Infection and Drug Resistance Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW A Vaccine Against Group B Streptococcus: Recent Advances This article was published in the following Dove Press journal: Infection and Drug Resistance 1,2 Abstract: Group B streptococcus (GBS) causes a high burden of neonatal and infant disease Clara Carreras-Abad 1 globally. Implementing a vaccine for pregnant women is a promising strategy to prevent Laxmee Ramkhelawon Paul T Heath 1 neonatal and infant GBS disease and has been identified as a priority by the World Health Kirsty Le Doare 1,3,4 Organisation (WHO). GBS serotype-specific polysaccharide – protein conjugate vaccines are at advanced stages of development, but a large number of participants would be required to 1 Paediatric Infectious Diseases Research undertake Phase III clinical efficacy trials. Efforts are therefore currently focused on estab- Group and Vaccine Institute, Institute for Infection and Immunity, St George’s, lishing serocorrelates of protection in natural immunity studies as an alternative pathway for University of London, London, UK; licensure of a GBS vaccine, followed by Phase IV studies to evaluate safety and effective- 2 Department of Paediatrics, Obstetrics and Gynecology and Preventive Medicine ness. Protein vaccines are in earlier stages of development but are highly promising as they and Public Health, Universitat Autònoma might confer protection irrespective of serotype. Further epidemiological, immunological de Barcelona, Barcelona, Spain; 3Pathogen and health economic studies are required to enable the vaccine to reach its target population Immunity Group, Public Health England, Porton Down,UK; 4Medical Research as soon as possible. Council/Uganda Virus Research Institute Keywords: Group B streptococcus, Streptococcus agalactiae, maternal vaccines, maternal and London School of Hygiene and immunisation, neonatal sepsis, infant sepsis Tropical Medicine, Uganda Research Unit, Entebbe, Uganda Introduction Group B streptococcus (GBS) is a leading cause of neonatal and infant sepsis and meningitis globally.1–3 GBS can also cause stillbirths, prematurity and disease in pregnant women, immunocompromised adults and the elderly but the highest incidence of disease is in neonates and young infants.4 A systematic review and meta-analysis conducted in 2017 estimated a global incidence of invasive infant GBS disease of 0.49 (95%Cl 0.43–0.56) per 1000 live births.5 In 2015, GBS was estimated to have caused 319,000 cases of invasive neonatal GBS disease globally, resulting in 90,000 deaths.3 Serotypes Ia, Ib, II, III and V account for 98% of all rectovaginal colonisation in pregnant women worldwide.6 The most frequent GBS serotype causing disease in infants is serotype III (61.5%) followed by Ia (19.1%), V (6.7%) and Ib (5.7%).5 However, the fulminating nature of disease during the first hours of life and the technical difficulties in making an etiological diagnosis in many low- and middle-income settings means that this might represent a significant underestimation of the true Correspondence: Clara Carreras-Abad Paediatric Infectious Diseases Research GBS disease burden.7 Epidemiological data on the burden of GBS disease, espe- Group, Institute for Infection and cially from African countries, where most infant deaths from all-cause sepsis occur, Immunity, St George’s, University of London, Jenner Wing, Level 2 Mailpoint is urgently required.7 Infant mortality estimates are seven times higher in WHO J2C, Cranmer Terrace, London SW17 African region (51 per 1000 live births) compared to WHO European region (7 per 0RE, UK Email ccarrera@sgul.ac.uk 1000 live births).8 submit your manuscript | www.dovepress.com Infection and Drug Resistance 2020:13 1263–1272 1263 DovePress © 2020 Carreras-Abad et al. 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Carreras-Abad et al Dovepress Intrapartum Antibiotic Prophylaxis (IAP) has reduced rationale has been used to investigate new vaccines against the incidence of early onset disease (EOD, occurring common infections, such as respiratory syncytial virus from day 0 to 6 of life) in many countries using these (RSV) and GBS.20 A major characteristic of these new strategies, especially those that screen all pregnant women vaccines is that they are being specifically designed for for GBS rectovaginal colonisation during late pregnancy pregnant women.20 and give IAP to all GBS-colonised women regardless of presenting risk factors.9,10 However, IAP coverage is Vaccine Development: Overview of incomplete even in the best of settings,11 has no impact Current Efforts on late onset disease (LOD, occurring from day 7 to 90 of During the 2015 World Health Organisation (WHO) life), stillbirths and prematurity due to GBS, as well as Product Development for Vaccines Advisory Committee a limited impact on disease in pregnant women.10,12 meeting, GBS was identified as a high priority for the Widespread IAP use might also be an issue in the context development of a vaccine for maternal immunisation of international efforts to control antimicrobial resistance. because of the major public health burden posed by GBS Furthermore, antibiotics might have an effect on the infant in low- and middle-income countries (LMIC), and the high gut flora. Effects of early life events on the neonatal technical feasibility for successful development.21 Recent microbiome have been associated with increased rates of estimates suggest that an effective GBS maternal vaccine allergy, asthma and obesity.13–15 (>80% efficacy), with high (90%) global coverage, could prevent 231,000 infant and maternal GBS cases, 41,000 Novel Features of a Maternal stillbirths and 66,000 infant deaths annually.3 Vaccine for GBS Evidence suggests that maternal immunisation with A suitable vaccine against GBS given to pregnant women protein-conjugated GBS capsular polysaccharides may could provide effective protection to those forms of inva- reduce the disease risk in neonates and young infants in sive disease that cannot be prevented with IAP or where a serotype-specific manner.22–24 In addition, as there are IAP is not feasible or is incomplete. Furthermore, proteins that can be present in different serotypes, protein- a vaccine would be more easily accessible than GBS based vaccines have the potential to provide protection culture in all settings and would avoid the need for anti- across the serotype spectrum. These are also under microbial administration, avoiding the potential negative evaluation.25,26 Table 1 summarizes the development sta- consequences of IAP in the long term. tus of current vaccine candidates. Maternal immunisation is already a successful tool to prevent tetanus,16 influenza17 and pertussis18 in young Capsular Polysaccharide Conjugate infants. The placental transfer of maternal antibodies Vaccines from mother to infant reduces the window of susceptibility A number of virulence factors expressed by GBS are to infections during the first months of life.19 This same involved in colonisation, adherence, invasion and immune Table 1 Summary of Different Vaccine Candidates Vaccine Candidate Preclinical Phase I Phase II Trials in Pregnant Women Phase III Monovalent and bivalent conjugates (tetanus toxoid/ x x x x CRM197-CPS) Trivalent CRM197-CPS conjugates x x x x Hexavalent CRM197-CPS conjugates x x x x N-terminal domains of the Rib and AlphaC proteins x x Pilus proteins x Other proteins x Biotinylated CPS conjugates x submit your manuscript | www.dovepress.com Infection and Drug Resistance 2020:13 1264 DovePress Dovepress Carreras-Abad et al evasion27–29 and these could be used as potential vaccine aim to cover at least 98% of GBS isolates causing neonatal candidates. One of the most well-studied virulence factors of invasive disease (NCT03170609).5,54 In order to verify the GBS is its unique sialic acid-rich capsular polysaccharide clinical safety and immunogenicity of this hexavalent vac- (CPS) which inhibits complement deposition and protects the cine, further clinical trials will be required. Currently, bacteria from opsonophagocytosis by immune cells, thus a phase I/II clinical trial (NCT03765073) is being con- contributing to the evasion of host immune defense ducted in South Africa to evaluate the safety, tolerability mechanisms.30,31 The CPS also enhances biofilm formation, and immunogenicity of a hexavalent vaccine in healthy inhibits the binding of antimicrobial peptides and neutrophil non-pregnant and pregnant women. extracellular traps (NET) as well as disturbing bacterial It has been shown that opsonophagocytosis is the main adherence to the epithelium and mucus, thus increasing mechanism for the host to clear GBS infection.24 A recent GBS invasiveness.32–38 Phase II study (NCT01446289) demonstrated that mater- GBS expresses 10 types of CPS (Ia, Ib, II–IX) that are nal antibodies of pregnant women vaccinated with structurally and antigenically different.39–41 Variously a trivalent glycoconjugated vaccine composed of CPS Ia, arranged monosaccharides and a sialic acid residue on Ib and III result in opsono-phagocytic killing (OPK) titers the branching terminus of the repeating unit make up the against each GBS serotype. Analysis of cord sera revealed CPS. According to recent meta-analyses, 97% of invasive a strong positive correlation between IgG concentrations isolates in all geographical regions are caused by five of and OPK titers, which