaltrials.gov/ct2/ NCT00420316. Long-term efficacy and safety of subjects show/NCT01021397 (first received 30 November 2009). approximately 3 years after priming with 2 doses of GSK NCT01139437 {published data only} Bio's HRV vaccine [To assess long-term efficacy & safety of subjects approximately 3 years after priming with 2 doses of NCT01139437. Safety of a live attenuated human parainfluenza GlaxoSmithKline (GSK) biologicals' oral live attenuated human virus type 2 (HPIV2) vaccine for adults, children, and infants rotavirus (HRV) vaccine (Rotarix) in the primary vaccination [A phase I study of the safety and immunogenicity of the study (102247)]. clinicaltrials.gov/ct2/show/NCT00420316 (first recombinant live-attenuated human parainfluenza type 2 virus received 11 January 2007). vaccine, rHPIV2 15C/948L/Δ1724 lot PIV2#109C, delivered as nose drops to adults 18 to 49 years of age, HPIV2-seropositive NCT00496821 {published data only} children 15 to 59 months of age, and HPIV2-seronegative infants NCT00496821. Intranasal ALN-RSV01 administered to adult and children 6 to 59 months of age]. clinicaltrials.gov/ct2/show/ volunteers experimentally inoculated with respiratory syncytial NCT01139437 (first received 8 June 2010). virus [A study to investigate the safety and efficacy of intranasal NCT01254175 {published data only} ALN-RSV01 administered to adult volunteers experimentally inoculated with respiratory syncytial virus]. clinicaltrials.gov/ NCT01254175. Evaluating the safety and immunogenicity of ct2/show/NCT00496821 (first received 4 July 2007). a human parainfluenza type 3 (HPIV3) virus vaccine in infants and children [Phase 1 study to determine the safety, infectivity, NCT00641017 {published data only} immunogenicity and tolerability of 2 doses of live attenuated NCT00641017. Safety of and immune response to recombinant recombinant cold-passaged (cp) 45 human parainfluenza live-attenuated parainfluenza type 1 virus vaccine [A phase I type 3 virus vaccine, rHPIV3cp45, lot PIV3#102A, delivered as study of the safety and immunogenicity of the recombinant live- nose drops to HPIV3-seronegative infants and children 6 to 36 attenuated human parainfluenza type 1 virus vaccine, rHPIV1 months of age, at a 6 month interval]. clinicaltrials.gov/ct2/ 84/del170/942A, lot PIV1 #104A, delivered as nose drops to show/NCT01254175 (first received 6 December 2010). adults 18 to 49 years of age, HPIV1-seropositive children 15 to NCT01290419 {published data only} 59 months of age, and hpiv1-seronegative infants and children 6 to 59 months of age]. clinicaltrials.gov/ct2/show/NCT00641017 NCT01290419. Safety study of respiratory syncytial virus (RSV)- (first received 21 March 2008). fusion (F) protein particle vaccine [A phase 1 randomized, observer-blinded,placebo-controlled trial to evaluate the NCT00686075 {published data only} safety and immunogenicity of a recombinant respiratory NCT00686075. A study to evaluate the safety, tolerability, syncytial virus f protein particle vaccine in healthy adults]. immunogenicity and vaccine-like viral shedding of MEDI-534, clinicaltrials.gov/ct2/show/NCT01290419 (first received 7 against respiratory syncytial virus (RSV) and parainfluenza February 2011). virus type 3 (PIV3), in healthy 6 to < 24 month-old children and NCT01475305 {published data only} in 2 month-old infants [A phase 1/2a, randomized, double- blind, placebo-controlled, dose-escalation study to evaluate NCT01475305. Intranasal challenge of healthy adults with the safety, tolerability, immunogenicity and vaccine-like viral respiratory syncytial virus (RSV) [A phase 1 randomized, shedding of MEDI-534, a live, attenuated intranasal vaccine placebo-controlled, double-blind study to evaluate against respiratory syncytial virus (RSV) and parainfluenza virus the safety and efficacy of MEDI-557 in healthy adults type 3 (PIV3), in healthy 6 to < 24 month-old children and in 2 intranasally challenged with respiratory syncytial virus (RSV)]. month-old infants]. clinicaltrials.gov/ct2/show/NCT00686075 clinicaltrials.gov/ct2/show/NCT01475305 (first received 21 (first received 29 May 2008). November 2011). NCT00767416 {published data only} NCT01709019 {published data only} NCT00767416. A randomized, double-blind, placebo-controlled NCT01709019. RSV-F vaccine and influenza vaccine co- study to evaluate safety of MEDI-559 in healthy 1 to < 24 administration study in the elderly [A phase I randomized, month-old children [A phase 1/2a, randomized, double-blind, observer-blinded, dose-ranging study to evaluate the placebo-controlled study to evaluate the safety, tolerability, immunogenicity and safety of an RSV-F protein nanoparticle immunogenicity, and viral shedding of MEDI-559, a live vaccine, with or without aluminum adjuvant, and co- attenuated intranasal vaccine against respiratory syncytial virus administered with a licensed inactivated influenza vaccine, in Vaccines for the common cold (Review) 22 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews healthy subjects ≥ 60 years of age]. clinicaltrials.gov/ct2/show/ NCT02440035 {published data only} NCT01709019 (first received 17 October 2012). NCT02440035. A study to evaluate the safety, tolerability and immunogenicity of Ad35.RSV.FA2 regimens boosted NCT01852266 {published data only} with Ad26.RSV.FA2 in healthy adult participants [Phase 1, NCT01852266. Evaluating the safety and immune response to first in human study to evaluate the safety, tolerability and a single dose of a respiratory syncytial virus (RSV) vaccine in immunogenicity of Ad35.RSV.FA2 regimens boosted with RSV-seronegative infants and children [A phase I study of the Ad26.RSV.FA2 in healthy adult volunteers]. clinicaltrials.gov/ct2/ safety and immunogenicity of a single dose of the recombinant show/NCT02440035 (first received 17 April 2015). live-attenuated respiratory syncytial virus vaccine RSV cps2, lot RSV#005A, delivered as nose drops to RSV-seronegative infants NCT02472548 {published data only} and children 6 to 24 months of age]. clinicaltrials.gov/ct2/show/ NCT02472548. A study to evaluate the safety and reactogenicity NCT01852266 (first received 13 May 2013). of DPX-RSV(A), a respiratory syncytial virus [A phase I randomized, observer-blind, controlled, dose escalation trial NCT01905215 {published data only} of the safety and tolerability of two intramuscular doses of NCT01905215. Study to evaluate the safety, reactogenicity DPX-RSV(A), a respiratory syncytial virus vaccine containing and immunogenicity of GlaxoSmithKline (GSK) biologicals' respiratory syncytial virus (RSV) SHe antigen and a novel investigational respiratory syncytial virus (RSV) vaccines [An adjuvant DepoVaxTM, or SHe a antigen co-administered with observer-blind study to evaluate the safety, reactogenicity and aluminum hydroxide, or placebo to healthy adults ≥50-64 years immunogenicity of GSK biologicals' respiratory syncytial virus of age]. clinicaltrials.gov/ct2/show/NCT02472548 (first received (RSV) investigational vaccine (GSK3003891A) in healthy men]. 16 June 2015). clinicaltrials.gov/ct2/show/NCT01905215 (first received 23 July 2013). NCT02479750 {published data only} NCT02479750. Evaluation of ColdZyme® on experimentally NCT02115815 {published data only} induced common cold [Evaluation of ColdZyme® on NCT02115815. A study to evaluate the safety of the respiratory experimentally induced common cold - a double-blind, syncytial virus vaccine MEDI7510 in older adults [A phase 1a randomized, placebo-controlled study in healthy volunteers]. study to evaluate the safety of the respiratory syncytial virus clinicaltrials.gov/ct2/show/NCT02479750 (first received 24 June vaccine MEDI7510 in older adults]. clinicaltrials.gov/ct2/show/ 2015). NCT02115815 (first received 16 April 2014). NCT02491463 {published data only} NCT02266628 {published data only} NCT02491463. A study to assess the safety, reactogenicity NCT02266628. Placebo-controlled study to evaluate the safety and immunogenicity of GlaxoSmithKline (GSK) biologicals' and immunogenicity of the RSV-F vaccine in elderly adults RSV investigational vaccine (ChAd155-RSV) (GSK3389245A) [A phase II randomized, observer-blind, placebo-controlled in healthy adults [A study to evaluate safety, reactogenicity study to evaluate the immunogenicity and safety of respiratory and immunogenicity of GSK biologicals' RSV investigational syncytial virus (RSV) F vaccine in healthy elderly subjects and to vaccine based on viral proteins encoded by chimpanzee-derived estimate the incidence rate of medically-attended RSV disease adenovector (ChAd155-RSV) (GSK3389245A) in healthy adults]. in vaccine and placebo recipients]. clinicaltrials.gov/ct2/show/ clinicaltrials.gov/ct2/show/NCT02491463 (first received 8 July NCT02266628 (first received 17 October 2014). 2015). NCT02296463 {published data only} NCT02561871 {published data only} NCT02296463. A phase I randomized, observer-blinded, dose- NCT02561871. A study to evaluate the safety, tolerability and ranging study in healthy subjects 24 to < 72 months of age immunogenicity of Ad26.RSV.FA2 followed by Ad35.RSV.FA2 [A phase I randomized, observer-blinded, dose-ranging study in healthy adult volunteers [Phase 1, first in human study to evaluate the immunogenicity and safety of a respiratory to evaluate the safety, tolerability and immunogenicity of syncytial virus (RSV) recombinant fusion (F) nanoparticle Ad26.RSV.FA2 followed by Ad35.RSV.FA2 in healthy adult vaccine, with or without aluminum adjuvant, in healthy volunteers]. clinicaltrials.gov/ct2/show/NCT02561871 (first subjects 24 to < 72 months of age]. clinicaltrials.gov/ct2/show/ received 28 September 2015). NCT02296463 (first received 20 November 2014). NCT02593071 {published data only} NCT02419391 {published data only} NCT02593071. Safety and immunogenicity of the RSV-F vaccine NCT02419391. Trial to evaluate the safety, tolerability and in older adults previously treated with the same vaccine or immunogenicity of the recombinant MVA BN® RSV vaccine [A placebo in the prior year [A phase II randomized, observer- randomized, single-blind, placebo-controlled phase i trial to blind, placebo-controlled study to evaluate the immunogenicity evaluate the safety, tolerability and immunogenicity of the and safety of a respiratory syncytial virus (RSV) recombinant F recombinant MVA BN® RSV vaccine in healthy adult subjects]. nanoparticle vaccine in healthy older adult subjects previously clinicaltrials.gov/ct2/show/NCT02419391 (first received 17 April treated with the same vaccine, or placebo, in the prior year; 2015). and to estimate the incidence rate of RSV disease and vaccine efficacy in subjects based on their RSV F vaccine experience over two consecutive years]. clinicaltrials.gov/ct2/show/ NCT02593071 (first received 30 October 2015). Vaccines for the common cold (Review) 23 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews NCT02601612 {published data only} NCT02890381 {published data only} NCT02601612. Safety and immunogenicity of the RSV NCT02890381. Evaluating the infectivity, safety and D46cpΔM2-2 Vaccine in RSV-seropositive children and RSV- immunogenicity of a recombinant live-attenuated respiratory seronegative infants and children [A phase I study of the safety syncytial virus vaccine (RSV LID cp ΔM2-2) in RSV-seronegative and immunogenicity of a single dose of the live recombinant infants 6 to 24 months of age [Phase I placebo-controlled RSV D46cpΔM2-2 vero grown virus vaccine (lot RSV #008A), study of the infectivity, safety and immunogenicity of a single delivered as nose drops to RSV-seropositive children 12 to 59 dose of a recombinant live-attenuated respiratory syncytial months of age and RSV-seronegative infants and children 6 to virus vaccine, LID cp ΔM2-2, lot RSV#009B, delivered as nose 24 months of age]. clinicaltrials.gov/ct2/show/NCT02601612 drops to RSV-seronegative infants 6 to 24 months of age]. (first received 10 November 2015). clinicaltrials.gov/ct2/show/NCT02890381 (first received 7 September 2016). NCT02624947 {published data only} NCT02624947. A study to determine the safety and efficacy of NCT02926430 {published data only} the RSV F vaccine to protect infants via maternal immunization NCT02926430. A study to evaluate the safety, tolerability and [A phase 3, randomized, observer-blind, placebo-controlled immunogenicity of two vaccinations of Ad26.RSV.preF one study to determine the immunogenicity and safety of a year apart in adults aged 60 years and older in stable health respiratory syncytial virus (RSV) F nanoparticle vaccine with [A