CASE REPORT published: 21 March 2022 doi: 10.3389/fpubh.2022.797569 Description of Symptoms Caused by the Infection of the SARS-CoV-2 B.1.621 (Mu) Variant in Patients With Complete CoronaVac Vaccination Scheme: First Case Report From Santiago of Chile Edited by: Carlos Barrera-Avalos 1 , Roberto Luraschi 1 , Claudio Acuña-Castillo 1,2 , Mabel Vidal 3 , Hamad Ali, Kuwait University, Kuwait Andrea Mella-Torres 1 , Ailen Inostroza-Molina 1 , Rodrigo Vera 4 , Sergio Vargas 4 , Iván Hernández 4 , Christian Perez 4 , Eva Vallejos-Vidal 1,5,6 , Daniel Valdés 1,2 , Reviewed by: Mónica Imarai 1,2 , Felipe E. Reyes-López 1,7* and Ana María Sandino 1,2* Rita Carsetti, Bambino Gesù Children’s Hospital 1 Centro de Biotecnología Acuícola, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile, (IRCCS), Italy 2 Department of Biology, Faculty of Chemistry and Biology, University of Santiago de Chile, Santiago, Chile, 3 Department of Kishu Ranjan, Computer Science, University of Concepcion, Concepción, Chile, 4 Hospital de Urgencia Asistencia Pública (HUAP), Yale University, United States Santiago, Chile, 5 Centro de Nanociencia y Nanotecnología CEDENNA, Universidad de Santiago de Chile, Santiago, Chile, 6 *Correspondence: Facultad de Medicina Veterinaria y Agronomía, Universidad de Las Américas, Santiago, Chile, 7 Department of Cell Biology, Ana María Sandino Physiology and Immunology, Universitat Autònoma de Barcelona, Bellaterra, Spain ana.sandino@usach.cl Felipe E. Reyes-López felipe.reyes.l@usach.cl Vaccine administration is one of the most efficient ways to control the current coronavirus disease 2019 (COVID-19) pandemic. However, the appearance of severe Specialty section: acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants can avoid the immunity This article was submitted to Infectious Diseases - Surveillance, generated by vaccines. Thus, in patients with a complete vaccine schedule, the infection Prevention and Treatment, by SARS-CoV-2 may cause severe, mild, and asymptomatic manifestations of the a section of the journal disease. In this case report, we describe for the first time the clinical symptoms of Frontiers in Public Health four patients (three symptomatic; one asymptomatic) from Santiago of Chile, with a Received: 20 October 2021 Accepted: 31 January 2022 complete vaccination schedule with two doses of CoronaVac (Sinovac Life Science) Published: 21 March 2022 infected with the variant of interest (VOI) B.1.621 (Mu). They were compared with Citation: four unvaccinated patients, who had a higher prevalence of symptoms after infection Barrera-Avalos C, Luraschi R, Acuña-Castillo C, Vidal M, compared to vaccinated patients. In the CoronaVac-vaccinated group, an 80-year-old Mella-Torres A, Inostroza-Molina A, patient who registered various comorbidities required Invasive mechanical ventilation for Vera R, Vargas S, Hernández I, 28 days with current home medical recovery discharge. By contrast, in the unvaccinated Perez C, Vallejos-Vidal E, Valdés D, Imarai M, Reyes-López FE and group, a 71-year-old presented more symptoms with more than 45 days of Invasive Sandino AM (2022) Description of mechanical ventilation, which continues to date, presenting greater lung damage than Symptoms Caused by the Infection of the SARS-CoV-2 B.1.621 (Mu) Variant the vaccinated hospitalized patient. This first report evidence differences in the clinical in Patients With Complete CoronaVac symptomatology of patients vaccinated and non-vaccinated infected with the VOI Vaccination Scheme: First Case B.1.621 (Mu) and suggest the protective effects of CoronaVac against this variant. Report From Santiago of Chile. Front. Public Health 10:797569. Keywords: SARS-CoV-2 B.1.621 variant, genomic surveillance, inactivated SARS-CoV-2 vaccine, CoronaVac, case doi: 10.3389/fpubh.2022.797569 report, symptoms, COVID-19 Frontiers in Public Health | www.frontiersin.org 1 March 2022 | Volume 10 | Article 797569 Barrera-Avalos et al. CoronaVac Vaccine and B.1.621 Variant INTRODUCTION and aged 35 and 80 years old. They become COVID- 19 positive after 175, 183, 50, and 183, days respectively The coronavirus disease 2019 (COVID-19) pandemic has left after the second