key: cord-0963079-qrr9us3a authors: Soto, J. A.; Melo-Gonzalez, F.; Gutierrez-Vera, C.; Schultz, B. M.; Berrios-Rojas, R. V.; Rivera-Perez, D.; Pina-Iturbe, A.; Hoppe-Elsholz, G.; Duarte, L. F.; Vazquez, Y.; Moreno-Tapia, D.; Rios, M.; Palacios, P. A.; Garcia-Betancourt, R.; Santibanez, A.; Mendez, C.; Diethelm-Varela, B.; Astudillo, P.; Calvo, M.; Cardenas, A.; Gonzalez, M.; Goldsack, M.; Gutierrez, V.; Potin, M.; Schilling, A.; Tapia, L. I.; Twele, L.; Villena, R.; Grifoni, A.; Sette, A.; Weiskopf, D.; Fasce, R. A.; Fernandez, J.; Mora, J.; Ramirez, E.; Gaete-Argel, A.; Acevedo, M.; Valiente-Echeverria, F.; Soto-Rifo, R.; Reta, title: An inactivated SARS-CoV-2 vaccine is safe and induces humoral and cellular immunity against virus variants in healthy children and adolescents in Chile date: 2022-02-22 journal: nan DOI: 10.1101/2022.02.15.22270973 sha: 15c5e89d0a86893b388fb3c95cb1f20121087d57 doc_id: 963079 cord_uid: qrr9us3a Background. Multiple vaccines against SARS-CoV-2 have been evaluated in clinical trials, but very few include the pediatric population. The inactivated vaccine CoronaVac(R) has shown to be safe and immunogenic in a phase 1/2 clinical trial in a pediatric cohort in China. This study is an interim safety and immunogenicity report of a phase 3 clinical trial for CoronaVac(R) in healthy children and adolescents in Chile. Methods. Participants aged 3 to 17 years old received two doses of CoronaVac(R) in a four-week interval. Local and systemic adverse reactions were registered in 699 participants that received the first dose and 381 that received the second dose until December 31st, 2021. Whole blood samples were collected from 148 participants for humoral and cellular immunity analyses. Results. The primary adverse reaction reported after the first and second dose was pain at the injection site. The adverse reactions observed were primarily mild and local, and no severe adverse events were reported. Four weeks after the second dose, a significant increase in the levels of total and neutralizing antibodies was observed. Increased activation of specific CD4+ T cells was also observed four weeks after the second dose. Although antibodies induced by vaccination neutralize variants Delta and Omicron, titers were lower than the D614G variant. Importantly, comparable T cell responses were detected against these variants of concern. Conclusions. CoronaVac(R) is safe and immunogenic in subjects aged 3-17 years old and is thus likely to confer protection against infection caused by SARS-CoV-2 variants in this target population. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID- 19) , has been responsible for over 307.2 million cases and 5.4 millions deaths worldwide (at February 2 nd , 2022) 1 . Currently, multiple vaccines based on different platforms have been developed to reduce the transmission and severity of COVID-19 2 . Clinical trials for these vaccines have been conducted in different countries in healthy adults, but relatively few have been performed or reported in adolescents and children [3] [4] [5] . Although adolescents and children are usually asymptomatic upon infection with SARS-CoV-2 and mostly develop mild disease, they still can be hospitalized needing intensive care and even mechanical ventilation 6 . In addition, in rare cases, they can suffer a disease called multisystem inflammatory syndrome in children (MIS-C) 7 . Thus, more studies on SARS-CoV-2 vaccines are needed in children and adolescents to understand better the immune responses associated with vaccination. The inactivated SARS-CoV-2 vaccine CoronaVac ® , developed by Sinovac Life Sciences Co., Ltd. (Beijing, China), has been approved by the World Health Organization (WHO) for its use in adults against COVID-19 based on several clinical trials that have proven its safety, immunogenicity, and efficacy [8] [9] [10] [11] [12] . This vaccine was tested in clinical trials in adults in several countries, including China, Brazil, Turkey, and Chile. Clinical trials in these countries have shown that CoronaVac ® promotes anti-Spike IgG antibodies and anti-Spike Receptor-Binding Domain (RBD) neutralizing antibodies, together with cellular immune responses against SARS-CoV-2 antigens in healthy adult participants 13 . A clinical trial conducted in China with CoronaVac ® also showed favorable safety and immunogenicity results in children and adolescents aged