randomized, double-blind, first-in-human phase 1 study to aluminum in healthy third-trimester pregnant women; and evaluate the safety, tolerability and immunogenicity of two safety and efficacy of maternally transferred antibodies in vaccinations of Ad26.RSV.preF one year apart in adults aged 60 preventing rsv disease in their infants]. clinicaltrials.gov/ct2/ years and older in stable health]. clinicaltrials.gov/ct2/show/ show/NCT02624947 (first received 9 December 2015). NCT02926430 (first received 6 October 2016). NCT02794870 {published data only} NCT02952339 {published data only} NCT02794870. Evaluating the infectivity, safety and NCT02952339. Evaluating the infectivity, safety and immunogenicity of a recombinant live-attenuated respiratory immunogenicity of a recombinant live-attenuated respiratory syncytial virus vaccine in RSV-seronegative infants 6 to 24 syncytial virus vaccine (RSV LID cp ΔM2-2) in RSV-seronegative months of age [Phase I placebo-controlled study of the infants 6 to 24 months of age [Phase I placebo-controlled study infectivity, safety and immunogenicity of a single dose of a of the infectivity, safety and immunogenicity of a single dose recombinant live-attenuated respiratory syncytial virus vaccine, of a recombinant live-attenuated respiratory syncytial virus LID ΔM2-2 1030s, lot RSV#010A, delivered as nose drops to RSV- vaccine, LID ΔM2-2 1030s, lot RSV#010A, delivered as nose drops seronegative infants 6 to 24 months of age]. clinicaltrials.gov/ to RSV-seronegative infants and children 6 to 24 months of ct2/show/NCT02794870 (first received 9 June 2016). age]. clinicaltrials.gov/ct2/show/NCT02952339 (first received 2 November 2016). NCT02830932 {published data only} NCT02830932. Dose-ranging trial of safety & immunogenicity NCT03026348 {published data only} of an oral adenoviral-vector based RSV vaccine (VXA-RSV-f) NCT03026348. Safety and immunogenicity study to evaluate [A phase 1, randomized, double-blind, placebo-controlled, single- or two-dose regimens of RSV F vaccine with and without dose-ranging trial to determine the safety and immunogenicity aluminum phosphate or Matrix-M1™ adjuvants in clinically- of an adenoviral-vector based respiratory syncytial virus stable older adults. clinicaltrials.gov/ct2/show/NCT03026348 (RSV) F protein vaccine (VXA-RSV-f) expressing protein F and (first received 20 January 2017). dsRNA adjuvant administered orally to healthy volunteers]. clinicaltrials.gov/ct2/show/NCT02830932 (first received 13 July NCT03049488 {published data only} 2016). NCT03049488. Dose, safety, tolerability and immunogenicity of a stabilized prefusion RSV F subunit protein vaccine, VRC- NCT02864628 {published data only} RSVRGP084-00-VP (DS-Cav1), alone or with alum adjuvant, NCT02864628. RSV-MVA-BN vaccine phase I trial, intranasal in healthy adults [VRC 317: a phase I randomized, open- application in adults [A partially randomized, partly placebo label clinical trial to evaluate dose, safety, tolerability and controlled phase i trial to evaluate the safety, tolerability and immunogenicity of a stabilized prefusion RSV F subunit protein immunogenicity of the recombinant MVA-BN® RSV vaccine after vaccine, VRC-RSVRGP084-00-VP (DS-Cav1), alone or with intranasal and intramuscular administration]. clinicaltrials.gov/ alum adjuvant, in healthy adults]. clinicaltrials.gov/ct2/show/ ct2/show/NCT02864628 (first received 12 August 2016). NCT03049488 (first received 10 February 2017). NCT02873286 {published data only} NCT03191383 {published data only} NCT02873286. RSV-MVA-BN vaccine phase II trial in ≥ 55 year NCT03191383. A study to evaluate the safety, reactogenicity old adults [A randomized, single-blind, placebo controlled, and immunogenicity of the GlaxoSmithKline (GSK) biologicals' dose-ranging phase II trial in ≥ 55 year old adults to evaluate respiratory syncytial virus (RSV) investigational vaccine the safety and immunogenicity of the recombinant MVA-BN- (GSK3003891A) in healthy pregnant women and infants born RSV vaccine]. clinicaltrials.gov/ct2/show/NCT02873286 (first to vaccinated mothers [An observer-blind study to assess the received 19 August 2016). safety, reactogenicity and immunogenicity of GSK biologicals' investigational RSV vaccine (GSK3003891A), in healthy pregnant women and infants born to vaccinated mothers]. Vaccines for the common cold (Review) 24 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews clinicaltrials.gov/ct2/show/NCT03191383 (first received 19 June NCT03572062 {published data only} 2017). NCT03572062. A study to evaluate the safety and immunogenicity of an adjuvanted RSV vaccine in healthy NCT03303625 {published data only} older adults [A phase 1/2, placebo-controlled, randomized, NCT03303625. A study to evaluate the safety, tolerability and observer-blind, dose-finding, first-in-human study to describe immunogenicity of an investigational RSV vaccine candidate the safety, tolerability, and immunogenicity of an adjuvanted (Ad26.RSV.preF) in adults 18 to 50 years of age, and RSV- respiratory syncytial virus (RSV) vaccine in healthy older adults]. seropositive toddlers 12 to 24 months of age [A randomized, clinicaltrials.gov/ct2/show/NCT03572062 (first received 28 June double-blind, phase 1/2a study to evaluate the safety, 2018). tolerability and immunogenicity of Ad26.RSV.preF in adults 18 to 50 years of age, RSV-seropositive toddlers 12 to 24 months of NCT03674177 {published data only} age]. clinicaltrials.gov/ct2/show/NCT03303625 (first received 6 NCT03674177. A study to evaluate different dose levels of October 2017). GlaxoSmithKline (GSK) biologicals' investigational respiratory syncytial virus (RSV) vaccine (GSK3888550A), based on the NCT03334695 {published data only} vaccine safety and the antibodies (body defences) produced NCT03334695. An exploratory study to evaluate the following vaccine administration [A study to evaluate the prophylactic efficacy of a single immunization of Ad26.RSV.preF safety, reactogenicity and immunogenicity of GSK biologicals' against respiratory syncytial virus infection in a virus challenge investigational unadjuvanted RSV maternal vaccine compared model in healthy 18 to 50 year-old adults [An exploratory, phase to placebo when administered to healthy non-pregnant 2a, randomized, double-blind, placebo-controlled study to women]. clinicaltrials.gov/ct2/show/NCT03674177 (first evaluate the prophylactic efficacy of a single immunization of received 17 September 2018). Ad26.RSV.preF against respiratory syncytial virus infection in a virus challenge model in healthy 18 to 50 year-old adults]. NCT03814590 {published data only} clinicaltrials.gov/ct2/show/NCT03334695 (first received 17 NCT03814590. A study to assess the safety, reactogenicity November 2017). and immune response of GlaxoSmithKline (GSK) biologicals' investigational respiratory syncytial virus (RSV) vaccine NCT03392389 {published data only} (GSK3844766A) in older adults [Phase I/II, observer-blind, NCT03392389. Safety, reactogenicity, and immunogenicity of safety, reactogenicity and immunogenicity study of GSK mRNA-1653 in healthy adults [A phase 1, randomized, observer- biologicals' respiratory syncytial virus (RSV) vaccine blind, placebo-controlled, dose-ranging study to evaluate the GSK3844766A in subjects aged 18-40 or 60-80 years]. safety, reactogenicity, and immunogenicity of mRNA-1653, a clinicaltrials.gov/ct2/show/NCT03814590 (first received 24 combined human metapneumovirus and human parainfluenza January 2019). virus type 3 vaccine, when administered to healthy adult]. clinicaltrials.gov/ct2/show/NCT03392389 (first received 8 NCT04071158 {published data only} January 2018). NCT04071158. A study of a RSV vaccines when given together with TDAP in healthy non-pregnant women aged between NCT03403348 {published data only} 18 to 49 years [A phase 2b, placebo-controlled, randomized, NCT03403348. A first-in-human study of orally administered observer-blind study to evaluate the safety, tolerability, and JNJ-64417184 to evaluate the safety, tolerability, and immunogenicity of a respiratory syncytial virus (RSV) vaccine pharmacokinetics of single and multiple ascending doses, when administered concomitantly with tetanus, diphtheria, and the antiviral activity of multiple doses in a respiratory and acellular pertussis vaccine (TDAP) in healthy nonpregnant syncytial virus (RSV) challenge study in healthy participants [A women 18 through 49 years of age]. clinicaltrials.gov/ct2/show/ randomized, double-blind, placebo-controlled, first-in-human, NCT04071158 (first received 28 August 2019). 6-part study of orally administered JNJ-64417184 to evaluate the safety, tolerability, and pharmacokinetics of single and NCT04086472 {published data only} multiple ascending doses, and the antiviral activity of multiple NCT04086472. Phase 2a respiratory syncytial virus (RSV) doses in a respiratory syncytial virus (RSV) challenge study in human challenge study of MK-1654 in healthy participants healthy subjects]. clinicaltrials.gov/ct2/show/NCT03403348 (MK-1654-005) [A phase 2a double-blind, randomized, placebo- (first received 18 January 2018). controlled study to evaluate the efficacy and safety of MK-1654 in healthy participants inoculated with experimental respiratory NCT03473002 {published data only} syncytial virus]. clinicaltrials.gov/ct2/show/NCT04086472 (first NCT03473002. A safety and immunogenicity study of intranasal received 11 September 2019). sendai virus vectored respiratory syncytial virus (SeVRSV) vaccine in healthy adults [A phase I double-blind placebo NCT04752644 {published data only} controlled trial to evaluate the safety and immunogenicity of NCT04752644. Phase 2a study of MVA-BN-RSV vaccination intranasal sendai virus vectored respiratory syncytial virus and RSV challenge in healthy adults [A phase 2a, randomised, (SeVRSV) vaccine in healthy adults]. clinicaltrials.gov/ct2/show/ double-blinded, placebo-controlled study to assess the safety, NCT03473002 (first received 21 March 2018). immunogenicity and efficacy of the recombinant MVA-BN®- RSV vaccine against respiratory syncytial virus infection in the virus challenge model in healthy adult participants]. Vaccines for the common cold (Review) 25 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews clinicaltrials.gov/ct2/show/NCT04752644 (first received 12 a phase 1, randomised, open-label, dose-escalation clinical February 2021). trial. Lancet Respiratory Medicine 2021;9(10):1111-20. [DOI: 10.1016/S2213-2600(21)00098-9] [PMID: 33864736] NTR7173 {published data only} NTR7173. Clinical study to evaluate safety, tolerability and Sadoff 2021a {published data only} effects on the immune system of a common cold vaccine in Sadoff J, De Paepe E, DeVincenzo J, Gymnopoulou E, Menten J, healthy adults [Randomised, double-blind, placebo-controlled Murray B, et al. Prevention of respiratory syncytial virus study to evaluate the safety, tolerability, immunogenicity and infection in healthy adults by a single immunization of shedding of live-attenuated RSV vaccine in healthy adults]. Ad26.RSV.preF in a human challenge study. Journal of Infectious www.who.int/trialsearch/Trial2.aspx?TrialID=NTR7173 (first Diseases 2022;226(3):396-406. [DOI: 10.1093/infdis/jiab003] received 18 May 2018). [PMID: 33400792] Paradiso 1994 {published data only} Sadoff 2021b {published data only} Paradiso PR, Hildreth SW, Hogerman DA, Speelman DJ, Sadoff J, De Paepe E, Haazen W, Omoruyi E, Bastian AR, Lewin EB, Oren J, et al. Safety and immunogenicity of a subunit Comeaux C. Safety and immunogenicity of the Ad26.RSV.preF respiratory syncytial virus vaccine in children 24 to 48 months investigational vaccine coadministered with an influenza old. Pediatric Infectious Disease Journal 1994;13(9):792-8. [PMID: vaccine in older adults. Journal of Infectious Diseases 7808848] 2021;223(4):699-708. [DOI: 10.1093/infdis/jiaa409] [PMID: 32851411] Philpott 2016 {published data only} Philpott E, Englund J, Tielsch J, Katz J, Khatry S, Leclerq SC, Samy 2020 {published data only} et al. Effect of febrile rhinovirus illness during pregnancy Samy N, Reichhardt D, Schmidt D, Chen LM, Silbernagl G, on adverse birth outcomes in Nepal. Open Forum Infectious Vidojkovic S, et al. Safety and immunogenicity of novel Diseases 2016;3(Suppl 1):1751. [DOI: 10.1093/ofid/ofw194.131] modified vaccinia Ankara-vectored RSV vaccine: a randomized phase I clinical trial. Vaccine 2020;38(11):2608-19. [DOI: 10.1016/ Philpott 2017 {published data only} j.vaccine.2020.01.055] Philpott EK, Englund JA, Katz J, Tielsch J, Khatry S, LeClerq SC, et al. Febrile rhinovirus