dose of vaccination (Figures 1A–D). The more than 4.8 million deaths around the world and 240 second group describes the symptoms of four unvaccinated million infections to date. Therefore, the health authorities of male patients of 27, 38, 43, and 71 years old infected all countries have implemented various protocols to prevent with the Mu variant as well. The main symptoms and its spread. In this way, massive vaccination has been the frequent comorbidities associated with the COVID-19 disease most effective strategy to reduce the number of positive cases are described according to the Centers for Disease Control in the population and the severe clinical manifestations of and Prevention (CDC) (11, 12). The nasopharyngeal swab the disease (1–3). However, the appearance of new variants samples (NPSs) for COVID-19 diagnosis by RT-qPCR were of severe acute respiratory syndrome coronavirus 2 (SARS- obtained through the massive search strategy for cases carried CoV-2) could evade the immune protection of people with a out by the Chilean Ministry of Health and from patients completed vaccination scheme and manifest as symptomatic treated at the Hospital de Urgencia Asistencia Pública (HUAP), disease. Hacisuleyman et al., reported that SARS-CoV-2 variants Santiago, Chile. can reinfect patients and generate new symptomatologic manifestations of the disease (4), while asymptomatic cases may decrease even up to 65% in some study populations DIAGNOSTIC ASSESSMENT with B.1.1.7 (Alpha) variant (5). Therefore, the prevalence and severity of the symptoms generated by the different SARS- The patients were diagnosed for COVID-19 using the total RNA CoV-2 variants in a scenario of a complete vaccination scheme extracted from NPSs through the amplification of SARS-CoV- are of great scientific and public interest. In this report, we 2 ORF1ab and N gene by RT-qPCR (TaqManTM 2019nCoV describe for the first time the clinical symptoms of patients Assay Kit v1, Thermo Fisher Scientific, Massachusetts, USA. infected with the new variant of interest (VOI) B.1.621 (Mu) Cat. No. A47532 and E, N, and RdRp gene for AllplexTM 2019- under a complete vaccination scheme with the inactivated nCoV Assay, Seegene, Seúl, South Korea. Cat, No RP10244Y) virus vaccine CoronaVac from Sinovac Life Sciences, the widest as previously reported by our group (13) and other authors immunization strategy administered in Chile (6). The WHO (14, 15). The detection of virus-specific mutations by Real-Time listed the Mu as a VOI on August 31, 2021 (7) and shared RT-PCR kit (Bioneer, Daejeon, South Korea. Cat. No. SMVR- mutations with variants of concern (VOC) (8). The B.1.621 2112 and AllplexTM SARS-CoV-2 Variants I Assay, Seegene variant could evade neutralizing antibodies in patients fully Company, Seúl, South Korea) was made following manufacturer vaccinated with the BNT162b2 (Pfizer/BioNTech) vaccine (9) instructions. In the Seegene kit, the presence of E484K and and is 10 times more resistant to neutralizing antibodies than N501Y suggested the presence of Mu variant, while Bioneer the ancestral strain (10). Therefore, it is interesting to increase kit, the N501Y, E484K, P681H mutations. All samples were the knowledge about the Mu variant spreading in countries confirmed by NGS at the Public Health Institute of Chile (ISP, following a different vaccination scheme schedule. In this for her Spanish acronym) and Microbial Genome Sequencing scenario, currently, there is no information available regarding Center laboratory, USA. Representative MiSeq and NextSeq the clinical manifestations of Mu variant infection versus a 2000 sequencing confirmed the presence of the Mu variant complete vaccination schedule with the CoronaVac vaccine. of SARS-CoV-2, being classified on the Nextstrain Clade 21H In this case report, we detected fewer symptoms in patients (NextClade software version 1.9, Biozentrum, University of fully vaccinated with CoronaVac compared to the unvaccinated. Basel, Swiss) (Figure 1E) and following the World Health Furthermore, between two hospitalized patients, we observed Organization (WHO) recommendations (16). This variant that the vaccinated patient, even having four