between 3-17 years old, which displayed neutralizing antibodies titers against SARS-CoV-2 after immunization 3 . Similarly, other vaccines such as Pfizer BNT162b2 and Moderna mRNA-1273 have been tested in children between 6-11 years old and adolescents, showing to be safe and to induce neutralizing antibodies against SARS-CoV-2 4, 5 . However, these reports lack a characterization of the cellular immune responses elicited in vaccinated children and adolescents after immunization, as well as the characterization of the neutralizing capacity of antibodies against SARS-CoV-2 variants of concern. Here, we further characterize the immune responses elicited in participants aged between 3 and 17 years old four weeks after the second dose of CoronaVac ® applied in a 4 week interval (or 0-28-day vaccination schedule), demonstrating that this vaccine is safe and elicit significant levels of both humoral and cellular immunity in adolescents and children. This study is a global multi-center, randomized, double-blinded, and placebocontrolled phase 3 clinical trial that aims to assess the safety, efficacy, and immunogenicity of CoronaVac ® among children aged six months to 17 years. Four countries participated in this study, including South Africa, Malaysia, Philippines, and Chile (clinicaltrials.gov #NCT04992260). This report will only focus on the study performed in Chile for participants that received CoronaVac®. In Chile, this trial has been conducted at eleven different sites, eight in the center of the country (seven in Santiago and one in Valparaiso), two in the South (Puerto Montt and Valdivia), and All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 22, 2022 Participants were assigned to the 3-5 (children), 6-11 (children), and 12-17 (adolescents) age group and immunogenicity subgroup, safety subgroup, or nonsubgroup. For the present study, we combined the 3-11 age group (children) ( Figure 1B ). Safety group includes registration of every local and systemic non-immediate adverse events (AE) in the seven days after vaccination and any other AE until 28 days after each dose. For all participants, immediate AE (30 min post-vaccination) and serious adverse events (SAE), and adverse events of special interest (AESI) were recorded. The study aims were to evaluate the immunogenicity of CoronaVac ® in a subgroup of participants 4 weeks after 2 doses and the frequency of solicited immediate (first 30 min post-dose) and non-immediate adverse events (AEs) that occur during seven days after each dose, stratified by age group (3-11 and 12-17 years old), and the frequency of SAE/AESI and any other AE occurring 28 days after each dose, and the frequency of any SAE/AESI occurring 12 months after the second dose. Subjects enrolled in one specific clinical center (CL01, Marcoleta) were assigned to the immunogenicity branch. Blood samples were obtained in heparinized tubes before administration of the first dose (pre-immune) and four weeks after the second dose, as described in Suppl. Figure 1 . Samples were used to obtain plasma and peripheral blood mononuclear cells (PBMCs) and stored at -80ºC (plasma) and -170ºC (PBMCs) until humoral and cellular immunity analyses were performed. The sample size included in each experimental analyses is described in Suppl. Figure 1 . IgG anti-S1-RBD of SARS-CoV-2 were tested using ADVIA Centaur® XP SARS-CoV-2 IgG (sCOVG, Siemens) 15, 16 , an automated two-step sandwich antibody-binding immunoassays using indirect chemiluminescence. sCOVG was used for quantitative detection expressed in BAU/mL after interpolating the WHO standard NIBSC code 20/136 calibration 3. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. A pseudotyped virus neutralization test (pVNT) assay was performed to assess the neutralization capacity of the antibodies against SARS-CoV-2 variants of concern (VOC). As previously reported 19 In order to assess the cellular immune response in vaccinated children and adolescents, PBMCs of sixty participants were stimulated with six Mega Pools (MPs) of peptides derived from the proteome of SARS-CoV-2, including peptides from the S protein of SARS-CoV-2 (MP-S) 21 , the remaining proteins of the viral particle (excluding S protein peptides) (MP-R) 21 , peptides from the M protein (Miltenyi, Cat#130-126-702), peptides from the N protein (Miltenyi, Cat#130-126-698) and MHC-I restricted peptides from the whole proteome