illness during pregnancy is associated Scaggs Huang 2021 {published data only} with low birth weight in Nepal. Open Forum Infectious Diseases Scaggs Huang F, Bernstein DI, Slobod KS, Portner A, Takimoto T, 2017;4(2):ofx073. [DOI: 10.1093/ofid/ofx073] Russell CJ, et al. Safety and immunogenicity of an intranasal sendai virus-based vaccine for human parainfluenza virus Piedra 1995 {published data only} type I and respiratory syncytial virus (SeVRSV) in adults. Piedra PA, Glezen WP, Kasel JA, Welliver RC, Jewel AM, Human Vaccines & Immunotherapeutics 2021;17(2):554-9. [DOI: Rayford Y, et al. Safety and immunogenicity of the PFP vaccine 10.1080/21645515.2020.1779517] against respiratory syncytial virus (RSV): the western blot assay aids in distinguishing immune responses of the PFP vaccine Schwarz 2019 {published data only} from RSV infection. Vaccine 1995;13(12):1095-101. [PMID: Schwarz TF, McPhee RA, Launay O, Leroux-Roels G, Talli J, 7491817] Picciolato M, et al. Immunogenicity and safety of 3 formulations of a respiratory syncytial virus candidate vaccine in non- Pierce 1968 {published data only} pregnant women: a phase II, randomized trial. Journal of Pierce WE, Rosenbaum MJ, Edwards EA, Peckinpaugh RO, Infectious Diseases 2019;220(11):1816-25. [DOI: 10.1093/infdis/ Jackson GG. Live and inactivated adenovirus vaccines for jiz395] the prevention of acute respiratory illness in naval recruits. American Journal of Epidemiology 1968;87(1):237-46. [PMID: Shakib 2019 {published data only} 4295428] Shakib JH, Varner MW, Fiuza M, Trenholme AA, Baqui A, Frech S, et al. Immunoglobulin A, immunoglobulin G, and neutralizing Power 2001 {published data only} antibodies to respiratory syncytial virus increase in human Power UF, Nguyen TN, Rietveld E, de Swart RL, Groen J, milk following immunization with an RSV F protein vaccine. Osterhaus AD, et al. Safety and immunogenicity of a novel International Journal of Stroke 2019;221(6):669-70. [DOI: recombinant subunit respiratory syncytial virus vaccine 10.1016/j.ajog.2019.10.080] (BBG2Na) in healthy young adults. Journal of Infectious Diseases 2001;184(11):1456-60. [PMID: 11709789] Shaw 2019 {published data only} Shaw C, Lee H, Knightly C, Kalidindi S, Zaks T, Smolenov I, et al. Ritchie 1958 {published data only} Phase 1 trial of an mRNA-based combination vaccine against Ritchie JM. Autogenous vaccine in prophylaxis of the common HMPV and PIV3. Open Forum Infectious Diseases 2019;6(Suppl cold. Lancet 1958;1(7021):615-8. [PMID: 13515297] 2):S970. [DOI: 10.1093/ofid/ofz360.2431] Ruckwardt 2021 {published data only} Simoes 2001 {published data only} Ruckwardt T, Morabito K, Phung E, Crank M, Costner P, Simoes EA, Tan DH, Ohlsson A, Sales V, Wang EE. Respiratory Holman L, et al. Safety, tolerability, and immunogenicity of the syncytial virus vaccine: a systematic overview with emphasis respiratory syncytial virus prefusion F subunit vaccine DS-Cav1: Vaccines for the common cold (Review) 26 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews on respiratory syncytial virus subunit vaccines. Vaccine Williams 2020 {published data only} 2001;20(5-6):954-60. [PMID: 11738763] Williams K, Bastian AR, Feldman RA, Omoruyi E, de Paepe E, Hendriks J, et al. Phase 1 safety and immunogenicity study of a Swamy 2019 {published data only} respiratory syncytial virus vaccine with an adenovirus 26 vector Swamy GK, Munoz FM, Polack F, Madhi SA, Trenholme AA, encoding prefusion F (Ad26.RSV.preF) in adults aged ≥ 60 years. Simoes EA, et al. Safety of third trimester immunization with Journal of Infectious Diseases 2020;222(6):979-88. [DOI: 10.1093/ a respiratory syncytial virus F protein vaccine and protection infdis/jiaa193] [PMID: 32320465] of infants over the first 180 days of life against all-cause lower respiratory tract infection. American Journal of Obstetrics & Wilson 1960 {published data only} Gynecology 2019;221(6):670. [DOI: 10.1016/j.ajog.2019.10.081] Wilson JS, Grant PJ, Miller DL, Taylor CE, McDonald JC. Trial of adenovirus vaccine in Royal Air Force recruits. British Medical Tang 2008 {published data only} Journal 1960;1(5179):1081-3. [PMID: 13845090] Tang RS, Spaete RR, Thompson MW, MacPhail M, Guzzetta JM, Ryan PC, et al. Development of a PIV-vectored RSV vaccine: Wright 1976 {published data only} preclinical evaluation of safety, toxicity, and enhanced Wright PF, Shinozaki T, Fleet W, Sell SH, Thompson J, Karzon DT. disease and initial clinical testing in healthy adults. Vaccine Evaluation of a live, attenuated respiratory syncytial virus 2008;26(50):6373-82. [PMID: 18822334] vaccine in infants. Journal of Pediatrics 1976;88(6):931-6. [PMID: 178852] Top 1971 {published data only} Top FH Jr, Buescher EL, Bancroft WH, Russell PK. Immunization Yu 2020 {published data only} with live types 7 and 4 adenovirus vaccines. II. Antibody Yu J, Powers JH, Vallo D, Falloon J. Evaluation of efficacy response and protective effect against acute respiratory endpoints for a phase IIb study of a respiratory syncytial virus disease due to adenovirus type 7. Journal of Infectious Diseases vaccine in older adults using patient-reported outcomes with 1971;124(2):155-60. [PMID: 4330998] laboratory confirmation. Value Health 2020;23(2):227-35. [DOI: 10.1016/j.jval.2019.09.2747] Tristram 1993 {published data only} Tristram DA, Welliver RC, Mohar CK, Hogerman DA, Hildreth SW, Paradiso P. Immunogenicity and safety of respiratory syncytial References to ongoing studies virus subunit vaccine in seropositive children 18-36 months NCT01893554 {published data only} old. Journal of Infectious Diseases 1993;167(1):191-5. [PMID: 8418166] NCT01893554. Evaluating the safety and immune response to a single dose of a respiratory syncytial virus (RSV) vaccine Van Der Plas 2020 {published data only} in infants and children [A phase I study of the safety and Van Der Plas J, Verdijk P, Van Brummelen E, Roestenberg M, immunogenicity of a single dose of the recombinant live- Burggraaf J, Kamerling I. First-in-human, randomized study to attenuated respiratory syncytial virus vaccine RSV ΔNS2 assess the safety, tolerability, immunogenicity, and shedding Δ1313 I1314L, lot RSV#006A, delivered as nose drops to RSV- of a live attenuated respiratory syncytial virus vaccine. British seropositive children 12 to 59 months of age, RSV-seronegative Journal of Clinical Pharmacology 2020;86(6):1189-90. [DOI: infants and children 6 to 24 months of age, and infants 4 to 6 10.1111/bcp.14266] months of age]. clinicaltrials.gov/ct2/show/NCT01893554 (first received 9 July 2013). Verdijk 2020 {published data only} NCT03387137 {published data only} Verdijk P, van der Plas JL, van Brummelen E, Jeeninga RE, de Haan C, Roestenberg M, et al. First-in-human administration NCT03387137. Evaluating the infectivity, safety, and of a live-attenuated RSV vaccine lacking the G-protein immunogenicity of a respiratory syncytial virus vaccine (RSV assessing safety, tolerability, shedding and immunogenicity: a 6120/∆NS2/1030s) in RSV-seropositive children and RSV- randomized controlled trial. Vaccine 2020;38(39):6088-95. [DOI: seronegative infants and children [Phase I placebo-controlled 10.1016/j.vaccine.2020.07.029] [PMID: 32718816] study of the infectivity, safety and immunogenicity of a single dose of a recombinant live-attenuated respiratory syncytial Watt 1990 {published data only} virus vaccine, 6120/∆NS2/1030s, lot RSV#012A, delivered as Watt PJ, Robinson BS, Pringle CR, Tyrrell DA. Determinants nose drops to RSV-seropositive children 12 to 59 months of age of susceptibility to challenge and the antibody response of and RSV-seronegative infants and children 6 to 24 months of adult volunteers given experimental respiratory syncytial virus age]. clinicaltrials.gov/ct2/show/NCT03387137 (first received 29 vaccines. Vaccine 1990;8(3):231-6. [PMID: 2363300] December 2017). Welliver 1994 {published data only} NCT03422237 {published data only} Welliver RC, Tristram DA, Batt K, Sun M, Hogerman D, NCT03422237. Evaluating the infectivity, safety, and Hildreth S. Respiratory syncytial virus-specific cell-mediated immunogenicity of the recombinant live-attenuated respiratory immune responses after vaccination with a purified fusion syncytial virus (RSV) vaccines RSV ΔNS2/Δ1313/I1314L or RSV protein subunit vaccine. Journal of Infectious Diseases 276 in RSV-seronegative infants and children 6 to 24 months 1994;170(2):425-8. [PMID: 8035030] of age [Randomized phase I study of the infectivity, safety, and immunogenicity of a single dose of the recombinant live- Vaccines for the common cold (Review) 27 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews attenuated respiratory syncytial virus (RSV) vaccines RSV ΔNS2/ followed by a 2nd dose of the RSV vaccine to healthy non- Δ1313/I1314L or RSV 276 or placebo, delivered as nose drops pregnant women [A phase II study of a primary dose of to RSV-seronegative infants and children 6 to 24 months of investigational RSV maternal vaccine, given alone or with age]. clinicaltrials.gov/ct2/show/NCT03422237 (first received 5 Boostrix, with a 2nd dose investigational RSV maternal vaccine]. February 2018). clinicaltrials.gov/ct2/show/NCT04138056 (first received 24 October 2019). NCT03596801 {published data only} NCT03596801. Evaluating the infectivity, safety and NCT04681833 {published data only} immunogenicity of respiratory syncytial virus vaccines, RSV NCT04681833. Safety and efficacy of BARS13 in the elderly [A 6120/∆NS1 and RSV 6120/F1/G2/∆NS1, in RSV-seropositive randomised, double-blind, placebo-controlled, dose-ranging children and RSV-seronegative infants and children [Phase phase II study in 60 to 80-year-old adults to assess the safety I placebo-controlled study of the infectivity, safety and and immunogenicity of BARS13]. clinicaltrials.gov/ct2/show/ immunogenicity of a single dose of a recombinant live- NCT04681833 (first received 23 December 2020). attenuated respiratory syncytial virus vaccine, RSV 6120/∆NS1, lot RSV#018A, or RSV 6120/F1/G2/∆NS1, lot RSV#016A, delivered NCT04732871 {published data only} as nose drops to RSV-seropositive children 12 to 59 months of NCT04732871. Immunogenicity, safety, reactogenicity and age and RSV-seronegative infants and children 6 to 24 months persistence of an investigational respiratory syncytial virus of age]. clinicaltrials.gov/ct2/show/NCT03596801 (first received (RSV) vaccine in adults aged 60 years and above [A phase 3, 24 July 2018). randomized, open-label, multi-country study to evaluate the immunogenicity, safety, reactogenicity and persistence of a NCT03916185 {published data only} single dose of the RSVPreF3 OA investigational vaccine and NCT03916185. Safety and immunogenicity of a single different revaccination schedules in adults aged 60 years and dose of the recombinant live-attenuated respiratory above]. clinicaltrials.gov/ct2/show/NCT04732871 (first received syncytial virus (RSV) vaccines RSV ΔNS2/Δ1313/I1314L, RSV 1 February 2021). 6120/ΔNS2/1030s, RSV 276 or placebo, delivered as nose drops to RSV-seronegative children 6 to 24 months of age NCT04980391 {published data only} [Randomized phase I/II study of the safety and immunogenicity NCT04980391. A study on the safety and immune response of a single dose of the recombinant live-attenuated respiratory to an unadjuvanted RSV maternal vaccine, in high-risk syncytial virus (RSV) vaccines RSV ΔNS2/Δ1313/I1314L, RSV pregnant women aged 15 to 49 years and infants born to the 6120/ΔNS2/1030s, RSV 276 or placebo, delivered as nose vaccinated mothers [A phase III, double-blind, randomized, drops to RSV-seronegative children 6 to 24 months of age]. placebo-controlled study to evaluate the safety, reactogenicity clinicaltrials.gov/ct2/show/NCT03916185 (first received 16 April and immune response of a single intramuscular dose of 2019). unadjuvanted RSV maternal vaccine, in high-risk pregnant women aged 15 to 49 years and infants born to the vaccinated NCT04032093 {published data only} mother]. clinicaltrials.gov/ct2/show/NCT04980391 (first NCT04032093. A phase 2B placebo-controlled, randomized received July 28 2021). study of a respiratory syncytial virus (RSV) vaccine in pregnant women [A phase 2B, randomized, placebo-controlled, NCT05127434 {published data only} observer-blinded trial to evaluate the safety, tolerability, and NCT05127434. A study to evaluate the safety and efficacy immunogenicity of a respiratory syncytial virus (RSV) vaccine in of mRNA-1345 vaccine targeting respiratory syncytial virus pregnant women 18 through 49 years of age and their infants]. (RSV) in adults ≥60 years of age [A phase 2/3, randomized, clinicaltrials.gov/ct2/show/NCT04032093 (first received 25 July observer-blind, placebo-controlled study to evaluate the 2019). safety and efficacy of mRNA-1345, an mRNA vaccine targeting respiratory syncytial virus (RSV), in adults ≥60 years of age]. NCT04126213 {published data only} clinicaltrials.gov/ct2/show/NCT05127434 (first received 19 NCT04126213. Study of safety, reactogenicity and November 2021). immunogenicity of GlaxoSmithKline's (GSK) respiratory syncytial virus (RSV) maternal unadjuvanted vaccine in healthy NCT05238025 {published data only} pregnant women (aged 18 to 40 years) and their infants NCT05238025. Phase 3 MVA-BN-RSV vaccine efficacy trial [A [A phase II, randomised, observer-blind, placebo controlled randomized, double-blind, phase 3 trial to assess clinical multi-country study to assess the safety, reactogenicity efficacy, safety and reactogenicity of the recombinant MVA-BN® and immunogenicity of a single intramuscular dose of GSK -RSV vaccine in adults ≥60 years of age]. clinicaltrials.gov/ct2/ biologicals' investigational RSV maternal unadjuvanted vaccine show/NCT05238025 (first received 14 February 2022). (GSK3888550A), in healthy pregnant women aged 18 to 40 years and infants born to vaccinated mothers]. clinicaltrials.gov/ct2/ show/NCT04126213 (first received 15 October 2019). 