is predictive of functional activity the most common serotypes of GBS (Ia, Ib, II, III and V) against GBS infection.55 with serotype III the most commonly found cause of dis- The role of anti-capsular antibodies in preventing GBS ease in infants.5 Serotype IV is an emerging and increasing maternal colonisation, as well as ascending infection and cause of invasive disease, especially in non-pregnant neonatal transmission was recently evaluated in an animal adults, with the potential to become an important cause model.56 Results show that systemic immunisation with of neonatal disease, with some cases already reported.42–45 a type III CRM197-glycoconjugate vaccine produces high As polysaccharides are T-cell independent antigens, the levels of IgG that can reduce vaginal acquisition of ser- polysaccharide is conjugated to a protein carrier in order to otype III during pregnancy.56 Studies in pregnant women trigger both a protective and a memory B-cell response. showed the same association with natural immunity.57,58 Earlier vaccines were conjugated to a tetanus toxoid, such Further studies will be needed to confirm the same results vaccines might have particular value in LMIC where neo- in vaccinated women. natal tetanus is still a concern.46,47 However, the main Few studies have evaluated the number of doses that carrier protein currently used is CRM197, a nontoxic will be required per pregnancy for full immunity. In one mutant of diphtheria toxin, which is highly immunogenic. study in healthy, non-pregnant women, no increase in anti- Studies using either carrier protein demonstrated better body levels was shown after a second dose of a trivalent immunogenicity with high levels of antibodies with CPS- CRM197-glycoconjugate vaccine administered one month conjugates compared to unconjugated vaccines.48,49 after the first dose.59 A recent study published in 2019 The first clinical trials were conducted with monova- (NCT02690181) evaluated the safety and immunogenicity lent vaccines (Ia, Ib, II, III and V).48–52 However, single of a second dose of a trivalent (Ia, Ib and III) CRM197 serotypes do not generally produce cross-reactive immu- conjugate vaccine in non-pregnant women over a long per- nity against other serotypes, thus multivalent vaccines iod of time (4 to 6 years) after the administration of the first were developed. A phase I/II clinical trial (registered as dose. Antibody levels from previously GBS-vaccinated NCT01193920 at the ClinicalTrials.gov database) of women increased ≥200-fold after a second dose. Women a trivalent (Ia, Ib and III) CRM197 conjugate vaccine in presenting with undetectable antibody levels after first dose pregnant women reported higher levels of CPS-specific also experienced an increase of anti-GBS concentrations antibodies in infants at birth and no safety concerns .53 after a second dose.60 These results suggest that further In 2017, a clinical trial of a GBS polysaccharide conjugate doses might be required in subsequent pregnancies. vaccine targeting serotypes Ia, Ib, II, III and V was started but, more recently, in view of the increase of disease Serocorrelates of Protection caused by serotype IV, this serotype was added to create Although several vaccine candidates are undergoing pre- an hexavalent vaccine (Ia, Ib, II, III, IV, and V) with the clinical and clinical trials, in order to achieve licensure of submit your manuscript | www.dovepress.com Infection and Drug Resistance 2020:13 1265 DovePress Carreras-Abad et al Dovepress a vaccine for GBS, phase III clinical trials may be recently developed for pneumococcal CPS.68 The latter required. These would need to be very large in order to could generate up to 143 test results in a single 96-well demonstrate efficacy in countries able to conduct such plate using similar principles to an ELISA assay for eval- trials.61 As there is a good correlation between immune uating vaccines in clinical trials. MIAs quantifying IgG response and clinical protection, licensure of a GBS vac- antibodies against the six most frequent GBS capsular cine could also be based on antibody measurement, if variants (Ia, Ib, II, III, IV and V) would prove to be a specific antibody response can be correlated with extremely useful in the standardisation of the assay used protection.62–65 A review undertaken in 2019 synthesised for GBS vaccine development. the scientific evidence to define a serocorrelate of protec- The functionality of antibodies may also have tion against GBS disease based on studies of natural a significant role in protection against GBS infections. infection.66 In such a scenario, a phase IV study will be ELISAs are limited in this aspect as they cannot distin- required