of SARS-CoV-2 (MP-CD8-A and All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 21 . MP of peptides from the S protein of SARS-CoV-2 VOC Delta and Omicron were provided by La Jolla Institute for Immunology 22 . Positive and negative controls were included in each assay. The number of Spot Forming Cells (SFC) for IFN-g and IL-4 were determined by ELISPOT, and the expression of Activation-Induced Markers (AIM + ) and memory markers by T cells was evaluated by flow cytometry using a LSR Fortessa X-20 flow cytometer (BD Biosciences). Assays were performed according to the manufacturer's instructions and as reported previously 17 . Supernatants from PBMCs stimulated with SARS-CoV-2 MPs for 20h were evaluated using the Luminex ® technology (R&D systems, USA) to assess IL-2 and IFN-g production. Briefly, supernatants of samples stored at -80ºC were thawed at room temperature and diluted 1:2 before analysis. After 2 h incubation with spectrally encoded beads, coated with analyte-specific biotinylated primary antibodies, the samples were incubated with streptavidin R-phycoerythrin and analyzed using a Luminex 200 xMap multiplex system (Luminex Corporation, Austin, TX). According to the manufacturer's instruction the detection limit for the cytokines measured ranged from 4.2 to 13,390 pg/mL. Statistical differences for the immunogenicity results were assessed using the use of Wilcoxon test analyzed data to compare the levels of antibodies four weeks after the second dose against the pre-immune levels, whereas the Mann-Whitney test was used to compare the level of antibodies four weeks after the second dose All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 22, 2022. ; https://doi.org/10.1101/2022.02.15.22270973 doi: medRxiv preprint between both age groups (Total IgG, sVNT, pVNT, and cVNT). A two-way ANOVA was used for cellular immune response to compare the percentage of AIM + , memory AIM + CD4 + T cells, and cytokines secretion four weeks after the second dose against the pre-immune levels in both age groups. The significance level was set at 0.05 for all the analyses. All data were analyzed with GraphPad Prism 9.0.1. Nine hundred sixty-three participants were recruited between September 10th and December, 31th, 2021, 482 of them are male (51.1%), average age 6.35 years old (SD 3.12). Figure 1B shows the enrolled population and distribution by age, dose and safety group. In the 30 min post-vaccination, local pain was reported by 3.8% and 1.7% of participants 3-11 years old after the first and second dose, respectively, and in 2.2% and 8.2% of adolescents. Pain was statistically significantly higher in adolescents than in children after the second dose (p= 0.002791). The rest of local AEs were reported in 2% or fewer participants, without age or dose differences (Suppl. Table 1 ). Systemic immediate AE were reported in less than 1% of 3-11 years old participants. Meanwhile, adolescents reported 2.2% and 1.2% headaches after the All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Table 2 ). Only the safety group reported non-immediate AEs ( Figure 1B) . The most frequent local non-immediate AEs was pain, observed in around 15% of 3-11 years old children after the first dose and in 8% after the second dose (p=0.003). In adolescents, pain was reported in around 25% after each dose, being significantly higher than children after the second dose (p=0.0063). The rest of the local AEs were reported in less than 5% of 3-11 years old and in less than 10% of adolescents. Most local AEs resolved in 2 days ( Table 1) . Systemic AEs were reported at a frequency lower than 10% each. Headache was the most common AE in adolescents; meanwhile, it was fever in 3-11 years old children. In these age groups, fever was reported in 9 and 7% after the first and second dose, respectively, but in just one adolescent after the first dose. The rest of the systemic AEs were reported in less than 10% of the vaccinated subjects ( Table 2 ). Comparison by age and dose showed significantly higher headache in adolescents than in younger children after both doses (p=0.00016 and 0.0028), and higher fatigue in children 3-11 years old after the first than after the second dose (p=0.0117). The severity of systemic AE was grade 1 in 62-79% of participants and grade 3 in only 1.7-2.7%. There was no grade 4 AE (data not shown). There was just one no related SAE reported in the