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Machine learning reduced workload with Schulz 1995 minimal risk of missing studies: development and evaluation of Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence a randomized controlled trial classifier for Cochrane Reviews. of bias. Dimensions of methodological quality associated Journal of Clinical Epidemiology 2021;133:140-51. [DOI: 10.1016/ with estimates of treatment effects in controlled trials. JAMA j.jclinepi.2020.11.003] 1995;273(5):408-12. [PMID: 7823387] Thompson 2003 Shibata 2018 Thompson WW. Mortality associated with influenza and Shibata M, Iwane T, Higuchi R, Suwa K, Nakajima K. Potential respiratory syncytial virus in the United States. JAMA common factors associated with predisposition to common 2003;289(2):179-86. [MEDLINE: 12517228] cold in middle-aged and elderly Japanese: a community-based cross-sectional study. Medicine (Baltimore) 2018;97(20):e10729. To 2017 [DOI: 10.1097/MD.0000000000010729] [PMID: 29768343] To KK, Yip CC, Yuen KY. Rhinovirus - from bench to bedside. Journal of the Formosan Medical Association Vaccines for the common cold (Review) 33 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews 2017;116(7):496-504. [DOI: 10.1016/j.jfma.2017.04.009] [PMID: 2020;112(3):501-2. [DOI: 10.1093/ajcn/nqaa165] [PMID: 28495415] 32584964] Tomita 2012 Wooden 2018 Tomita K, Sano H, Iwanaga T, Ishihara K, Ichinose M, Kawase I, et Wooden SL, Koff WC. The human vaccines project: towards a al. Association between episodes of upper respiratory infection comprehensive understanding of the human immune response and exacerbations in adult patients with asthma. Journal of to immunization. Human Vaccines & Immunotherapeutics Asthma 2012;49(3):253-9. [DOI: 10.3109/02770903.2012.661009] 2018;14(9):2214-6. [DOI: 10.1080/21645515.2018.1476813] [PMID: 22376075] [PMID: 29847214] Tsuzuki 2020 Zimmermann 2020 Tsuzuki S, Kimura Y, Ishikane M, Kusama Y, Ohmagari N. Cost of Zimmermann P, Curtis N. Coronavirus infections in children inappropriate antimicrobial use for upper respiratory infection including COVID-19: an overview of the epidemiology, clinical in Japan. BMC Health Services Research 2020;20(1):153. [DOI: features, diagnosis, treatment and prevention options in 10.1186/s12913-020-5021-1] [PMID: 32111202] children. Pediatric Infectious Disease Journal 2020;39(5):355-68. [DOI: 10.1097/INF.0000000000002660] [PMID: 32310621] Veiga 2021 Veiga A, Martins LG, Riediger I, Mazetto A, Debur M, Zumla 2016 Gregianini TS. More than just a common cold: endemic Zumla A, Chan JF, Azhar EI, Hui DS, Yuen KY. Coronaviruses - coronaviruses OC43, HKU1, NL63, and 229E associated with drug discovery and therapeutic options. 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Rhinovirus replication the common cold. Cochrane Database of Systematic and innate immunity in highly differentiated human airway Reviews 2013, Issue 6. Art. No: CD002190. [DOI: epithelial cells. Respiratory Research 2019;20(1):150. [DOI: 10.1002/14651858.CD002190.pub4] 10.1186/s12931-019-1120-0] [PMID: 31299975] Simancas-Racines 2017 Westerterp 2020 Simancas-Racines D, Franco JV, Guerra CV, Felix ML, Hidalgo R, Westerterp KR. Absence of evidence is no evidence for absence Martinez-Zapata MJ. Vaccines for the common cold. Cochrane of the phenomenon. American Journal of Clinical Nutrition Database of Systematic Reviews 2017, Issue 5. Art. No: CD002190. [DOI: 10.1002/14651858.CD002190.pub4] CHARACTERISTICS OF STUDIES Characteristics of included studies [ordered by study ID] Griffin 1970 Study characteristics Methods Design: double-blind RCT (2 arms) Country: USA (1 site) Clinical setting: Great Lakes Naval Training Center Follow-up: 9 weeks' basic-training period Intention-to-treat: yes Randomisation unit: participant Vaccines for the common cold (Review) 34 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews Griffin 1970 (Continued) Analysis unit: participant Participants Great Lakes Naval Training Center, new recruits Randomised: 2307 participants Vaccines group: 1139 (49.3%) Placebo group: 1168 (50.7%) Participants receiving intervention: 1139 Vaccines group: 1139 (49.3%) Placebo group: 1168 (50.7%) Lost postrandomisation: 0% Analysed participants: Vaccines group: 1139 (49.3%) Placebo group: 1168 (50.7%) Age median (mean (SD)): did not report Gender (number of men): 2307 Inclusion criteria: 1. Aged 17 to 20 years 2. Great Lakes Naval Training Center, new recruits Exclusion criteria: not reported Interventions Experimental group: the vaccines used were composed of orally administered live adenovirus 4, par- enterally administered inactivated adenovirus 4, and parenterally administered inactivated adenovirus 4 and 7 preparations Control group: placebo Co-interventions: 1. 1.2 million units of benzathine penicillin G 2. polyvalent influenza vaccine Outcomes This RCT did not specify primary or secondary outcomes. Incidence of admissions of participants with respiratory illness (not only hospitalised participants): 1. Acute undifferentiated respiratory disease 2. Common cold syndrome: an acute inflammation of the upper respiratory tract with coryza as a promi- nent feature and temperature, taken orally, of 100 ºF or less on admission 3. Exudative pharyngitis 4. Atypical pneumonia 5. Viral exanthem Toxic effects Notes 1. Trial registration: not reported 2. A priori sample size estimation: not reported 3. Conducted: 19 February to 16 April, with observations continued to 20 June 1965 4. Funder: "This investigation was supported in part by the Department of the Navy, research project MF 022.03.07-4014, and in part by the Public Health Service Vaccine Development Branch, contract 43-65-1031" (p 981) 5. Role of funder: "Capt. Robert O. Peckinpaugh, MC, USN; LCDR Wayne E. Frazier, MC, USN; and Willard E. Pierce aided in the design, conduct, and statistical interpretation of this investigation" (p 981) Vaccines for the common cold (Review) 35 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews Griffin 1970 (Continued) 6. Declared conflicts of interest: "The opinions and assertions contained here in are those of the authors and are not to be construed as official or as reflecting the views of the Navy Department or the Naval Service at large." (p 981) Risk of bias Bias Authors' judgement Support for judgement Random sequence genera- Unclear risk Quote: "Epidemiologic design of this study consisted of the random assign- tion (selection bias) ment of one half of the recruits ..." (p 982) Insufficient information to permit a judgement Allocation concealment Unclear risk Insufficient information to permit a judgement (selection bias) Blinding of participants Low risk Quote: "Double-blind procedure was followed with paramedical personnel ad- and personnel (perfor- ministering the appropriate vaccine or placebo to recruits on their third day af- mance bias) ter arrival at Great Lakes, just prior to initiation of basic training" (p 982) All outcomes Quote: "Placebo for the parenterally administered vaccines consisted of an injection of physiological saline, and that for the orally administered vaccine consisted of an identical appearing inert gelatin capsule" (p 982) Comment: blinding of participants and key study personnel ensured, and it is unlikely that the blinding could have been broken Blinding of outcome as- Low risk Comment: blinding of outcome assessment was performed with the use of sessment (detection bias) placebo All outcomes Incomplete outcome data Low risk No losses to follow-up (attrition bias) All outcomes Selective reporting (re- Unclear risk Comment: the study protocol is not available, but it is clear that the published porting bias) reports include all expected outcomes. However, some outcomes are de- scribed in a narrative fashion and not per group. Quote: "... there was no observable toxic reaction to this new live vaccine preparation within the study design." (p 985) Other bias Unclear risk The sample size was not reported. There is no table with baseline characteris- tics of the participants. RCT: randomised controlled trial SD: standard deviation Characteristics of excluded studies [ordered by study ID] Study Reason for exclusion Abarca 2020 Phase I study - did not assess incidence of common cold, did not define common cold Ahmad 2022 Phase 2a - did not assess incidence of common cold Aliprantis 2018 Phase I study - did not assess incidence of common cold, did not define common cold Vaccines for the common cold (Review) 36 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews Study Reason for exclusion Aliprantis 2020 Phase I study - did not assess incidence of common cold, did not define common cold Ascough 2019 Phase I study - did not assess incidence of common cold, did not define common cold August 2017 Phase II study - did not assess incidence of common cold, did not define common cold Belshe 1982 Unknown phase - did not assess incidence of common cold, did not define common cold Belshe 1992 Unknown phase - did not assess incidence of common cold, did not define common cold Belshe 2004a Assessed lower respiratory tract infection Belshe 2004b Phase II study - did not assess incidence of common cold, did not define common cold Beran 2018 Phase II study - did not assess incidence of common cold, did not define common cold Bourne 1946 Assessed common cold symptoms caused by bacterial infections Cicconi 2020 Phase I - did not assess incidence of common cold Clements 1991 Wrong design, not RCT Cunningham 2019 Phase I study - did not assess incidence of common cold, did not define common cold DeVincenzo 2010 Wrong design, experimental infection DeVincenzo 2019 Duplicate record - conference abstract of Sadoff 2021a Doggett 1963 Wrong study design, not RCT Domachowske 2017 Assessed lower respiratory tract infection Domachowske 2018 Assessed lower respiratory tract infection Dudding 1972 Wrong design, not RCT Esposito 2019 Assessed common cold symptoms caused by bacterial infections EUCTR2008-001714-24-GB Phase I study - did not assess incidence of common cold EUCTR2012-001107-20-GB Phase II study - did not assess incidence of common cold, did not define common cold EUCTR2013-004036-30-GB Phase II study - did not assess incidence of common cold, did not define common cold EUCTR2014-005041-41-GB Phase II study - did not assess incidence of common cold, did not define common cold EUCTR2015-004296-77-GB Phase II study - did not assess incidence of common cold, did not define common cold EUCTR2016-000117-76-ES Phase I/II study - did not assess incidence of common cold, did not define common cold EUCTR2016-000117-76-PL Assessed lower respiratory tract infection EUCTR2016-001135-12-FR Phase II study - did not assess incidence of common cold, did not define common cold EUCTR2016-002733-30-ES Phase I/II study - did not assess incidence of common cold, did not define common cold Vaccines for the common cold (Review) 37 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews Study Reason for exclusion EUCTR2018-001340-62-FI Unknown phase - did not assess incidence of common cold, did not define common cold Falloon 2017a Phase I study - did not assess incidence of common cold, did not define common cold Falloon 2017b Phase II study - did not assess incidence of common cold, did not define common cold Falsey 1996 Unknown phase - did not assess incidence of common cold, did not define common cold Falsey 2008 Unknown phase - did not assess incidence of common cold, did not define common cold Fries 2019 Assessed lower respiratory tract infection Fulginiti 1969 Wrong study design, not RCT Glenn 2016 Assessed lower respiratory tract infection Gomez 2009 Assessed lower respiratory tract infection Gonzalez 2000 Unknown phase - did not assess incidence of common cold, did not define common cold Greenberg 2005 Phase II study - did not assess incidence of common cold, did not define common cold Hamory 1975 Wrong study design, not RCT Israel 2016 Unknown phase - did not assess incidence of common cold, did not define common cold Karppinen 2019 Assessed respiratory symptoms caused by bacterial infections Karron 1995a Phase I study - did not assess incidence of common cold, did not define common cold Karron 1995b Phase I study - did not assess incidence of common cold, did not define common cold Karron 1997 Wrong study design, not RCT Karron 2003 Wrong study design, not RCT Karron 2005 Unknown phase - did not assess incidence of common cold, did not define common cold Karron 2015 Phase I study - did not assess incidence of common cold, did not define common cold Karron 2020a Wrong study design, not RCT Karron 2020b Phase I study - did not assess incidence of common cold, did not define common cold Kumpu 2015 Assessed respiratory symptoms caused by bacterial infections Langley 2009 Unknown phase - did not assess incidence of common cold, did not define common cold Langley 2016 Duplicate record - clinical trial register of Langley 2018 Langley 2017 Assessed lower respiratory tract infection Langley 2018 Assessed lower respiratory tract infection Lee 2001 Did not assess incidence of common cold or vaccine safety Vaccines for the common cold (Review) 38 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews Study Reason for exclusion Lee 2004 Wrong study design, not RCT Leroux-Roels 2019 Assessed lower respiratory tract infection Lyons 2008 Phase I study - did not assess incidence of common cold, did not define common cold Madhi 2006 Unknown phase - did not assess incidence of common cold, did not define common cold Madhi 2020 Phase III - did not assess incidence of common cold, did not define common cold McFarland 2018 Unknown phase - did not assess incidence of common cold, did not define common cold McFarland 2020a Unknown phase - did not assess incidence of common cold, did not define common cold McFarland 2020b Unknown phase - did not assess incidence of common cold, did not define common cold Munoz 2003 Unknown phase - did not assess incidence of common cold, did not define common cold Munoz 2019 Phase II - did not assess incidence of common cold, did not define common cold Murphy 1994 Wrong study design, not RCT NCT00139347 Wrong intervention, this study assessed human rotavirus associated with gastroenteritis NCT00308412 Assessed lower respiratory tract infection NCT00345670 Assessed lower respiratory tract infection NCT00345956 Wrong intervention, this study assessed human rotavirus associated with gastroenteritis NCT00363545 Wrong intervention, this study assessed human rotavirus associated with gastroenteritis NCT00366782 Phase I - did not assess incidence of common cold, did not define common cold NCT00383903 Wrong intervention, this study assessed human rotavirus associated with gastroenteritis NCT00420316 Wrong intervention, this study assessed human rotavirus causing gastroenteritis NCT00496821 Duplicate record - clinical trial register of DeVincenzo 2010 NCT00641017 Phase I - did not assess incidence of common cold, did not define common cold NCT00686075 Did not assess incidence of common cold or vaccine safety NCT00767416 Phase I and II - did not assess incidence of common cold, did not define common cold NCT01021397 Phase I - did not assess incidence of common cold, did not define common cold NCT01139437 Phase I - did not assess incidence of common cold, did not define common cold NCT01254175 Phase I - did not assess incidence of common cold, did not define common cold NCT01290419 Phase I - did not assess incidence of common cold, did not define common cold NCT01475305 Terminated, and no results available Vaccines for the common cold (Review) 39 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews Study Reason for exclusion NCT01709019 Phase I - did not assess incidence of common cold, did not define common cold NCT01852266 Phase I - did not assess incidence of common cold, did not define common cold NCT01905215 Duplicate record - clinical trial register of Langley 2017 NCT02115815 Phase I - did not assess incidence of common cold, did not define common cold NCT02266628 Phase II - did not assess incidence of common cold, did not define common cold NCT02296463 Phase I - did not assess incidence of common cold, did not define common cold NCT02419391 Phase I - did not assess incidence of common cold, did not define common cold NCT02440035 Phase I - did not assess incidence of common cold, did not define common cold NCT02472548 Phase I - did not assess incidence of common cold, did not define common cold NCT02479750 Wrong intervention, not a vaccine NCT02491463 Phase I - did not assess incidence of common cold, did not define common cold NCT02561871 Phase I - did not assess incidence of common cold, did not define common cold NCT02593071 Assessed lower respiratory tract infection NCT02601612 Assessed lower respiratory tract infection NCT02624947 Duplicate record - clinical trial register of Madhi 2020 NCT02794870 Phase I - did not assess incidence of common cold, did not define common cold NCT02830932 Phase I - did not assess incidence of common cold, did not define common cold NCT02864628 Withdrawn, no reasons specified NCT02873286 Phase II - did not assess incidence of common cold, did not define common cold NCT02890381 Duplicate record - clinical trial register of Cunningham 2019 NCT02926430 Phase II - did not assess incidence of common cold, did not define common cold NCT02952339 Assessed lower respiratory tract infection NCT03026348 Phase II - did not assess incidence of common cold, did not define common cold NCT03049488 Phase I - did not assess incidence of common cold, did not define common cold NCT03191383 Withdrawn due to instability of the PreF antigen during manufacturing NCT03303625 Phase I and II - did not assess incidence of common cold, did not define common cold NCT03334695 Duplicate record - clinical trial register of Sadoff 2021a NCT03392389 Phase I - did not assess incidence of common cold, did not define common cold Vaccines for the common cold (Review) 40 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews Study Reason for exclusion NCT03403348 Phase I - did not assess incidence of common cold, did not define common cold NCT03473002 Duplicate record - clinical trial register of Scaggs 2020 NCT03572062 Terminated NCT03674177 Phase I - did not assess incidence of common cold, did not define common cold NCT03814590 Phase I and II - did not assess incidence of common cold, did not define common cold NCT04071158 Phase II - did not assess incidence of common cold, did not define common cold NCT04086472 Wrong study design, not RCT NCT04752644 Phase IIa - did not assess incidence of common cold NTR7173 Duplicate record - clinical trial register of Verdijk 2020 Paradiso 1994 Unknown phase - did not assess incidence of common cold, did not define common cold Philpott 2016 Duplicate record - conference abstract of Philpott 2017 Philpott 2017 Wrong intervention, study assessed influenza Piedra 1995 Unknown phase - did not assess incidence of common cold, did not define common cold Pierce 1968 Did not assess incidence of common cold or vaccine safety Power 2001 Unknown phase - did not assess incidence of common cold, did not define common cold Ritchie 1958 Wrong design, not RCT Ruckwardt 2021 Phase I - did not assess incidence of common cold Sadoff 2021a Phase II - did not assess incidence of common cold, did not define common cold Sadoff 2021b Phase II - did not assess incidence of common cold, did not define common cold Samy 2020 Phase I - did not assess incidence of common cold, did not define common cold Scaggs Huang 2021 Phase I - did not assess incidence of common cold, did not define common cold Schwarz 2019 Phase II - did not assess incidence of common cold, did not define common cold Shakib 2019 Did not assess incidence of common cold or vaccine safety Shaw 2019 Phase I - did not assess incidence of common cold, did not define common cold Simoes 2001 Wrong study design, not RCT Swamy 2019 Duplicate record - conference abstract of Madhi 2020 Tang 2008 Unknown phase - did not assess incidence of common cold, did not define common cold Top 1971 Did not assess incidence of common cold or vaccine safety Vaccines for the common cold (Review) 41 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews Study Reason for exclusion Tristram 1993 Assessed lower respiratory tract infection Van Der Plas 2020 Duplicate record - conference abstract of Verdijk 2020 Verdijk 2020 Phase I - did not assess incidence of common cold, did not define common cold Watt 1990 Wrong study design, not RCT Welliver 1994 Did not assess incidence of common cold or vaccine safety Williams 2020 Phase I - did not assess incidence of common cold, did not define common cold Wilson 1960 Wrong study design, not RCT Wright 1976 Wrong study design, not RCT Yu 2020 Did not assess incidence of common cold or vaccine safety RCT: randomised controlled trial Characteristics of ongoing studies [ordered by study ID] NCT01893554 Study name Evaluating the safety and immune response to a single dose of a respiratory syncytial virus (RSV) vaccine in infants and children Methods Randomised clinical trial; parallel assignment Participants 105 Interventions Biological: RSV ΔNS2 Δ1313 I1314L vaccine; other: placebo Outcomes Frequency and severity of vaccine-related solicited AEs; proportion of participants that develop 4- fold or greater rises in RSV neutralising antibody titre following vaccination Starting date June 2013 Contact information Jocelyn San Mateo; 410-614-4306; jsanmate@jhsph.edu Notes NCT03387137 Study name Evaluating the infectivity, safety, and immunogenicity of a respiratory syncytial virus vaccine (RSV 6120/∆NS2/1030s) in RSV-seropositive children and RSV-seronegative infants and children Methods Randomised clinical trial; parallel assignment Participants 45 Interventions Biological: RSV 6120/∆NS2/1030s; other: placebo Vaccines for the common cold (Review) 42 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews NCT03387137 (Continued) Outcomes Grades of: study product-related solicited AEs (RSV-seropositive participants); study product-re- lated solicited AEs (RSV-seronegative participants); study product-related unsolicited AEs (RSV- seropositive participants); study product-related unsolicited AEs (RSV-seronegative participants); study product-related SAEs (RSV-seropositive participants). Frequency of infection with: RSV (RSV- seropositive participants); with RSV (RSV-seronegative participants). Peak titre of vaccine virus shed (RSV-seropositive participants). Duration of virus shedding in nasal washes (RSV-seropositive participants). RSV-neutralising serum antibody titre (RSV-seropositive participants). IgG serum an- tibody titres to RSV F glycoprotein ELISA (RSV-seropositive participants) Starting date 13 October 2017 Contact information Ruth A Karron Notes NCT03422237 Study name Evaluating the infectivity, safety, and immunogenicity of the recombinant live-attenuated RSV vac- cines RSV ΔNS2/Δ1313/I1314L or RSV 276 in RSV-seronegative infants and children 6 to 24 months of age Methods Randomised clinical trial; parallel assignment Participants 80 Interventions Biological: RSV ΔNS2/Δ1313/I1314L; biological: RSV 276; other: placebo Outcomes Grades of: study product-related solicited AEs; product-related unsolicited AEs; product-related SAEs; number of participants infected with RSV; peak titre of vaccine virus shed; duration of virus shedding in nasal washes. Frequency of: ≥ 4-fold rise in RSV serum neutralising antibody titre; RSV neutralising antibody responses; ≥ 4-fold rise in serum antibody titres to RSV F glycoprotein; anti- body responses to RSV F glycoprotein Starting date 4 October 2017 Contact information Ruth A Karron Notes NCT03596801 Study name Evaluating the infectivity, safety and immunogenicity of respiratory