comorbidities presented nucleotide diversity, mainly in the ORF1a, S, ORF7a and 80 years, recovered faster compared to the 71-year-old / b, and N genes (Figure 1F), and mutations shared with unvaccinated patient with only one comorbidity, who Regrettably other variants of concern (VOC) including S: P681H, S: is still hospitalized. Our report reinforces the relevance of public D614G, and S: D950N (8). The sequence analysis also showed health policies aimed to massify the vaccination strategy in the the substitutions S:T95I, S: R346K, ORF8:T11K, S: Y144S, population and the differences in the manifestation of disease in and S: Y145N (Figure 1F), Altogether, these substitutions are people fully immunized with CoronaVac schedule against new associated with variant B.1.621 according to the characterization viral variants. reported by Laiton-Donato et al. (17). From the four patients vaccinated with CoronaVac, three were symptomatic (P1–P3) CASES DESCRIPTION and one was asymptomatic (P4). All the unvaccinated patients manifested symptoms of disease (Table 1). In addition, the The first case of symptomatology description includes four highest prevalence of reported symptoms was in unvaccinated patients with complete vaccination schedule (two doses) of patients, with dry cough, and muscle or body aches in CoronaVac (Sinovac Life Science) infected with the VOI all patients (Table 1). On the other hand, in vaccinated Mu. The data describe two patients who are men and aged patients, the main symptoms associated with the infection 27 and 33 years old, and two patients who are women were dry cough, nasal congestion, loss of taste, and headache Frontiers in Public Health | www.frontiersin.org 2 March 2022 | Volume 10 | Article 797569 Barrera-Avalos et al. CoronaVac Vaccine and B.1.621 Variant FIGURE 1 | Representative SARS-CoV-2 genome sequencing of the nasopharyngeal swab samples (NPSs) and severity of infection in hospitalized patients. (A–D) Timeline of vaccination scheme from P1, P2, P3, and P4, respectively. (E) Representative phylogenetic tree placement of all NPSs using Nextstrain clades (Continued) Frontiers in Public Health | www.frontiersin.org 3 March 2022 | Volume 10 | Article 797569 Barrera-Avalos et al. CoronaVac Vaccine and B.1.621 Variant FIGURE 1 | classification, all samples belong to clade 21H. (F) The sequence was aligned with a representation of the global SARS-CoV-2 genetic diversity and amino acid substitutions identified in the SARS-CoV-2 Mu sequence are shown. (G–J) Representative chest computed angio-tomography (CCA-T) of patients hospitalized with IVM. (G) Image of the 80-year-old patient (P1) vaccinated with CoronaVac. Ground-glass opacity (GGO) and 32.88% of pulmonary involvement are shown, upon admission to the hospital emergency department (September 27). (H) CCA-T is shown 19 days after the first CCA-T, after a cycle of IMV, with pulmonary involvement and recovery of 17.69%. (I) Image of the 71-year-old patient (P7) unvaccinated. GGO and 18.59% lung involvement are shown upon admission to the hospital emergency department (November 6). (J) CCA-T is shown 26 days after the first CCA-T after a cycle of IMV. GGO is shown with a pulmonary involvement of 68.63%. All black arrows indicate GGO. All images were obtained from similar focal planes between both patients. TABLE 1 | Summary of symptom prevalence and severity in CoronaVac were just coughing with expectoration and shortness of breath vaccinated and unvaccinated patients (n◦ ). (Table 2). She is currently without IMV at-home care assistance CoronaVac Unvaccinated and monitoring. The first chest computed angio-tomography (CCA-T) was done at admission in the emergency department Symptomatic 3 4 of HUAP, Chile on September 27, 2021, showing predominantly Asymptomatic 1 0 subpleural bilateral ground-glass opacity (GGO) with 32% Age range 27–80 27–71 pulmonary area involvement (Figure 1G). The patient was admitted to ICU and intubated with IMV on September 30, 2021. Symptoms On October 1, a second CCA-T was performed, and the lung Fever or chills 0 2 involvement decreased to 19.55% (Table 3). On October 9, she Dry cough 2 3 was extubated, and 6 days later a third CCA-T