period (a 3-year-old participant hospitalized for 24 hours due to influenza A infection). All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Ninethy-two participants from the immunogenicity branch, who received two doses of the CoronaVac ® , were included in this study (Suppl. Figure 1) . Samples analyzed were obtained before vaccination (pre-inmmune) and four weeks after the second dose. We evaluated the induction of IgG against RBD-S1 of SARS-CoV-2 by chemoelectroluminescence (Figure 2A-C) , which are significantly increased following two doses of CoronaVac as compared to the pre-immune sample. Accordingly, we detected significant neutralizing capacity in plasma obtained from Figure 2D -F), which is in line with previous reports in adult cohorts 13 . In addition, the seropositivity reached 100% for the samples analyzed four weeks after the second dose in both groups. Similarly, when analyzing neutralization against the live virus using a cVNT, we observed a significant increase in both age groups (Suppl. Figure 2A and B): GMT 128, 95% CI= 74.8-219.2 for age group 3-11 years old and GMT 34.02, 95% CI= 18.1-64.0 for age group 12-17 years old ( Table 3) . A significant difference in the titers of neutralizing antibodies is observed between both age groups ( Figure 2C and Suppl. Figure 2C ). All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. We also analyzed the cellular immune responses following two doses of CoronaVac ® in children and adolescents, which to our knowledge has not been reported in other studies with CoronaVac ® or mRNA vaccines against SARS-CoV-2. Compared to the pre-immune samples, we observed a significant increase in CD4 + T cell activation four weeks after the second dose of CoronaVac ® upon stimulation with four Mega-pools S, R, M, and N ( Figure 3A-B) . A significant increase in the activation of CD4 + T cells was found in 12-17 aged groups for all the MPs evaluated. In contrast, in the 3-11 years old group, a significant increase in the activation of CD4 + T cells with the stimulus S and N was found (Figure 3C-F) . Additionally, the induction of memory cells induced by vaccination two weeks after the second dose compared to the pre-immune sample was analyzed (Figure 4A-B ). An increase in the ratio of memory cells with respect to the pre-immune sample was Figure 4F) . We see an increase in IFN-g production by ELISPOT upon stimulation with S, R and N MPs after the second dose in the age group of 12-17 years old, but this is not significant as compared to the pre-immune sample (Suppl. Fig 3A-D) . In addition, we did not observe any changes in the secretion of IL-4 using ELISPOT in response to SARS-CoV-2 MPs (Suppl. Figure 3E-H) . On the other hand, we did not observe an increase in CD8 + AIM + T cells with MP CD8A and CD8B for participants aged 3 to 11 years or 12 to 17 years following the second dose of CoronaVac ® , as compared to the pre-immune sample (Data not All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. shown). Only a significant increase in memory CD8 + AIM + T cells after vaccination with CoronaVac ® was only observed upon stimulation with MP CD8A in the age group of 3-11 years old (Suppl. Figure 4C ). Secretion of the cytokines IL-2 and IFN-g were evaluated using Luminex ® in PBMCs stimulated with MPs of peptides. We observed a significant increase in IL-2 secretion in response to the S and R MPs and M and N MPs for participants aged 12-17 years (Figure 5A-D) . In the case of the 3-11 group, we observed a significant increase in response to the S, M, and N MP. In contrast, we did not observe a significant increase in IFN-g release after the MP stimulation for participants aged 12-17 years (Figure 5E-H) . However, participants between 3-11 years present a significant increase in the production of IFN-g in response to the S, M, and N MPs ( Figure 5E and 5H) . To assess whether CoronaVac ® induces immune responses against SARS-CoV-2 variants of concern, we evaluated by a pseudotype virus neutralization assay (pVNT) the neutralizing antibody production against variants of concern Delta and Omicron as compared to D614G (Figure 6) . A 1.9-fold reduction relative to strain All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (Figure 6A) . The percentages of seropositivity show that an important reduction is observed for the Omicron variant (Suppl. Table 3 ). When we compare the response between