syncytial virus vaccines, RSV 6120/∆NS1 and RSV 6120/F1/G2/∆NS1, in RSV-seropositive children and RSV-seronegative infants and children Methods Randomised clinical trial; parallel assignment Participants 75 Interventions Biological: RSV 6120/∆NS1; biological: RSV 6120/F1/G2/∆NS1; other: placebo Outcomes Grades of study product-related: solicited AEs; unsolicited AEs; SAEs. Frequency of infection with RSV. Peak titre of vaccine virus shed. Duration of virus shedding in nasal washes. Frequency of ≥ 4- Vaccines for the common cold (Review) 43 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews NCT03596801 (Continued) fold rise in RSV-neutralising antibody titre. Frequency of ≥ 4-fold rise in IgG antibody responses to RSV F glycoprotein. Frequency of symptomatic, medically attended respiratory and febrile illness in the RSV-seronegative (group 2) vaccine and placebo recipients who experience natural infec- tion with wt RSV during the RSV season. Severity of symptomatic, medically attended respiratory and febrile illness in the RSV-seronegative (group 2) vaccine and placebo recipients who experience natural infection with wt RSV during the RSV season. Frequency of antibody responses in the RSV- seronegative vaccine and placebo recipients who experience natural infection with wt RSV during the RSV season. Measurement of mucosal antibody titres to vaccine Starting date 25 June 2018 Contact information Kristi Herbert; 410-502-3333; kherber1@jhu.edu Notes NCT03916185 Study name Safety and immunogenicity of a single dose of the recombinant live-attenuated RSV vaccines RSV ΔNS2/Δ1313/I1314L, RSV 6120/ΔNS2/1030s, RSV 276 or placebo, delivered as nose drops to RSV- seronegative children 6 to 24 months of age Methods Randomised clinical trial; parallel assignment Participants 160 Interventions Biological: RSV ΔNS2/Δ1313/I1314L vaccine; RSV 6120/ΔNS2/1030s vaccine; RSV 276 vaccine; other: placebo Outcomes Primary: frequency of Grade 1 or higher solicited AEs [Time Frame: measured through Day 28]; frequency of Grade 2 or higher lower respiratory illnesses [Time Frame: measured through Day 28]; frequency of serious AEs [Time Frame: measured through Day 56]; frequency of ≥ 4-fold rise in serum RSV-neutralising antibody titre [Time Frame: measured through Day 56] Secondary: frequency of ≥ 4-fold rise in serum RSV F IgG [Time Frame: measured through Day 56]; titre of serum RSV F IgG [Time Frame: measured at the Day 56 visit]; titre of serum RSV-neutralis- ing antibodies [Time Frame: measured at the Day 56 visit]; frequency of RSV-MAARI [Time Frame: measured through the last day of the RSV season, which will occur between 5 and 12 months af- ter study entry, depending on when the participant enrolls in the study]; maximum grade (if more than 1 illness within a participant) of RSV-MAARI [Time Frame: measured through the last day of the RSV season, which will occur between 5 and 12 months after study entry, depending on when the participant enrolls in the study]; frequency of RSV-MAALRI [Time Frame: measured through the last day of the RSV season, which will occur between 5 and 12 months after study entry, depending on when the participant enrolls in the study]; maximum grade (if more than 1 illness within a partici- pant) of RSV-MAALRI [Time Frame: measured through the last day of the RSV season, which will oc- cur between 5 and 12 months after study entry, depending on when the participant enrolls in the study] Starting date 16 May 2019 Contact information Coleen Cunningham and Ruth Karron Notes Vaccines for the common cold (Review) 44 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews NCT04032093 Study name A phase 2B placebo-controlled, randomised study of a RSV vaccine in pregnant women Methods Randomised clinical trial; parallel assignment Participants 650 Interventions Biological: RSV vaccine; other: placebo Outcomes Percentage of participants reporting: local reactions and systemic events from day of vaccination (Day 1) until Day 7; AEs within 1 month after vaccination; obstetric complications, MAEs and SAEs throughout the study. Percentage of infant participants: with specific birth outcomes; with AE from birth to 1 month of age; with SAE, AE of special interest (congenital anomalies, developmental de- lay), and MAE through 12 months of age. Immune responses measured by RSV neutralising anti- body titres in maternal participants. Geometric mean ratio for RSV neutralising antibody titres in maternal participants Starting date 7 August 2019 Contact information Pfizer Notes NCT04126213 Study name Study of safety, reactogenicity and immunogenicity of GlaxoSmithKline's (GSK) respiratory syncy- tial virus (RSV) maternal unadjuvanted vaccine in healthy pregnant women (aged 18 to 40 years) and their infants Methods Randomised clinical trial; parallel assignment Participants 420 Interventions Biological: RSVPreF3 formulation 2; biological: RSVPreF3 formulation 3; other: placebo Outcomes Percentage of maternal participants reporting: solicited administration site events; solicited sys- temic events; with haematological and biochemical laboratory abnormality at baseline; with haematological and biochemical laboratory abnormality at Day 8; unsolicited AEs; at least 1 SAE; with AEs leading to study withdrawal; with at least 1 MAE; pregnancy outcomes; pregnancy-relat- ed AESIs; neonatal AESIs; at least 1 SAE; AEs leading to study withdrawal; at least 1 MAE. RSVPreF3 IgG-specific antibody concentration in terms of GMCs at Day 1, before vaccination for each group, and by age category. RSVPreF3 IgG antibody GMCs at Day 31. RSVPreF3 IgG antibody GMCs at de- livery. RSV-A neutralising antibody GMTs at Day 1, before vaccination. RSV-A neutralising antibody GMTs at Day 31. RSV-A neutralising antibody GMTs at delivery. RSVPreF3 IgG antibody GMCs in in- fants born to maternal participants. RSV-A neutralising antibody GMTs in infants born to maternal participants. Geometric mean ratio between cord blood and maternal RSVPreF3 IgG-specific anti- body concentrations Starting date 5 November 2019 Contact information GlaxoSmithKline Notes Vaccines for the common cold (Review) 45 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews NCT04138056 Study name A study of a vaccine against respiratory syncytial virus (RSV) when given alone and together with a vaccine against diphtheria, pertussis and tetanus (Tdap) viruses followed by a 2nd dose of the RSV vaccine to healthy non-pregnant women Methods Randomised clinical trial; parallel assignment Participants 509 Interventions Biological: RSVPreF3 formulation 3; biological: RSVPreF3 formulation 2; biological: Boostrix-ex-US; other: placebo Outcomes Percentage of participants with: at least 1 solicited local AE for each study group, after the 1st vac- cination; at least 1 solicited general AE for each study group, after the 1st vaccination. Percentage of participants with: any unsolicited AEs for each study group, after the 1st vaccination; at least 1 SAE for each study group, after the 1st vaccination; at least 1 solicited local AE for each study group, after the 2nd vaccination; at least 1 solicited general AE for each study group, after the 2nd vacci- nation; any unsolicited AEs for each study group, after the 2nd vaccination; at least 1 SAE for each study group, after the 2nd vaccination. Humoral immune response in terms of RSV A neutralising antibody GMTs for each group, at screening. RSV A neutralising antibody GMTs for each group at Day 8, after the 1st vaccination. RSV A neutralising antibody GMTs for each group at Day 31, after the 1st vaccination. Humoral immune response in terms of RSV PreF3 IgG antibody GMCs for each group, at screening. RSV PreF3 IgG GMCs for each group, at Day 8, after the 1st vaccination. RSV PreF3 IgG GMCs for each group, at Day 31, after the 1st vaccination Starting date 5 November 2019 Contact information GlaxoSmithKline Notes NCT04681833 Study name Safety and efficacy of BARS13 in the elderly Methods Randomised clinical trial; parallel assignment Participants 120 Interventions Drug: recombinant respiratory syncytial virus vaccine (BARS13)/placebo; drug: recombinant respi- ratory syncytial virus vaccine (BARS13); drug: placebo Outcomes Incidence and severity of vaccine-related AEs including the following solicited AEs; incidence and severity of vaccine-related AEs including the following solicited AEs; incidence and severity of vac- cine-related AEs including the following solicited AEs; occurrence of any SAE; occurrence of any clinically significant clinical laboratory abnormalities Starting date 24 May 2021 Contact information Xuefen Huai: +8618351991682; xuefenhuai@advaccine.com Alex Cheng: +86 17600221846; alexcheng@advaccine.com Notes Vaccines for the common cold (Review) 46 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews NCT04732871 Study name A phase 3, randomised, open-label, multi-country study to evaluate the immunogenicity, safety, re- actogenicity and persistence of a single dose of the RSVPreF3 OA investigational vaccine and differ- ent revaccination schedules in adults aged 60 years and above Methods Randomised clinical trial; parallel assignment Participants 1720 Interventions Biological: RSVPreF3 OA investigational vaccine Outcomes Humoral immune response in terms of RSV-A neutralising antibody GMTs; RSV-A neutralising anti- body GMTs; humoral immune response in terms of RSV-B neutralising antibody titres; humoral im- mune response in terms of RSV-B neutralising antibody titres; humoral immune response in terms of RSVPreF3 IgG antibody GMCs; humoral immune response in terms of RSV-A neutralising antibody GMTs; cell-mediated immune response in terms of frequency of RSVPreF3-specific cluster of dif- ferentiation (CD)4+ and/or CD8+ T cells expressing at least 2 activation markers; number of partic- ipants with at least 1 solicited administration-site event and solicited systemic event; number of participants with SAEs; number of participants with a fatal SAE, related SAE, and related pIMDs Starting date 15 February 2021 Contact information GlaxoSmithKline Notes NCT04980391 Study name A phase III, double-blind, randomised, placebo-controlled study to evaluate the safety, reacto- genicity and immune response of a single intramuscular dose of unadjuvanted RSV maternal vac- cine, in high-risk pregnant women aged 15 to 49 years and infants born to the vaccinated mother Methods Randomised clinical trial; parallel assignment Participants 353 Interventions Biological: RSV MAT; drug: placebo Outcomes Percentage of maternal participants reporting solicited administration site events; percentage of maternal participants reporting solicited systemic events; percentage of maternal participants reporting unsolicited AEs; percentage of maternal participants reporting SAEs, (S)AEs leading to study withdrawal, and medically attended adverse events; percentage of maternal participants re- porting pregnancy outcomes; percentage of maternal participants reporting pregnancy-related AESIs; humoral immune response in terms of RSV MAT IgG-specific antibody concentrations at pre- dosing (Day 1) for maternal participants; geometric mean ratio between cord blood and maternal RSV MAT IgG-specific antibody concentrations; humoral immune response in terms of RSV-A neu- tralising antibody titres at delivery for infant participants Starting date 3 August 2021 Contact information GlaxoSmithKline Notes Vaccines for the common cold (Review) 47 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews NCT05127434 Study name A phase 2/3, randomised, observer-blind, placebo-controlled study to evaluate the safety and ef- ficacy of mRNA-1345, an mRNA vaccine targeting respiratory syncytial virus (RSV), in adults ≥ 60 years of age Methods Randomised clinical trial; parallel assignment Participants 34,000 Interventions mRNA-1345; placebo Outcomes Number of participants with solicited local and systemic adverse reactions up to 7 days postinjec- tion; number of participants with unsolicited AEs up to 28 days postinjection; number of partici- pants with medically attended AEs, AESIs, SAEs, and AEs leading to withdrawal up to 24 months postinjection; VE of mRNA-1345 to prevent a first episode of RSV-LRTD within the period of 14 days postinjection up to 12 months postinjection; VE of mRNA-1345 to prevent RT-PCR confirmed pro- tocol-defined RSV-LRTD, defined as 100*(1 − RR), where RR is the ratio of attack rates in the mR- NA-1345 group and the placebo group; VE of mRNA-1345 to prevent a first episode of RSV-ARD with- in the period of 14 days postinjection up to 12 