was performed, Cough w/expectoration 1 1 showing minimal GGO patches, basal subpleural consolidations Shortness of breath or difficulty breathing 1 0 with a pulmonary involvement of 17.69% (Figure 1H). On Fatigue 0 0 October 16, she was re-intubated with IMV due to bronchial Muscle or body aches 0 4 aspiration. On October 31, a fourth CCA-T was performed, Loss of smell 1 1 with 18.41% pulmonary involvement (Table 3). The patient was Headache 2 2 extubated on November 3, and a fifth CCA-T was performed on Loss of taste 2 1 November 21, even with pulmonary involvement and detection of GGO of the upper lobes (Table 3). On December 7, the last Sore throat 1 1 CCA-T showed regression and residual GGO as post-COVID- Congestion or runny nose 2 1 19 results. The patient was discharged with home monitoring on Lumbar pain 0 2 December 12. In Figures 1G,H, only CCA-T representative of the Nausea or vomiting 0 1 initial state (September 27) and during the infection (October 15) Diarrhea 0 1 by COVID-19 disease are shown. Total symptoms 12 19 On the other hand, in the unvaccinated group, we registered Hospitalization a 71-year-old patient (P7) with arterial hypertension, who Mechanic ventilation 1 1 presented fever, dry cough, body aches, and nasal congestion. The patient remains hospitalized until the date of this report, with 58 days in the ICU and 45 days of IMV. He was admitted to the emergency department on November 6, 2021, (Table 1). The patients (P1–P8) presented different viral loads a CCA-T was performed, showing bilateral, subpleural, and at the beginning of the disease. The lowest viral load was greater GGO toward the bases, which involved 18.59% of detected in unvaccinated P6 (2.5 × 103 copies/µl), who the lungs (Figure 1I). The patient was intubated with IMV presented several symptoms (Table 2). The highest viral load on November 8, and a second CCA-T was performed on was presented in vaccinated P4 (3.4 × 105 copies/µl), who November 19, with identification of GGO and condensed areas were asymptomatic (Table 2). Patient P2 reported no other with lung involvement of 48.1% (Table 3). He was extubated positive case among her social circle (close contact, work on November 24 with a high-flow basal cannula (H-FBC) colleagues, and family). This patient did not report RT- for 2 days. On November 26, the patient was subjected to qPCR at the end of his quarantine. For the other patients, Non-invasive mechanical ventilation (NIMV) until November there is no follow-up information available at the end of 30, when he was re-intubated due to high pulmonary rigidity the symptoms. (Table 3). On December 1, he was subjected to a third CCA-T, A vaccinated 80-year-old patient (P1) with comorbidities, showing extensive areas of GGO and laminar bilateral pleural such as Diabetes type 1 (DM1), hypothyroidism, arterial effusion with 68.63% pulmonary involvement (Figure 1J). The hypertension, and mitral valve disease was hospitalized and patient undergoes a prone cycle between December 6 and 8. admitted into the intensive care unit (ICU) for 48 days with 28 The last CCA-T was performed on December 15, maintaining days of invasive mechanical ventilation (IMV). Her symptoms extensive areas of GGO and bilateral pleural effusion with 60.04% Frontiers in Public Health | www.frontiersin.org 4 March 2022 | Volume 10 | Article 797569 Barrera-Avalos et al. CoronaVac Vaccine and B.1.621 Variant TABLE 2 | Specific symptomatology and clinical records reported by B.1.621 (Mu) variant infection in full vaccinated with CoronaVac and unvaccinated patients. CoronaVac Unvaccinated P1 P2 P3 P4 P5 P6 P7 P8 Age 80 35 27 33 38 27 71 43 Gender F F M M M M M M Symptomatic ✓ ✓ ✓ X ✓ ✓ ✓ ✓ Asymptomatic X X X ✓ X X X X Days after the 2nd dose* 183 50 175 183 Not applicable Symptoms Fever or chills X X X X X X ✓ ✓ Dry cough X ✓ ✓ X ✓ ✓ ✓ X Cough w/expectoration ✓ X X X X X X ✓ Shortness of breath or difficulty breathing ✓ X X X X X X X Fatigue X X X X X X X X Muscle or body aches X X X X ✓ ✓ ✓ ✓ Loss of smell X ✓ X X X ✓ X X Headache X ✓ ✓ X X ✓ X ✓ Loss of taste X ✓ ✓ X X ✓ X X Sore throat X X ✓ X X X X ✓ Congestion or runny nose X ✓ ✓ X X X ✓ X Lumbar pain X X X X ✓ X X ✓ Nausea