both age groups, we do not find significant differences in any of the variants evaluated ( Figure 6B ). However, a significant mild reduction of AIM + T cell against MP-S of the Delta variant (1.67fold reduction) and a significant mild increase against MP-S of the Omicron variant (1.63-fold increase) was observed, as compared to the response obtained for MP-S of the wild type (WT) strain ( Figure 6C ). This T cell response was equivalent in both age groups ( Figure 6D ). Previous studies have shown a 65.9% of effectiveness for immunization with two doses of CoronaVac ® in a 0-28 schedule 23 . Here, we show that this vaccine has a very good safety profile, comparable to what was reported by Han 3 , being pain the main AE in both age groups but statistically higher in adolescents than in children. Most of the AEs were mild or moderate and no SAE related to the vaccine were reported. Here we have also assessed the capacity of plasma samples from children and adolescents vaccinated with CoronaVac ® to neutralize SARS-CoV2, performing surrogate neutralizing antibody assays (sVNT), a pseudotyped virus (pVNT) assay, and conventional microneutralization assays in Vero E6 Cells (cVNT). Additionally, our study assessed T cell immunity 3, 4 and immune responses against variants of All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. concern Delta and Omicron. Two doses of CoronaVac ® administered in a 4-week interval stimulate the induction of both total and neutralizing antibodies in participants aged 3-17 years old four weeks after the second dose. This is the first report of total antibodies anti-S1-RBD expressed as WHO arbitrary units in children and (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Our results suggest that CoronaVac ® promotes CD4 + T cell responses against SARS-CoV-2, which can be protective against infection and/or severe disease. Here we report a significant increase in CD4 + AIM + T cells in response to S, R, M, and N MPs but no differences in CD8 + AIM + T cells, in line with the results previously observed in adults vaccinated with two doses of CoronaVac ® 13 . We did not observe significant differences between age groups in CD4 + AIM + T cells, suggesting that both children and adolescents can activate CD4 + T cell responses against SARS-CoV-2 following vaccination. Consistent with this, we show a significant increase in IL-2 secretion in response to S and N MPs in both age groups, whereas we detected a significant increase in response to the M MPs only in subjects aged 12-17 years old. Furthermore, we observed an increase in the frequency of memory CD4 + AIM + T cells in response to SARS-CoV-2 MPs, although we observed a slightly higher All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. induction of memory T cells in subjects aged 12-17 years old as compared to subjects aged 3-11 years old. These results agree with reports showing that memory T cell responses against SARS-CoV-2 structural proteins increase with age 26 . As the formulation of CoronaVac ® contains the full-inactivated virus is important to understand whether the induction of cellular responses against viral antigens other than Spike may be important in conferring protection against severe disease. To our knowledge, this is the first study to report cellular immunity in children and adolescents vaccinated against SARS-CoV-2. Moreover, we evaluated the neutralization using a pseudotyped virus using an ID80 against variants Delta and Omicron compared to the more ancestral strain D614G and found decreased antibody neutralization capacity against these variants. While we observed high seropositivity against D614G (100%), lower seropositivity against the variant Omicron was found (45.5%, Supp. Table 3 ) in line with previous reports indicating lower protection against variants of concern in adult cohorts after two doses of CoronaVac ® 13,19,27,28 . However, a booster dose of CoronaVac ® has been shown to increase virus neutralization of the variants of concern Gamma and Delta 25 . Thus, it is possible that a booster dose of CoronaVac ® may be required to increase virus neutralization of circulating SARS-CoV-2 variants in children and adolescents, although this remains to be determined empirically. Previous studies performed in Israel showed a decrease in the transmission and the severe disease by SARS-CoV-2 twelve or more days after booster inoculation 