post-licensure to assess effectiveness. This is the guish between antibodies with low avidity and those with same approach used for meningococcal B vaccine licen- high avidity. Therefore, the opsonophagocytosis killing sure in the United Kingdom.67 assay (OPkA) enables the measurement of antibody functionality.72 For the validation of the pneumococcal vaccine, the granulocytic cell line (HL60) was used, mak- Assays for Antibody Quantification and ing the assay more reproducible.73 The assay was also Evaluation multiplexed, which proved to be advantageous as it was The concentration of antibodies against serotype-specific less time-consuming and the amount of serum needed for CPS antigens can be quantified using standard immuno- the assay was reduced.74,75 Although a multiplexed OPkA genicity assays (IA). However, there are several limitations for GBS (GBS-MOPA) has been developed for use in to using current IA as the concentration measurement is newborns, it only targets serotypes Ia, III and V.76 very dependent on how well CPS is immobilized on an Therefore, a GBS-OPA targeting all possible vaccine ser- ELISA plate. There are other technical difficulties including otypes is necessary for future GBS vaccine development inconsistent binding of immobilized CPS to the solid phase and evaluation. or a nonspecific serotype-independent binding, of antibo- dies with lower avidity.49 There has been much debate Protein Vaccines about the methods of CPS-binding, for example that used Although CPS-conjugate vaccines have been demonstrated in pneumococcal assays (poly-L-lycine) or the novel biotin- to induce good immunogenicity, there are still several lim- streptavidin methods.66,68,69 The biotinylated method has itations, including potential immune interference with other the advantage of being able to use mass spectroscopy to types of conjugate vaccines such as Haemophilus influenzae determine the exact binding site of the biotin to the CPS, type b, meningococcal and pneumococcal conjugate enabling the monitoring of any potential conformational vaccines.77,78 There is also the possibility of serotype repla- changes to the CPS.69 However, whether this affects the cement and switching post vaccination, as well as an performance of the assay is unknown. increase in non-encapsulated GBS strains.79–81 Alternative The radio-antigen binding assay (RABA) had been vaccine candidates include structurally conserved protein used successfully to quantify levels of anti-GBS antibody antigens which can induce a strong immune response as it measures antibody in its native state;70 however, as against most GBS strains. In order to develop a vaccine with most assays, there are several limitations, including that can confer broad protection against GBS, several stu- low detection sensitivity, difficulties in obtaining and using dies have identified proteins common to all GBS strains. radioisotopes and limited ability to quantify IgG isotopes. Members of the Alp family, including AlphaC, Alp1 Therefore, it is imperative for techniques quantifying cap- (Epsilon), Alp2, Alp3 (R28), Alp4 and Rib, are the most sular serotype-specific antibodies in serum to be sensitive well-known and abundant surface proteins. These proteins as well as serotype-specific.71 Multiplex immunoassays are expressed by different serotypes (Table 2).82–85 (MIAs) based on the Luminex technology are very useful Although there have been preclinical vaccine investigations in simultaneously quantifying the concentration of IgG using AlphaC, Alp3 and Rib proteins, the heterogeneity of antibodies against the capsule of multiple GBS serotypes. the Alp sequence restricts the use of Alp proteins as poten- A Luminex-based direct immunoassay (dLIA) was tial vaccine candidates.86,87 Nonetheless, a protein vaccine submit your manuscript | www.dovepress.com Infection and Drug Resistance 2020:13 1266 DovePress Dovepress Carreras-Abad et al Table 2 Alp Family Proteins Commonly Expressed in Different Several obstacles exist in moving the most advanced vac- GBS Serotypes cines into phase III clinical trials. Given the relatively low GBS Serotype Alp Family Protein Commonly Expressed incidence of GBS disease in Europe and the USA, large numbers of participants would be needed to determine vaccine Ia AlphaC, Alp1, Alp2 Ib AlphaC efficacy.98 In addition, obstacles exist in determining what II AlphaC, Rib concentration of antibody is required to protect the infant for III Rib, Alp2 the duration of the period at risk (the 3 first months of life) as V Alp2, Alp3 there are currently no internationally recognised correlates of Notes: This table includes only the Alp family proteins that are mostly expressed protection with which to