or vomiting X X X X X X X ✓ Diarrhea X X X X X X X ✓ Comorbidities Diabetes mellitus II ✓ X X X X X X X Arterial hypertension ✓ X X ✓ X X ✓ X Diabetes mellitus I X X X X X ✓ X X Hypothyroidism ✓ X X X X X X X Mitral valve disease ✓ X X X X X X X Hospitalization Mechanic ventilation ✓** X X X X X ✓# X Viral load (Viral copies/µl) 7.1 × 104 9.0 × 104 1.2 × 105 3.4 × 105 1.4 × 105 2.5 × 103 5.2 × 104 4.8 × 104 *Elapsed time from the 2nd dose to the day positive COVID-19 diagnosis. **Currently home care monitoring. # Currently in oxygen administration at HUAP. ✓, presence; X, absence. In the “Symptoms” section, the gray color highlights the presence of symptoms. pulmonary involvement (Table 3). Until January 11, he remained of COVID-19 disease caused by some variants in vaccinated in hospitalization with nasal oxygen administration. patients is a matter of great public interest and concern. In Chile, the most administered vaccine is the inactivated- virus-CoronaVac (Sinovac Life Sciences), approved by the ISP DISCUSSION for emergency use (20). A phase 3 trial reported by Jara et al., demonstrates the effectiveness of 65.9% against SARS-CoV-2 The current application of different COVID-19 vaccines has infection, while its capacity for hospitalizations prevention was made it possible to reduce the spreading of the infection and 87.5% (21). A study carried out in São Paulo, Brazil, in a severity of the disease in several countries (3). However, this cohort of people >70 years old, indicated that the percentage protection has been threatened by the new variants of the of hospitalizations after a complete vaccination scheme with virus originally described in Wuhan, China (18). The decrease CoronaVac was 77.6% for VOC P.1 (Gamma) (22), suggesting in the protection effectiveness of vaccines can be related to a greater symptoms compared to SARS-CoV-2 Wuhan. However, slight increase in symptoms against infections by SARS-CoV-2 there are no reports of symptoms associated with Mu variant in variants like in B.1.617.2 (Delta) (19) and sometimes developing patients with a complete CoronaVac vaccine scheme. The Mu severe disease scenarios (20). Therefore, the symptomatology variant was cataloged as VOI by the WHO on August 31, 2021(7). Frontiers in Public Health | www.frontiersin.org 5 March 2022 | Volume 10 | Article 797569 Barrera-Avalos et al. CoronaVac Vaccine and B.1.621 Variant TABLE 3 | Progression of COVID-19 disease in vaccinated (P1) and related to the disease, including cough with expectoration, a sign non-vaccinated (P7) patients requiring invasive mechanical ventilation. of severe infection (24). Imaging examination of hospitalized P1 P7 patients (P1: vaccinated with CoronaVac; P7: unvaccinated) show greater pulmonary involvement in the unvaccinated Symptom onset September 18, 2021 October 28, 2021 patient, who unfortunately remains on IMV due to the infection Admission to the September 27, 2021 November 6, 2021 by Mu variant to date of this report. Although age affects the emergency immune response (25), in our study we observe differences department in disease progression between P1 and P7. Finally, fewer 1st Chest September 27, 2021: November 6, 2021: symptoms and greater comorbidity were reported by P1 who Computed Angio- 32.88% pulmonary 18.59% pulmonary was discharged from the hospital with home care monitoring. Tomography involvement involvement (CCA-T) The patient P7 presented more symptoms, fewer comorbidities, 1st intubation with September 30, 2021 November 8, 2021 and greater pulmonary involvement by Mu infection in the invasive mechanical setting of severe illness. These data suggest a protective effect ventilation (IMV) relationship of the CoronaVac vaccine against the Mu variant 2nd CCA-T October 01, 2021: November 19, 2021: and the severe manifestation of disease. This could be related 19.55% pulmonary 48.10% pulmonary to other reports that indicate, for example, that an infection by involvement involvement VOC B.1.1.7 (Alpha) in full vaccinates induces asymptomatic 1st Extubation October 9, 2021 November 24, 2021 scenes or mild symptoms (26). Other variants such as Gamma 3rd CCA-T October 15, 2021: December 1, 2021: can