key: cord-0774037-l7i4l440
authors: Ranzani, O. T.; Hitchings, M.; de Melo, R. L.; de Franca, G. V. A.; Fernandes, C. d. F. R.; Lind, M.; Torres, M. S. S.; Tsuha, D. H.; David, L. C. S.; Said, R. F. C.; Almiron, M.; de Oliveira, R. D.; Cummings, D. A. T.; Dean, N. E.; Andrews, J. R.; Ko, A. I.; Croda, J.
title: Effectiveness of an Inactivated Covid-19 Vaccine with Homologous and Heterologous Boosters against the Omicron (B.1.1.529) Variant
date: 2022-04-01
journal: nan
DOI: 10.1101/2022.03.30.22273193
sha: 042dfc87384f938280f6b9a99d64d8e72a0604ac
doc_id: 774037
cord_uid: l7i4l440

Background Large outbreaks of the SARS-CoV-2 Omicron (B.1.1.529) variant have occurred in countries with high coverage of inactivated Covid-19 vaccines, raising urgent questions about effectiveness of these vaccines against disease and hospitalization with Omicron. Methods We conducted a nationwide, test-negative, case-control study of adults who were tested for SARS-CoV-2 infection. We evaluated vaccine effectiveness against symptomatic Covid-19 and severe Covid-19 (hospital admission or deaths) for the primary series of CoronaVac and homologous and heterologous (BNT162b2) booster doses. Findings Between September 6, 2021, and March 10, 2022, a total of 1,339,986 cases were matched to 1,339,986 test-negative controls. In the period of Omicron predominance, vaccine effectiveness [≥]180 days after the second CoronaVac dose was 8.1% (95% CI, 7.0 to 9.1) and 57.0% (95% CI, 53.5 to 60.2) against symptomatic and severe Covid-19, respectively. Vaccine effectiveness against symptomatic disease was 15.0% (95% CI, 12.0 to 18.0) and 56.8% (95% CI, 56.3 to 57.4) in the period 8-59 days after receiving a homologous and heterologous booster, respectively. During the same interval, vaccine effectiveness against severe Covid-19 was 71.3% (95% CI, 60.3 to 79.2) and 85.5% (95% CI, 83.3 to 87.0) after receiving a homologous and heterologous booster, respectively. Whereas waning of vaccine effectiveness against symptomatic Covid-19 was observed [≥]90 days after a homologous and heterologous booster, waning against severe Covid-19 was only observed after a homologous booster. Interpretation A homologous CoronaVac booster dose provided limited additional protection, while a BNT162b2 booster dose afforded sustained protection against severe disease for at least three months.

Background Large outbreaks of the SARS-CoV-2 Omicron (B.1.1.529) variant have occurred in countries with high coverage of inactivated Covid-19 vaccines, raising urgent questions about effectiveness of these vaccines against disease and hospitalization with Omicron.

We conducted a nationwide, test-negative, case-control study of adults who were tested for SARS-CoV-2 infection. We evaluated vaccine effectiveness against symptomatic Covid-19 and severe Covid-19 (hospital admission or deaths) for the primary series of CoronaVac and homologous and heterologous (BNT162b2) booster doses.

Findings Between September 6, 2021, and March 10, 2022, a total of 1,339,986 cases were matched to 1,339,986 test-negative controls. In the period of Omicron predominance, vaccine effectiveness ≥180 days after the second CoronaVac dose was 8·1% (95% CI, 7·0 to 9·1) and 57·0% (95% CI, 53·5 to 60·2) against symptomatic and severe Covid-19, respectively. Vaccine effectiveness against symptomatic disease was 15·0% (95% CI, 12·0 to 18·0) and 56·8% (95% CI, 56·3 to 57·4) in the period 8-59 days after receiving a homologous and heterologous booster, respectively. During the same interval, vaccine effectiveness against severe Covid-19 was 71·3% (95% CI, 60·3 to 79·2) and 85·5% (95% CI, 83·3 to 87·0) after receiving a homologous and heterologous booster, respectively. Whereas waning of vaccine effectiveness against symptomatic Covid-19 was observed ≥90 days after a homologous and heterologous booster, waning against severe Covid-19 was only observed after a homologous booster.