interpret individual study results.99 by the common serotypes causing infant GBS disease; The uncommon serotypes IV, VI–IX have not been included as their expression of proteins in the Alp family have Therefore, a serocorrelate of protection against GBS is needed not yet been characterized. Alp1 can also be referred to as Epsilon and Alp3 as R28. to accelerate the licensure of a vaccine. The standardisation of reagents to measure antibodies against GBS is crucial for the based on the highly immunogenic N-terminal domains of establishment of serological correlates of protection and for the AlphaC and Rib (GBS-NN) has been studied in a Phase development of GBS vaccines. The GASTON consortium was I clinical trial (NCT02459262). The participants included recently set up with this aim.66 240 healthy women who were immunised with one or two On the other hand, efforts to identify common proteins doses of GBS-NN, generating an elevated level of GBS-NN to all GBS strains have been made in order to find specific antibodies by over-30 fold in both groups.82,88 GBS a vaccine that confers protection against all GBS sero- expresses either one of two-allelic serine-rich repeat 1 types. Recent use of molecular techniques, such as multi- (Srr1) and serine rich-repeat 2(Srr2) proteins,89 both of locus sequence type (MLST) and whole-genome sequen- which can bind to fibrinogen Aα chain through the “dock, cing (WGS), have allowed us to better characterise the lock and latch” mechanism, thus contributing to the patho- GBS structure, as well as to identify the virulent lineages genesis of GBS meningitis and GBS colonisation of the such as ST17 hypervirulent strain, strongly associated with vaginal surface.89–91 The antigenic latch domain consisting serotype III. As it is important to understand the genetic of 13 amino acids containing both Srr1 and Srr2, was shown lineages that are more likely to cause GBS disease in order to play a significant role in GBS pathogenesis. Murine to better define vaccine targets, a global genomic survey of models have exhibited serotype-independent protection GBS has been established (the JUNO project).100 against GBS infection after being vaccinated with the latch- peptide vaccine.92 C5a peptidase, which is a GBS virulence Other Areas for Future Research factor, was also considered as a universal protein vaccine or As mentioned above, it is important to establish rates of a carrier for GBS-CPS.93 C5a peptidase encapsulated maternal colonisation and GBS disease worldwide, as well within microspheres composed of lactic acid and glycolic as to understand the relationship between colonisation and invasive infection, to assist assessments of vaccine efficacy. acid co-polymer triggered systemic and mucosal immune Regional serotype distribution is also required, especially from responses in murine models, thus protecting them against many LMIC were few data are currently available. multiple GBS serotypes.94,95 Another type of surface pro- Once a vaccine is licensed, the number and timing of tein are the pilus proteins, which, in preclinical and human doses for optimum coverage during pregnancy and the num- studies, were found to induce immune responses against ber of doses required for full protection needs to be deter- different GBS serotypes.30,96,97 mined. There are other knowledge gaps remaining, including the placental transfer of vaccine-induced immune responses Next Steps, New Perspectives in special populations, such as women infected with HIV, The most advanced vaccine candidates are hexavalent malaria, syphilis and hepatitis B, among others. These infec- vaccines including serotypes Ia, Ib, II, III, IV, and V, tions, highly prevalent in LMIC, may alter the immune which are now in phase II trials.54 Immunogenicity and response to vaccines and impair antibody transfer across safety of these candidates has been demonstrated in non- the placenta. A phase II trial using a GBS trivalent vaccine pregnant and, more recently, in pregnant women.22 Protein (Ia, Ib, III) undertaken in Malawi and South Africa among vaccines are in phase I trials including human studies in 270 pregnant women with or without HIV infection non-pregnant women.88,92,94-96 (NCT01412801) showed that the immune response to submit your manuscript | www.dovepress.com Infection and Drug Resistance 2020:13 1267 DovePress Carreras-Abad et al Dovepress vaccines and serotype-specific antibody concentrations in group of cost-effectiveness of a potential hexavalent vac- infants at birth were lower in the HIV infected group.101 cine in the Gambia indicated that disease incidence was Maternal immunisation policies require understanding of the key factor in determining cost-effectiveness in