also cause hospitalizations in patients fully vaccinated with 17.69% pulmonary 68.3% pulmonary involvement involvement, and laminar CoronaVac (27). On the other hand, Messali et al., reported that bilateral pleural effusion the protection against Mu variant generated by other vaccines Complications Bronchial aspiration Lung rigidity following a RNA immunization strategy like the BNT162b2 Re-intubation with October 16, 2021 November 30, 2021 vaccine (Pfizer/BioNTech) could be significantly lower than IMV the generated against the original SARS-CoV-2 virus (9), a 4th CCA-T October 31, 2021: December 15, 2021: situation that could also happen for the case of other vaccines, 18.41% pulmonary Extensive lung involvement like CoronaVac. involvement of 60.04% in ground-glass This is a descriptive report of the Mu variant infection in opacity (GGO). Bilateral pleural effusion patients with a complete CoronaVac vaccine schedule. However, 2nd Extubatioon November 3, 2021 Not applicable the information is still limited to conclude that mild symptoms 5th CCA-T November 21, 2021: Not applicable are because of the complete vaccination of the patient. We Extensive upper lobe suggest a direct effect of this vaccine, but it is necessary to involvement in predominantly increase the number of cases. In this way, the genetic, age, and left ground-glass opacity comorbidities (among other factors of relevance) of the patients, (GGO) and their potential association to the severity of the disease is 6th CCA-T Regression and residual GGO Not applicable also a matter of interest to be considered. In any case, our data lattice images are of great interest for future clinical investigations related to Medical discharge December 12, 2021: Current hospitalization with hospitalization and home IMV (January 10, 2022) CoronaVac, its effectiveness against the new variants of SARS- monitoring CoV-2, and the direction of future public health policies aimed at eradicating the pandemic. Its mutations panel may suggest greater spread, immune escape, DATA AVAILABILITY STATEMENT and, therefore, a more severe situation of the COVID-19 disease The datasets presented in this study can be found in online (15, 16). Thus, full vaccinated patients with CoronaVac and the repositories. The names of the repository/repositories and development of disease in those infected cases is an important accession number(s) can be found at: https://www.ncbi.nlm.nih. and unexplored focus of interest and study. gov/, PRJNA772359. In this report, we describe for the first time the symptomatologic scenario of four patients infected with Mu variant after 172 (P1), 50 (P2), 171 (P3), and 183 (P4) ETHICS STATEMENT days of completing their two-doses vaccination schedule with CoronaVac vaccine. The patients P2 and P3 did not report The studies involving human participants were reviewed and comorbidities but reported five mild symptoms, while the P4 approved by Ethical Committee of the University of Santiago was asymptomatic even having the highest viral load of all of Chile (No. 226/2021) and the Scientific Ethical Committee patients and with a clinical history of arterial hypertension, of the Central Metropolitan Health Service, Ministry of Health, the most common COVID-19 comorbidity that increased risk Government of Chile (No. 370/2021). Written informed consent of severe disease (23). The unvaccinated P8 patient also does for participation was not required for this study in accordance not present comorbidities but reports at least eight symptoms with the national legislation and the institutional requirements. Frontiers in Public Health | www.frontiersin.org 6 March 2022 | Volume 10 | Article 797569 Barrera-Avalos et al. CoronaVac Vaccine and B.1.621 Variant AUTHOR CONTRIBUTIONS tasks. The authors also thank the Rapid Assignment of Resources for Research Projects on the Coronavirus (COVID-19) (project FER-L, CA-C, AS, EV-V, and MI: conceptualization. FER-L and number COVID1038; ANID, Government of Chile), Fondecyt RL: data curation. IH, CP, RV, SV, and MV: formal analysis. regular project numbers 1201664 (MI) and 1211841 (FER-L) AS: funding acquisition. CB-A, AM-T, and AI-M: investigation. (ANID, Government