Interpretation A homologous CoronaVac booster dose provided limited additional protection, while a BNT162b2 booster dose afforded sustained protection against severe disease for at least three months.

The substantial initial protection of primary series Covid-19 vaccines against moderate and severe

Covid-19 has been demonstrated through randomized clinical trials and observational studies. [1] [2] [3] Since then, accumulating evidence has demonstrated the importance of waning protection following primary series completion, [4] [5] [6] and decreased effectiveness of current vaccines to variants of concern (VoC), in particular the Omicron (B.1.1.529) variant. 4, 7 Delineating the effectiveness of the range of booster vaccination strategies is therefore critical for guiding national and global policy. 8 The majority of the existing vaccine effectiveness evidence is for mRNA vaccines, both as the primary series and as booster doses, 7, 9, 10 leaving significant evidence gaps regarding inactivated vaccine platforms. Inactivated vaccines are widely used, particularly in low-and middle-income countries, and represent half of the applied doses of Covid-19 vaccines worldwide as of Jan 2022. 11 Large Omicron epidemics associated with severe cases and deaths have been occurred in regions, most recently Eastern Asia, where inactivated vaccines have been extensively administered. 12 Brazil initiated booster vaccination in September 2021, after Delta VoC began to dominate in the country and three months before Omicron dominance. 5 Evidence concerning the effectiveness of inactivated vaccines with homologous or heterologous boosters is critically needed to inform vaccine policies in countries that used these vaccines in their initial rollout.

We evaluated the vaccine effectiveness of CoronaVac and BNT162b2 booster doses among Brazilian adults who completed the primary series of the CoronaVac vaccine in a nationwide test-negative case-control study. Our primary analysis focused on the period from December 25, 2021 to March 10, 2022, when circulation of the Omicron variant was predominant, and compared these findings . CC-BY-NC-ND 4.0 International license It is made available under a 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 April 1, 2022. ; https://doi.org/10.1101/2022.03.30.22273193 doi: medRxiv preprint with those from the prior period, from September 6, 2021 to December 14, 2021 when the Delta variant was predominant in the country.

We conducted a matched test-negative case-control study between September 6, 2021, and March All four vaccine platforms were administered as a homologous or heterologous booster dose. The booster vaccination followed an age-prioritization scheme. The interval between second and booster doses was initially six months and was subsequently shortened to four months during November 2021 in some states and nationally on December 20, 2021. The proportion of individuals with a primary series of CoronaVac who received a booster dose of Ad26.COV2.S or ChAdOx1 nCoV-19 was small; therefore we limited our analysis to booster doses of CoronaVac and BNT162b2.

We obtained individual-level information on Covid-19 outcomes from two national surveillance databases in Brazil: e-SUS and SIVEP-Gripe, which has information from notified cases, respectively, of mild Covid-19 illnesses and of severe acute respiratory illness, including all Covid-19 hospitalizations and deaths. 3, 5 We obtained individual-level vaccination status from the national vaccination database (SI-PNI). Notification to these three systems is compulsory in Brazil. The three . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 1, 2022. The study population was adults (aged ≥18 years) residing in Brazil, and who underwent SARS-CoV-2 RT-PCR or rapid antigen testing associated with symptomatic illness 13 during the study period. We excluded individuals with missing or inconsistent information on age, sex, municipality of residence, and on vaccination and testing status and dates. We excluded RT-PCR/antigen tests that were not collected within 10 days of symptom onset, positive or negative RT-PCR/antigen tests with a positive RT-PCR/antigen test in the previous 90 days, and negative RT-PCR/antigen tests with a positive RT-PCR/antigen test occurring in the following 14 days, to avoid potentially misclassification. For individuals who received multiple RT-PCR or antigen tests during the study period, we included all eligible tests up to and including the first positive test. The number of RT-PCR/antigen tests performed during the study period in Brazil is shown in eFigure 1.

To assess waning of the booster doses over time since administration, we performed a separate, secondary, case-control analysis on the same study population, restricting to cases and controls who received a primary series of CoronaVac and received an RT-PCR/antigen test at least six months after their second dose, i.e. when eligible for a booster dose. The study design and matching procedure was otherwise the same.