a low the role of these endemic infections in generating immune income setting as the cost of doing nothing is very inex- responses that ensure adequate protection of infants in these pensive as infants would classically die at home without challenging environments.102,103 receiving treatment.108 These studies, together with more Finally, cost-effectiveness evaluation is required. Cost- epidemiological data in LMIC, might raise the impact effectiveness studies have indicated that the predominant resulting from a vaccine prevention strategy. cost drivers are disease incidence, immunisation coverage Data provided in this review demonstrate that obtaining and vaccine efficacy.104 In high income countries, where a vaccine for pregnant women is a promising strategy to GBS disease is well characterized, it has been shown that prevent neonatal and infant GBS disease. Consensus among a maternal vaccine would be more cost-effective compared public health institutions and sponsors is now a priority to to IAP and doing nothing.105 A population-based eco- allow this breakthrough that will help reduce neonatal and nomic analysis in the USA concluded that vaccinating infant mortality, especially in the most vulnerable populations. 80% of pregnant women with a vaccine that prevents 80% of cases among infants born at or after 34 weeks of Disclosure gestation would prevent approximately 4100 neonatal Professor Paul T Heath and Dr Kirsty Le Doare are mem- cases annually with a net savings of 131 million USD.105 bers of the WHO Scientific Advisory Group to provide A study in South Africa also concluded that GBS maternal inputs to the development of a value proposition for Group vaccination would be very cost-effective by WHO B Streptococcus (GBS) Vaccines. Dr Kirsty Le Doare has guidelines.106 This study reported that, assuming that vac- received funding from Pfizer in 2016 for an unrelated cine efficacy varies from 50% to 90% with a 75% cover- project. The authors report no other conflicts of interest age, GBS immunisation alone, without IAP prevention, in this work. would prevent 30–54% of infant GBS cases compared to doing nothing. In contrast, risk factor based-IAP alone References prevents 10% of infant GBS cases compared to doing 1. O’Sullivan CP, Lamagni T, Patel D, et al. Group B streptococcal nothing. Furthermore, at a vaccination cost between 10 disease in UK and Irish infants younger than 90 days, 2014–15: and 30 USD, and mid-range efficacy, vaccine introduction a prospective surveillance study. Lancet Infect Dis. 2019;19 costs range from 676 to 2390 USD per disability-adjusted (1):83–90. doi:10.1016/S1473-3099(18)30555-3 2. Sigaúque B, Kobayashi M, Vubil D, et al. Invasive bacterial disease life-year (DALY) averted, compared to doing nothing.106 trends and characterization of group B streptococcal isolates among A modeling study of different sub-Saharan African coun- young infants in southern Mozambique, 2001–2015. PLoS One. 2018;13(1):e0191193. doi:10.1371/journal.pone.0191193 tries showed that maternal GBS immunisation could be 3. Seale AC, Bianchi-Jassir F, Russell NJ, et al. Estimates of the burden of a cost-effective intervention, with cost-effectiveness ratios Group B Streptococcal disease worldwide for pregnant women, stillbirths, similar to other recently introduced vaccines.107 37 and children. Clin Infect Dis. 2017;65:S200–19. doi:10.1093/cid/cix664 4. Raabe VN, Shane AL. Group B Streptococcus (Streptococcus agalactiae). African countries were clustered in four different groups Microbiol Spectr. 2019;7(2). doi:10.1128/microbiolspec.GPP3-0007-2018 according to their economic and health resources and 5. 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Clin Infect Dis. 2017;65:S89– Guinea-Bissau and 55–57% in Ghana. For a vaccine price 99. doi:10.1093/cid/cix653 8. Unicef; World Health Organisation; The world Bank; United Nations. of 7 USD per dose, maternal vaccination would cost from Levels and Trends in Child Mortality. Report 2019; 2019. 320 to 350 USD per DALY averted in Guinea-Bissau, 9. Verani JR, McGee L, Schrag SJ; Division of Bacterial Diseases, National Nigeria and Ghana, as well as 573 USD in Uganda. The Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention (CDC). Prevention of perinatal group vaccine would be less cost-effective in Uganda as neonatal B streptococcal disease–revised guidelines from CDC, 2010. MMWR mortality seems to be lower.107 A recent study by our Morb Mortal Wkly Rep. 2010;59(RR–10):1–36. submit your manuscript | www.dovepress.com Infection and Drug Resistance 2020:13 1268 DovePress Dovepress Carreras-Abad et al 10. Le Doare K, O’Driscoll M, Turner K, et al. 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