of Chile), Fondecyt iniciación grant (project FER-L: methodology. DV: supervision. CB-A and RL: writing— number 11221308; ANID, Government of Chile) (EV-V), and original draft. AMS, FR-L, CB-A, and RV: writing—review and DICYT-USACH project number 021943AC (CA-C) grants. The editing. All authors have read and agreed to the published version funders had no role in study design, data collection, and analysis, of the manuscript, contributed to the article, and approved the decision to publish, or preparation of the manuscript. submitted version. FUNDING ACKNOWLEDGMENTS The Laboratory of Virology had the support from the COVID- We thank to UCI-COVID-19 nurse Karla Barrera Ávalos for 19 diagnosis in the University Laboratories Network (Ministry of her help in interpreting the patients’ clinical records in an Sciences, Ministry of Health, Government of Chile) for diagnosis anonymized way. REFERENCES of nasopharyngeal swab samples to covid-19 diagnosis in Santiago of Chile. J Med Virol. (2021) 94:1167–74. doi: 10.1002/jmv.27446 1. UK Health Security Agency. COVID-19 Vaccine Surveillance Report—Week 14. Garg D, Muthu V, Sehgal IS, Ramachandran R, Kaur H, Bhalla A, et al. 41. (2021). Available online at: https://www.gov.uk/government/publications/ Coronavirus disease (covid-19) associated mucormycosis (CAM): case report covid-19-vaccine-weekly-surveillance-reports (accessed October and systematic review of literature. Mycopathologia. (2021) 186:289–98. 18, 2021). doi: 10.1007/s11046-021-00528-2 2. Alagoz O, Sethi AK, Patterson BW, Churpek M, Alhanaee G, Scaria E, 15. Freppel W, Merindol N, Rallu F, Bergevin M. Efficient SARS-CoV- et al. The impact of vaccination to control COVID-19 burden in the 2 detection in unextracted oro-nasopharyngeal specimens by rRT-PCR United States: a simulation modeling approach. PLoS ONE. (2021) 16:1–12. with the Seegene AllplexTM 2019-nCoV assay. Virol J. (2020) 17:1–10. doi: 10.1371/journal.pone.0254456 doi: 10.1186/s12985-020-01468-x 3. International Vaccine Access Center’s. COVID-19 Vaccine Effectiveness Forest 16. World Health Organization. Tracking SARS-CoV-2 Variants. (2021). Available Plots. (2021). Available online at: https://view-hub.org/resources (accessed online at: https://www.who.int/en/activities/tracking-SARS-CoV-2-variants October 18, 2021). (accessed October 18, 2021). 4. Hacisuleyman E, Hale C, Saito Y, Blachere NE, Bergh M, Conlon EG, et al. 17. Laiton-Donato K, Franco-Muñoz C, Álvarez-Díaz DA, Ruiz-Moreno HA, Vaccine breakthrough infections with SARS-CoV-2 variants. N Engl J Med. Usme-Ciro JA, Prada DA, et al. Characterization of the emerging B.1.621 (2021) 384:2212–8. doi: 10.1056/NEJMoa2105000 variant of interest of SARS-CoV-2. Infect Genet Evol. (2021) 95:105038. 5. Regev-Yochay G, Amit S, Bergwerk M, Lipsitch M, Leshem E, Kahn doi: 10.1016/j.meegid.2021.105038 R, et al. Decreased infectivity following BNT162b2 vaccination: a 18. Cevik M, Grubaugh ND, Iwasaki A, Openshaw P. COVID-19 vaccines: prospective cohort study in Israel. Lancet Reg Heal Eur. (2021) 7:100150. keeping pace with SARS-CoV-2 variants. Cell. (2021) 184:5077–81. doi: 10.1016/j.lanepe.2021.100150 doi: 10.1016/j.cell.2021.09.010 6. McGill COVID19 Vaccine Tracker Team. COVID-19 Vaccine Tracker. 19. Lopez Bernal J, Andrews N, Gower C, Gallagher E, Simmons R, Thelwall S, Sinovac: CoronaVac. (2021). Available online at: https://covid19. et al. Effectiveness of covid-19 vaccines against the B16172 (Delta) variant. N trackvaccines.org/vaccines/7/ (accessed October 20, 2021). Engl J Med. (2021) 385:585–94. doi: 10.1056/NEJMoa2108891 7. World Health Organization. Weekly Epidemiological Update on COVID- 20. Campos KR, Sacchi CT, Abbud A, Adele A. SARS-CoV-2 variants in severely 19 - 31 August 2021. (2021). Available online at: https://www.who.int/ symptomatic and deceased persons who had been vaccinated against. Panam publications/m/item/weekly-epidemiological-update-on-covid-19-$-$31- J Public Heal. (2021) 45:1–5. doi: 10.26633/RPSP.2021.126 august-2021 (accessed October 18, 2021). 