Cases were defined as those from the study population who had Covid-19 symptoms and a positive SARS-CoV-2 RT-PCR/antigen test result. Eligible controls were defined as those from the study population who had Covid-19 symptoms and a negative SARS-CoV-2 RT-PCR/antigen test result.

Finally, we excluded all RT-PCR/antigen tests that were obtained after receipt of a primary series of ChAdOx1 nCoV-19, BNT162b2 or Ad26.COV2.S vaccines.

We matched each case with one control according to the age category (ten-year bands), sex, municipality of residence, and RT-PCR/antigen test sample collection date (± 10 days). After identification of each case, we randomly chose one control from the set of all eligible matching controls, allowing for replacement of controls between cases.

We estimated the vaccine effectiveness of booster doses of CoronaVac and BNT162b2 against symptomatic Covid-19 in the 0-7 days, 8-59 days and ≥60 days after the booster dose. We also estimated the vaccine effectiveness of a booster dose against Covid-19 hospitalization and/or death by restricting the analysis population to case-control pairs in which the case was hospitalized or died. 3, 5 The reference group was unvaccinated individuals. For the secondary analysis assessing waning effectiveness, we estimated the relative vaccine effectiveness (rVE), 7,14 using booster eligible (≥180 days after the second dose) CoronaVac recipients as the reference group, and stratified the time since booster administration by 8-59 days, 60-89 days, and ≥90 days.

We used conditional logistic regression to estimate the adjusted odds ratio (aOR) of vaccination comparing cases and controls, and 1−aOR provided an estimate of vaccine effectiveness under the assumptions of a test negative design. 15 Because age is a strong determinant of Covid-19 outcomes, we adjusted for age (as a continuous variable, modeled with a restricted cubic spline) after matching to control for potential residual confounding within age bands. We also adjusted for . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 1, 2022. ; https://doi.org/10.1101/2022.03.30.22273193 doi: medRxiv preprint chronic comorbidities (including cardiovascular, renal, diabetes, chronic respiratory disorder, obesity, or immunosuppression, categorized as 0, 1, and ≥2 comorbidities), self-reported race, and any previous symptomatic event that were reported to the eSUS and SIVEP systems (categorized as 0, and ≥1).

We conducted an analysis of vaccine effectiveness within age subgroups (<60, 60-74 and vs ≥75 years old) by adding an interaction term with vaccination category. Because the analysis period incorporated a Delta (B.1.617.2) (September 6, 2021 to December 14, 2021) and Omicron (December 25, 2021 to March 10, 2022) period, we conducted separate analyses in each time period. We defined the end of the Delta period as when national Omicron VoC prevalence amongst sequenced genomes reached 25% and the beginning of the Omicron period as when the prevalence reached 75% in the GISAID database. 16 We conducted the same analyses using only RT-PCR tests as a sensitivity analysis, to address potential misclassification.

All analyses were done in R (v.4.1.2). 17

The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

During the study period, there was a low incidence of Covid-19 cases and hospital admissions or deaths during the Delta wave compared to earlier periods in Brazil, until the end of December 2021, . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 1, 2022. ; https://doi.org/10.1101/2022.03.30.22273193 doi: medRxiv preprint which corresponded to the introduction and spread of the Omicron variant (Figure 1) . Across all age groups in Brazil, on March 10, 2022, coverage was 82.3% for the first vaccine dose, 74.3% for second doses, and 32.6% for boosters (Figure 1) .

After applying the inclusion and exclusion criteria, there were 3,021,428 RT-PCR/antigen tests from 2,849,801 individuals eligible for matching for the primary analysis. After matching one control per case, with replacement, the analysis population was 2,679,972 RT-PCR/antigen tests from 1,825,349 individuals for the primary analysis (eFigure 2). Controls were matched to multiple cases a median of 2 (IQR: 1-3) times. The characteristics for the selected case-control sets for CoronaVac during the Delta and Omicron periods is shown in Table 1 .