29 and our previous study performed in adults showed that a booster dose of CoronaVac ® increases neutralization against SARS-CoV-2 WT strain and VOC Delta and Omicron 25 . All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. On the other hand, we observed that both age groups elicited CD4 + AIM + T cells in response to MPs from the variants Delta and Omicron. We observed a significant reduction in CD4 + AIM + T cells against the Delta variant and, surprisingly, an increase against the Omicron variant. Several studies in vaccinated adults have shown that CD4 + T cell responses against variants of concern are conserved, and cross-reactive T cells against the Omicron variant have been reported 22, 31 . However, it is unclear why this pediatric population exhibit increased CD4 + AIM + T cells against the Omicron variant, and further research is required to understand these results. Taken together, these results indicate that CoronaVac ® is safe in children and adolescents and induces both humoral and cellular responses able to recognize the variants of concern Delta and Omicron. This study presents some limitations, such as samples obtained at few time points after vaccination, as compared to recent clinical trials performed in adults. In addition, infectious virus neutralization assays against the variants of concern Delta and Omicron needs to be performed to confirm the results obtained with the pVNT assay. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. neutralizing antibody responses in individuals exposed to SARS-CoV-2 in All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 22, 2022. ; https://doi.org/10.1101/2022.02.15.22270973 doi: medRxiv preprint antibodies four weeks after the second dose in both age groups. **p<0.005, ****p<0.0001, n.s. non-significant. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. N (H) are shown from a total of twenty-three participants aged 3-11 years old and twenty-three participants aged 12-17 years old. A two-way ANOVA was used to compare the level All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. of cytokines four weeks after the second dose against the pre-immune sample. *p<0.5, **p<0.005, ***p<0.001, n.s. non-significant. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. World Health Organization. WHO Coronavirus (COVID-19) Dashboard. 2022 Association between BNT162b2 Vaccination and Incidence of SARS-CoV-2 Infection in Pregnant Women Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy children and adolescents: a double-blind, randomised, controlled Evaluation of mRNA-1273 SARS-CoV-2 Vaccine in Adolescents Evaluation of the BNT162b2 Covid-19 Vaccine in Children 5 to 11 Years of Age Clinical and epidemiological features of 36 children China: an observational cohort study Report: Case Series of Children With Multisystem Inflammatory Syndrome Following SARS-CoV-2 WHO approval of Chinese CoronaVac COVID vaccine will be crucial to curbing pandemic Development of an inactivated vaccine candidate for SARS-CoV-2 Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy adults aged 60 years and older: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial Interim report: Safety and immunogenicity of an inactivated vaccine against SARS-CoV-2 in healthy chilean adults in a phase 3 clinical trial Safety and Immunogenicity of an Inactivated SARS-CoV-2 Vaccine in a Subgroup of Healthy Adults in Chile World medical association. World Medical Association declaration of Helsinki: Ethical principles for medical research involving human subjects Clinical validation of the Siemens All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. quantitative SARS-CoV-2 spike IgG assay (sCOVG) reveals improved sensitivity and a good correlation with virus neutralization titers Improvements and limits of anti SARS-CoV-2 antibodies assays by WHO (NIBSC 20/136) standardization Safety and Immunogenicity of an Inactivated Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine in a Subgroup of Healthy Adults in Chile 2403 Establishment of the WHO International Standard and Reference Panel for anti-SARS-CoV-2 antibody Recognition of Variants of Concern by Antibodies and T Cells Induced by a SARS-CoV-2 Inactivated Vaccine. Front Immunol Infectivity and immune escape of the new SARS-CoV-2 variant of interest Lambda Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals Impact of SARS-CoV-2 variants on the