21. Jara A, Undurraga EA, González C, Paredes F, Fontecilla T, Jara G, et al. 8. Institute of Social and Preventive Medicine University of Bern, SIB Swiss Effectiveness of an inactivated SARS-CoV-2 vaccine in Chile. N Engl J Med. Insitute of Bioinformatics. Covariants; Shared Mutations. (2021). Available (2021) 385:875–84. doi: 10.1056/NEJMoa2107715 online at: https://covariants.org/shared-mutations (accessed January 7, 2022). 22. Ranzani OT, Hitchings MDT, Dorion M, D’Agostini TL, De Paula RC, De 9. Messali S, Bertelli A, Campisi G, Zani A, Ciccozzi M, Caruso A, Caccuri F. Paula OFP, et al. Effectiveness of the CoronaVac vaccine in older adults during A cluster of the new SARS-CoV-2 B1621 lineage in Italy and sensitivity of a gamma variant associated epidemic of covid-19 in Brazil: test negative the viral isolate to the BNT162b2 vaccine. J Med Virol. (2021) 93:6468–70. case-control study. BMJ. (2021) 374:n2015. doi: 10.1136/bmj.n2015 doi: 10.1002/jmv.27247 23. Kamyshnyi A, Krynytska I, Matskevych V, Marushchak M, Lushchak 10. Uriu K, Kimura I, Shirakawa K, Takaori-Kondo A, Nakada T, Kaneda A, et al. O. Arterial hypertension as a risk comorbidity associated with covid-19 Neutralization of the SARS-CoV-2 Mu variant by convalescent and vaccine pathology. Int J Hypertens. (2020) 2020:1–7. doi: 10.1155/2020/8019360 serum. N Engl J Med. (2021) 385:2397–9. doi: 10.1056/NEJMc2114706 24. Li J, Chen Z, Nie Y, Ma Y, Guo Q, Dai X. Identification of symptoms prognostic 11. Centers for Disease Control and Prevention. Symptoms of COVID-19. (2021). of COVID-19 severity: multivariate data analysis of a case series in Henan Available online at: https://www.cdc.gov/coronavirus/2019-ncov/symptoms- Province. J Med Internet Res. (2020) 22:1–11. doi: 10.2196/19636 testing/symptoms.html (accessed October 16, 2021). 25. Oh SJ, Lee JK, Shin OS. Aging and the immune system: the impact 12. Centers for Disease Control and Prevention. People With Certain Medical of immunosenescence on viral infection, immunity and vaccine Conditions. (2021). Available online at: https://www.cdc.gov/coronavirus/ immunogenicity. Immune Netw. (2019) 19:1–18. doi: 10.4110/in.2019.19.e37 2019-ncov/need-extra-precautions/people-with-medical-conditions.html 26. Rovida F, Cassaniti I, Paolucci S, Percivalle E, Sarasini A, Piralla A, et al. (accessed October 16, 2021). SARS-CoV-2 vaccine breakthrough infections are asymptomatic or mildly 13. Barrera-Avalos C, Luraschi R, Vallejos-Vidal E, Figueroa M, Arenillas E, Barría symptomatic and are infrequently transmitted. Nat Commun. (2021) 12:1–7. D, et al. Analysis by real-time pcr of five transport and conservation medium doi: 10.1038/s41467-021-26154-6 Frontiers in Public Health | www.frontiersin.org 7 March 2022 | Volume 10 | Article 797569 Barrera-Avalos et al. CoronaVac Vaccine and B.1.621 Variant 27. Hitchings MDT, Ranzani OT, Torres MSS, de Oliveira SB, Almiron M, the publisher, the editors and the reviewers. Any product that may be evaluated in Said R, et al. Effectiveness of CoronaVac among healthcare workers in the this article, or claim that may be made by its manufacturer, is not guaranteed or setting of high SARS-CoV-2 Gamma variant transmission in Manaus, Brazil: endorsed by the publisher. a test-negative case-control study. Lancet Reg Heal Am. (2021) 1:100025. doi: 10.1016/j.lana.2021.100025 Copyright © 2022 Barrera-Avalos, Luraschi, Acuña-Castillo, Vidal, Mella-Torres, Inostroza-Molina, Vera, Vargas, Hernández, Perez, Vallejos-Vidal, Valdés, Imarai, Conflict of Interest: The authors declare that the research was conducted in the Reyes-López and Sandino. This is an open-access article distributed under the terms absence of any commercial or financial relationships that could be construed as a of the Creative Commons Attribution License (CC BY). The use, distribution or potential conflict of interest. reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal Publisher’s Note: All claims expressed in this article are solely those of the authors is cited, in accordance with accepted academic practice. No use, distribution or and do not necessarily represent those of their affiliated organizations, or those of reproduction is permitted which does not comply with these terms. Frontiers in Public Health | www.frontiersin.org 8 March 2022 | Volume 10 | Article 797569