months postinjection; VE of mRNA-1345 to prevent RT-PCR confirmed protocol-defined RSV-ARD, defined as 100*(1 − RR), where RR is the ratio of at- tack rates in the mRNA-1345 group and the placebo group; VE of mRNA-1345 to prevent hospital- isations associated with RSV-ARD or RSV-LRTD within the period of 14 days postinjection up to 12 months postinjection; VE of mRNA-1345 to prevent RT-PCR confirmed protocol-defined RSV-ARD or RSV-LRTD, defined as 100*(1 − RR), where RR is the ratio of attack rates in the mRNA-1345 group and the placebo group; GMT of serum RSV neutralising and binding antibodies (Abs); geometric mean fold-rise of postbaseline/baseline Ab titres; proportion of participants with ≥ 4-fold increases in Ab titres from baseline Starting date 17 November 2021 Contact information Moderna Clinical Trials Support Center: 1-877-777-7187; clinicaltrials@modernatx.com Notes NCT05238025 Study name A randomised, double-blind, phase 3 trial to assess clinical efficacy, safety and reactogenicity of the recombinant MVA-BN® -RSV vaccine in adults ≥ 60 years of age Methods Randomised clinical trial; parallel assignment Participants 20,000 Interventions Biological: MVA-BN-RSV vaccine; biological: Tris buffered saline Outcomes Occurrence of LRTD; occurrence of ARD; occurrence of any SAEs; occurrence of complications and hospitalisations; occurrence of any grade 3 or higher adverse events; RSV-specific T-cell responses; RSV-specific serum neutralising antibody titres; RSV-specific serum IgG antibody titres; occurrence of solicited systemic adverse events Starting date April 2022 Contact information Heinz Weidenthaler: 004989255446 ext 300; hwe@bavarian-nordic.com Notes Vaccines for the common cold (Review) 48 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews AEs: adverse events AESIs: adverse events of special interest ARD: acute respiratory disease ARs: adverse reactions CS: clinically significant ELISA: enzyme-linked immunosorbent assay GMCs: geometric mean concentrations GMTs: geometric mean titres IgG: immunoglobulin G LRTD: lower respiratory tract disease MAE: medically attended adverse event pIMDs: potential immune-mediated disorders RSV: respiratory syncytial virus RSV-ARD: respiratory syncytial virus-associated acute respiratory disease RSV-LRTD: respiratory syncytial virus-associated lower respiratory tract disease RSV-MAARI: respiratory syncytial virus-associated medically attended acute respiratory illness RSV-MAALRI: respiratory syncytial virus-associated medically attended acute lower respiratory illness RT-PCR: reverse transcription polymerase chain reaction SAEs: serious adverse events Tdap: diphtheria, pertussis, and tetanus VE: vaccine efficacy wt RSV: wild-type respiratory syncytial virus DATA AND ANALYSES Comparison 1. Adenovirus vaccines versus placebo Outcome or subgroup title No. of studies No. of partici- Statistical method Effect size pants 1.1 Incidence of the common cold 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only Analysis 1.1. Comparison 1: Adenovirus vaccines versus placebo, Outcome 1: Incidence of the common cold Vaccines Placebo Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total M-H, Fixed, 95% CI M-H, Fixed, 95% CI Griffin 1970 13 1139 14 1168 0.95 [0.45 , 2.02] Test for subgroup differences: Not applicable 0.01 0.1 1 10 100 Favours vaccines Favours placebo APPENDICES Appendix 1. Glossary Term Definition Reference Vaccines for the common cold (Review) 49 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews (Continued) Common cold The common cold is a self-limiting acute upper respiratory tract infection char- Heikkinen 2003 acterised by rhinorrhoea, nasal congestion, sneezing, cough, sore throat, fever, and malaise. Vaccination Inoculation with a vaccine, i.e. a preparation of microbial antigen often com- Abbas 2001 bined with adjuvants administered to an individual in order to induce protec- tive immunity against microbial infections. The antigen may be in the form of live, avirulent micro-organisms or purified macromolecular components of mi- cro-organisms. Immune system The collection of cells, tissues, and molecules that mediate resistance to infec- Abbas 2001 tions Cell-mediated immu- The arm of the adaptative immune response whose role is to combat infec- Abbas 2001 nity tions by intracellular microbes. This type of immunity is mediated by T lym- phocytes. Antigenical variability Microbes have evolved mechanisms to evade immunity. Many bacteria and Abbas 2001 viruses mutate their antigenic surface molecules and can no longer be recog- nised by antibodies produced in response to previous infection. Serotypes An antigenically distinct subset of a species of an infectious organism that is Abbas 2001 distinguished from other subsets by serologic (i.e. serum antibody) tests. Hu- moral immune response to one serotype of microbes, e.g. influenza virus, may not be protective against another serotypes. Immune responses Once a foreign organism has been recognised, the immune system enlists the Goldsby 2000 participation of a variety of cells and molecules to mount an appropriate re- sponse in order to eliminate or neutralise the organism. Antigenic molecules Any molecule capable of being recognised by an antibody or T-cell receptor. Goldsby 2000; Roitt Any substance that elicits an immune response 2004 Allergens An antigen that elicits an immediate hypersensitivity (allergic) reaction. Aller- Abbas 2001 gens are proteins, or chemicals bound to proteins, that induce immunoglobu- lin E antibody production in atopic individuals. Immunopotentiation Non-specific immunostimulation given by various agents that can stimulate Gorczynski 2007 the immune response. It is believed that the mechanism of action is through some modification of local cytokines or growth of innate immune mecha- nisms. An increase in the functional capacity of the immune response Opsonisation The process by which particulate antigens are rendered more susceptible to Abbas 2001; Goldsby phagocytosis 2000 The process of attaching opsonins, such as immunoglobulin G or complement fragments, to microbial surfaces to target microbes for phagocytosis Phagocytosis Macrophages are capable of ingesting and digesting exogenous antigens, such Abbas 2001; Goldsby as whole micro-organisms and insoluble particles, and endogenous matter, 2000 such as injured or dead host cells, cellular debris, and activated clotting fac- tors. The process by which certain cells of the innate immune system, including macrophages and neutrophils, engulf large particles (> 0.5-micrometre diam- eter), such as intact microbes. The cell surrounds the particle by a cytoskele- Vaccines for the common cold (Review) 50 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews (Continued) ton-dependent process, leading to formation of an intracellular vesicle called a phagosome, which contains the ingested particle. Appendix 2. Differences between clinical characteristics of the common cold and influenza Feature Common cold Influenza References Aetiological agent > 100 viral strains; rhinovirus 3 strains of influenza virus: influenza A, B, C Czubak 2021; most common DDCP 2010; Gwalt- Site of infection Upper respiratory tract Entire respiratory system ney 1967; Gwaltney 2000; Symptom onset Gradual: 1 to 3 days Sudden: within a few hours Heikkinen 2003; Fever, chills Occasional, low grade (< 100 ºF) Fever is usually present with the flu (up to 80% of Roxas 2007; all flu cases). A temperature of 100 ºF or higher for 3 Thompson 2003 to 4 days is typically associated with the flu. Headache Frequent, usually mild Characteristic, more severe General aches, Mild, if any Characteristic, often severe and affecting the entire pains body Cough, chest con- Mild to moderate, with hacking Common, may become severe gestion cough Sore throat Common, usually mild Sometimes present Runny, stuffy nose Very common, accompanied by Sometimes present bouts of sneezing Fatigue, weakness Mild, if any Usual, may be severe and last 2 to 3 weeks Extreme exhaustion Never Frequent, usually in early stages of illness Season Year around, peaks in winter Most cases between November and February months Antibiotics helpful No, unless secondary bacterial No, unless secondary bacterial infection develops infection develops Appendix 3. Viral causes of the common cold Virus Estimated annual proportion of cases References Rhinoviruses 30% to 50%; during autumn 80%. Once considered to be limited to the upper Arruda 1997; Gwalt- airway, now recognised as an important cause of lower respiratory infections ney 1985; Heikkinen 2003; Lemanske 2005; Mäkelä 1998; Monto 1993; Regamey 2008 Vaccines for the common cold (Review) 51 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews (Continued) Coronaviruses 7% to 18% in adults with upper respiratory infections. Responsible for 2.1% of Larson 1980; Lau 2006; hospital admissions for acute respiratory tract infections in all age groups Mäkelä 1998; Nicholson 1997 Influenza viruses 5% to 15% Heikkinen 2003 Respiratory syncytial In low-income countries, 15% to 20% Berman 1991; Falsey virus (RSV) 2005; Thompson 2003 In hospital the proportion of children aged between birth and 5 months with RSV acute lower respiratory tract infections ranged between 9% and 87%. Amongst children up to at least 5 years of age reported with RSV, on average 39% (range 20% to 62%) were < 6 months old; on average 24% of cases (range 14% to 38%) were children aged 6 to 11 months, thus an average of 63% of children were under 1 year of age. On average 20% (range 13% to 29%) of chil- dren were between 1 and 2 years of age. RSV accounts for approximately 10,000 deaths annually in people over the age of 65 years in the USA. RSV in adults, 5% infection annually Parainfluenza viruses Acute respiratory infections cause 3% to 18% of all admissions to paediatric Berman 1991; Denny hospitals; however, this might vary at different times of the year. 1983; Henrickson 2003 Parainfluenza viruses account for 17% of hospitalised illness-associated virus isolation. In low-income countries, 7% to 10% Parainfluenza viruses cause 50% to 74.2% of croup cases. Adenoviruses In low-income countries, 2% to 4% Berman 1991 Metapneumovirus 10% short epidemic Esper 2003; Kahn 2003; Nissen 2002; Risnes 2005 Unknown 20% to 30% Mäkelä 1998; Monto 1993 Appendix 4. CENTRAL search strategy #1 mh "Common Cold" #2 "common cold*":ti,ab #3 "coryza":ti,ab #4 (acute near/5 ("upper respiratory infection*" or "upper respiratory tract infection*" or urti or uri)):ti,ab #5 mh "Picornaviridae Infections" #6 mh Rhinovirus #7 rhinovir* #8 "hrv":ti,ab #9 mh "Paramyxoviridae Infections" Vaccines for the common cold (Review) 52 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews #10 mh "parainfluenza virus 1, human" or mh "parainfluenza virus 3, human" #11 mh "parainfluenza virus 2, human" or mh "parainfluenza virus 4, human" #12 "parainfluenza*":ti,ab #13 mh coronavirus or mh "coronavirus 229e, human" or mh "coronavirus oc43, human" #14 mh "Coronavirus Infections" #15 coronavir* #16 mh adenoviridae or mh "adenoviruses, human" #17 mh adenoviridae or mh "adenoviruses, human" #18 adenovir* #19 mh "respiratory syncytial viruses" or mh "respiratory syncytial virus, human" #20 mh "Respiratory Syncytial Virus Infections" #21 ("respiratory syncytial virus*" or rsv):ti,ab #22 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 #23 mh Vaccines #24 mh Vaccination #25 (vaccin* or inocul* or immuni*):ti,ab #26 #23 or #24 or #25 #27 #22 and #26 with Cochrane Library publication date Between Sep 2016 and April 2022 Appendix 5. MEDLINE (Ovid) search strategy 1 Common Cold/ 2 common cold*.tw. 3 coryza.tw. 4 (acute adj5 (upper respiratory infection* or upper respiratory tract infection* or urti or uri)).tw. 5 Picornaviridae Infections/ 6 Rhinovirus/ 7 rhinovir*.tw. 8 hrv.tw. 9 Paramyxoviridae Infections/ 10 parainfluenza virus 1, human/ or parainfluenza virus 3, human/ 11 parainfluenza virus 2, human/ or parainfluenza virus 4, human/ 12 parainfluenza*.tw. 13 coronavirus/ or coronavirus 229e, human/ or coronavirus oc43, human/ 14 Coronavirus Infections/ 15 coronavir*.tw. 16 exp adenoviridae/ or adenoviruses, human/ Vaccines for the common cold (Review) 53 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews 17 Adenovirus Infections, Human/ 18 adenovir*.tw. 19 respiratory syncytial viruses/ or respiratory syncytial virus, human/ 20 Respiratory Syncytial Virus Infections/ 21 (respiratory syncytial virus* or rsv).tw. 22 or/1-21 23 exp Vaccines/ 24 exp Vaccination/ 25 (vaccin* or inocul* or immuni*).tw. 26 or/23-25 (724637) 27 randomized controlled trial.pt. 28 controlled clinical trial.pt. 29 randomi?ed.ab. 30 placebo.ab. 31 drug therapy.fs. 32 randomly.ab. 33 trial.ab. 34 groups.ab. 35 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 36 exp animals/ not humans.sh. 37 35 not 36 38 22 and 26 and 37 39 limit 38 to dt=20160901-20220426 Appendix 6. Embase (Elsevier) search strategy #28 #27 AND (2016:py OR 2017:py OR 2018:py OR 2019:py OR 2020:py OR 2021:py OR 2022:py) #27 #23 AND #26 #26 #24 OR #25 #25 random*:ab,ti OR placebo*:ab,ti OR factorial*:ab,ti OR crossover*:ab,ti OR 'cross over':ab,ti OR 'cross-over':ab,ti OR volunteer*:ab,ti OR assign*:ab,ti OR allocat*:ab,ti OR (((singl* OR doubl*) NEAR/1 blind*):ab,ti) #24 'randomized controlled trial'/exp OR 'single blind procedure'/exp OR 'double blind procedure'/exp OR 'crossover procedure'/exp #23 #18 AND #22 #22 #19 OR #20 OR #21 #21 'vaccination'/de #20 vaccin*:ab,ti OR immuni*:ab,ti OR inocul*:ab,ti #19 'vaccine'/exp Vaccines for the common cold (Review) 54 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews #18 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 #17 'respiratory syncytial virus':ab,ti OR 'respiratory syncytial viruses':ab,ti OR rsv:ab,ti #16 'respiratory syncytial pneumovirus'/de OR 'respiratory syncytial virus infection'/de #15 adenovir*:ab,ti #14 'adenovirus'/exp OR 'human adenovirus infection'/de #13 coronavir*:ab,ti #12 'coronavirus'/de OR 'coronavirus infection'/de #11 parainfluenza*:ab,ti #10 'parainfluenza virus 1'/de OR 'parainfluenza virus 2'/de OR 'parainfluenza virus 3'/de OR 'parainfluenza virus4'/exp #9 'parainfluenza virus'/exp #8 'paramyxovirus infection'/de #7 rhinovir*:ab,ti OR hrv:ab,ti #6 'rhinovirus infection'/de OR 'human rhinovirus'/de #5 coryza:ab,ti #4 'acute upper respiratory infection':ab,ti OR 'acute upper respiratory infections':ab,ti OR 'acute upper respiratory tract infection':ab,ti OR 'acute upper respiratory tract infections':ab,ti OR ((acute NEAR/5 (urti OR uri)):ab,ti) #3 'viral upper respiratory tract infection'/de OR 'upper respiratory tract infection'/de #2 'common cold':ab,ti OR 'common colds':ab,ti #1 'common cold'/de OR 'common cold symptom'/de Appendix 7. CINAHL (EBSCO) search strategy S34 S23 AND S33 Limiters - Published Date: 20160101-20220426 S33 S24 OR S25 OR S26 OR S27 OR S28 OR S29 OR S30 OR S31 OR S32 S32 (MH "Quantitative Studies") S31 TI placebo* or AB placebo* S30 (MH "Placebos") S29 TI random* or AB random* S28 TI (singl* mask* or doubl* mask* or tripl* mask* or trebl* mask*) or AB (singl* mask* or doubl* mask* or tripl* mask* or trebl* mask*) S27 TI (singl* blind* or doubl* blind* or trebl* blind* or tripl* blind*) or AB (singl* blind* or doubl* blind* or trebl* blind* or tripl* blind*) S26 TI clinic* w1 trial* or AB clinic* w1 trial* S25 PT clinical trial S24 (MH "Clinical Trials+") S23 S18 AND S22 S22 S19 OR S20 OR S21 S21 TI (vaccin* or immuni* or inocula*) or AB (vaccin* or immuni* or inocula*) S20 (MH "Immunization") Vaccines for the common cold (Review) 55 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews S19 (MH "Vaccines+") S18 S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 S17 TI (respiratory syncytial virus* or rsv ) or AB (respiratory syncytial virus* or rsv) S16 (MH "Respiratory Syncytial Virus Infections") S15 (MH "Respiratory Syncytial Viruses") S14 TI adenovir* or AB adenovir* S13 TI coronavir* or AB coronavir* S12 (MH "Coronavirus+") S11 (MH "Coronavirus Infections") S10 TI parainfluenza* or AB parainfluenza* S9 (MH "Paramyxovirus Infections") S8 (MH "Paramyxoviruses") S7 TI hrv or AB hrv S6 TI rhinovir* or AB rhinovir* S5 (MH "Picornavirus Infections") S4 TI (upper respiratory tract infection* or upper respiratory infection*) or AB (upper respiratory tract infection* or upper respiratory infection*) S3 TI coryza or AB coryza S2 TI common cold* or AB common cold* S1 (MH "Common Cold") Appendix 8. LILACS (BIREME) search strategy ((mh:"Common Cold" OR "common cold" OR "common colds" OR coryza OR "Resfriado Común" OR "Resfriado Comum" OR "Coriza Aguda" OR "Upper Respiratory Tract Infections" OR "upper respiratory tract infection" OR "Infecciones del Tracto Respiratorio Superior" OR "Infecciones de las Vías Respiratorias Superiores" OR "Infecções do Trato Respiratório Superior" OR "Infecções das Vias Respiratórias Superiores" OR "Infecções das Vias Aéreas Superiores" OR "Infecções do Sistema Respiratório Superior" OR mh:"Picornaviridae Infections" OR "Infecciones por Picornaviridae" OR "Infecções por Picornaviridae" OR "Picornavirus Infections" OR mh:rhinovirus OR rhinovir* OR "Virus de la Coriza" OR "Virus del Resfriado Común" OR "Vírus da Coriza" OR "Vírus do Resfriado Comum" OR hrv OR mh:"Paramyxoviridae Infections" OR parainfluenza* OR mh:"Parainfluenza Virus 1, Human" OR mh:"Parainfluenza Virus 2, Human" OR mh:"Parainfluenza Virus 3, Human" OR mh:"Parainfluenza Virus 4, Human" OR mh:"Coronavirus Infections" OR coronavir* OR mh:coronavirus OR mh:"Coronavirus 229E, Human" OR mh:"Coronavirus OC43, Human" OR mh:"Coronavirus NL63, Human" OR mh:adenoviridae OR mh:"Adenoviruses, Human" OR mh:"Adenovirus Infections, Human" OR adenovir* OR mh:"Respiratory Syncytial Viruses" OR "Virus Sincitiales Respiratorios" OR "Vírus Sinciciais Respiratórios" OR "Virus Sincitial Respiratorio" OR "Vírus Sincicial Respiratório" OR mh:"Respiratory Syncytial Virus, Human" OR "respiratory syncytial virus" OR "Virus Humano Respiratorio Sincitial" OR mh:"Respiratory Syncytial Virus Infections" OR "Infecciones por Virus Sincitial Respiratorio" OR "Infecções por Vírus Respiratório Sincicial" OR rsv) AND (mh:vaccines OR vaccin* OR vacunas OR vacinas OR mh:d20.215.894* OR mh:vaccination OR vacunación OR vacinação OR mh:"Mass Vaccination" OR mh:immunization OR inmunización OR imunização OR mh:e02.095.465.425.400* OR mh:e05.478.550* OR mh:n02.421.726.758.310* OR mh:n06.850.780.200.425* OR mh:n06.850.780.680.310* OR mh:sp2.026.182.113* OR mh:sp8.946.819.838* OR immuni* OR inmuni* OR imuni*) ) AND ( db:("LILACS") AND type_of_study:("clinical_trials")) AND (year_cluster:[2016 TO 2022]) WHAT'S NEW Date Event Description 26 April 2022 New search has been performed We did not identify any new trials for inclusion in this update. We excluded 109 new studies and identified 13 ongoing studies. We Vaccines for the common cold (Review) 56 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews Date Event Description recruited two new authors to update this review, and one of the previous review authors did not take part in this update. 26 April 2022 New citation required but conclusions Our conclusions remain unchanged. have not changed HISTORY Protocol first published: Issue 3, 2000 Review first published: Issue 6, 2013 Date Event Description 2 September 2016 New citation required but conclusions We recruited three new authors to update this review. have not changed 2 September 2016 New search has been performed We updated our searches and excluded three new trials (Glenn 2016; Karron 2015; Kumpu 2015). 22 January 2015 New search has been performed Searches conducted. 16 March 2011 New citation required and major Protocol taken over by a new team of review authors. changes 26 February 2009 Amended Protocol withdrawn (Issue 3, 2009). CONTRIBUTIONS OF AUTHORS 1. Conceiving the review: DSR 2. Designing the review: DSR, CVG, MLF, RH 3. Co-ordinating the review: DSR, CMG 4. Data collection for the review: DBG, CMG 5. Screening search results: MLF, MJMZ, CMG, DBG 6. Appraising quality of papers: DSR, CVG, RH, MJMZ 7. Extracting data from papers: DSR 8. Writing to authors of papers for additional information: CMG 9. Obtaining and screening data on unpublished studies: MLF, MJMZ 10.Data management for the review: DSR 11.Entering data into Review Manager 5: DSR, MJMZ 12.Interpretation of data: all authors 13.Providing a methodological perspective: MJMZ, DBG, CMG, DSR 14.Providing a clinical perspective: CVG, MLF, RH 15.Writing the review: CMG, DBG, MJMZ, DSR 16.All authors contributed to the improvement of this updated review and approved the final version of the review. DECLARATIONS OF INTEREST Camila Montesinos-Guevara: declared that they have no conflict of interest. Diana Buitrago-Garcia: declared that they have no conflict of interest. Maria L Felix: declared that they have no conflict of interest. Claudia V Guerra: declared that they have no conflict of interest. Vaccines for the common cold (Review) 57 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews Ricardo Hidalgo: declared that they have no conflict of interest. Maria José Martinez-Zapata: declared that they have no conflict of interest. Daniel Simancas-Racines: declared that they have no conflict of interest. SOURCES OF SUPPORT Internal sources • Cochrane Ecuador, Ecuador Methodological • Centro de Investigación en Salud Pública y Epidemiología Clínica (CISPEC). Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE., Ecuador Methodological External sources • Instituto de Salud Carlos III, Spain Mª José Martinez Zapata is funded by a Miguel Servet research contract from the Instituto de Salud Carlos III (CPII20/00023). DIFFERENCES BETWEEN PROTOCOL AND REVIEW 2022 update: 1. Two new authors contributed to the 2022 update: Diana Buitrago-Garcia and Camila Montesinos-Guevara. 2. Changes to outcomes: We split the outcome of mortality into: 1) due to all causes, and 2) vaccine related. 3. Studies' search and selection: We used Cochrane’s Screen4Me workflow to help assess the initial search results. We only included randomised controlled trials that reported data on the incidence of common cold, thus we excluded early-phase studies which did not assess the incidence of common cold. 4. Unit of analysis issues: In future updates in which multi-arm studies are included, differences between the study arms should be explored, compared to placebo. If no differences are found, data of all active arms should be pooled and compared with a placebo. If differences are found in one arm, results should be compared separately with placebo. In addition, for future updates with cluster- randomised controlled trials, if the sample size has been adequately calculated, data should be pooled using the generic inverse- variance approach. If sample size is incorrect, ‘effective sample size’ should be calculated following the recommendations in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021). 5. Dealing with missing data: In future updates, we will undertake a complete-case analysis and an intention-to-treat analysis in the case of available data, or perform multiple imputation methods if needed. If numerical outcome data are missing, such as standard deviations or correlation coefficients, and these could not be obtained from the authors, we will calculate them from other available statistics such as P values, following the methods in the Cochrane Handbook for Systematic Reviews of Interventions. 6. Assessment of heterogeneity: If in future updates we identify substantial heterogeneity as per the Cochrane Handbook (50% to 90%), we will explore this by performing a prespecified subgroup analysis (Higgins 2022). 7. Subgroup analysis and investigation of heterogeneity: Due to the limited number of included studies, we do not plan to perform a meta- regression in the future. 8. Sensitivity analysis: In future updates, we will perform a sensitivity analysis comparing parallel randomised clinical trials versus cluster- randomised clinical trials. 2016 update: 1. Three new authors contributed to the 2016 update: Juan VA Franco, Maria L Felix, and Maria José Martinez-Zapata. 2. We considered risk of bias for blinding as unclear in the 2013 publication of this review. In the 2016 update, we reassessed this as low because the study used a placebo. 3. We added two additional primary outcomes, vaccine safety and vaccine-related mortality, to the summary of findings table. 2014 update: 1. We did not search Scirus for this update as the service became unavailable in 2014. Vaccines for the common cold (Review) 58 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration. Cochrane Trusted evidence. Informed decisions. Library Better health. Cochrane Database of Systematic Reviews INDEX TERMS Medical Subject Headings (MeSH) *Adenovirus Vaccines [adverse effects]; *Common Cold [prevention & control]; Incidence; Randomized Controlled Trials as Topic; Systematic Reviews as Topic; Vaccines, Attenuated [adverse effects] MeSH check words Child; Humans; Male Vaccines for the common cold (Review) 59 Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.