Vaccine effectiveness estimates for two doses of CoronaVac, and for a booster dose of CoronaVac and BNT162b2, are displayed in Figure 2 and in eTable 1. Relative to the Delta period, the Omicron period was associated with a substantial decrease in vaccine effectiveness against symptomatic disease for the primary series of CoronaVac (VE ≥180 days after second dose 33.5%, 95% CI 31. 7 We observed lower vaccine effectiveness against hospitalization or death in individuals aged ≥75 years, compared to younger individuals, for a primary series of CoronaVac, a CoronaVac booster, . CC-BY-NC-ND 4.0 International license It is made available under a 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 April 1, 2022. ; https://doi.org/10.1101/2022.03.30.22273193 doi: medRxiv preprint and for a BNT162b2 booster ( Table 2) . However, vaccine effectiveness against hospitalization and death was significantly higher in individuals aged ≥75 years who received a heterologous BNT162b2 booster than a homologous CoronaVac booster ≥90 days of booster dose (79.9% vs 54.6%, respectively). Vaccine effectiveness against symptomatic disease was overall lower across age groups and an age-related trend was not discernable.

A total of 1,081,446 RT-PCR/antigen tests out of 1,234,305 eligible were selected into matched case-control pairs for the waning vaccine effectiveness (eTable 2). In the Omicron period, administration of a CoronaVac booster was associated with an increased VE against hospitalization or death relative to individuals who received their second dose ≥180 days previously ( Table 2 ; rVE 8-59 days after third dose 42%, 95% CI 19.1 to 58.5), but minimal increase in VE against symptomatic disease (rVE 8-59 days after booster dose 4.0%, 95% CI 0.2 to 7.6). In addition, the additional protection gained by the booster dose against hospitalization or death waned after three months (rVE ≥90 days after booster dose 14.8%, 95% CI 5.4 to 23.2). In contrast, a BNT162b2 booster was associated with substantial increase in protection against hospitalization or death that was maintained for at least three months ( Table 3 ; rVE ≥90 days after booster dose 66.9%, 95% CI 64.7 to 69.0). The gain in VE against symptomatic disease was lower and appeared to wane over time ( Table 3) .

A sensitivity analysis that was restricted to RT-PCR tests only (eFigure 3, eTable 3) obtained comparable estimates to the main analysis (eTable 4, eTable 5, eTable 6 and eTable 7).

. CC-BY-NC-ND 4.0 International license It is made available under a 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 April 1, 2022. ; https://doi.org/10.1101/2022.03.30.22273193 doi: medRxiv preprint

In this large observational study, we observed substantially lower effectiveness of a primary series of CoronaVac, and of a homologous CoronaVac and heterologous BNT162b2 booster dose, against symptomatic Covid-19 during an Omicron-dominated period compared to a Delta-dominated period. Effectiveness against severe outcomes was more similar between the two periods. In addition, a homologous booster dose conferred no additional protection against symptomatic disease during the Omicron-dominated period, and a moderate increase in protection against severe disease. Of note, the increased protection afforded by a homologous booster does waned during the three month period after its administration. In contrast, the effectiveness of a heterologous BNT162b2 booster dose was substantially higher against symptomatic and severe disease, and protection against severe disease appeared to be durable up to three months.

Our findings have immediate implications for the current policy recommendation to administer homologous booster doses of inactivated vaccines in the context of the current global spread of the Omicron variant. 8 There was overall a small benefit of a homologous booster and, for individuals aged ≥75 years, both the primary series and homologous booster afforded limited protection against severe disease (46-54%). However, a heterologous booster dose of BNT162b2 afforded a substantial increase in protection against severe disease in all age groups, including the elderly with age ≥75 years, compared to the primary series and some protection against symptomatic disease, albeit of uncertain duration. These findings suggest that the use of homologous CoronaVac booster doses, as currently recommended by the WHO 8 , may need to be revisited, as preference to heterologous booster doses may be crucial to reducing morbidity and mortality associated with Omicron epidemics. Further research should investigate combinations of heterologous booster doses other than BNT162b2, including non-mRNA vaccines.

. CC-BY-NC-ND 4.0 International license It is made available under a 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 April 1, 2022.

The reduced effectiveness of primary vaccination with CoronaVac and subsequent boosting schemes was observed primarily for mild to moderate cases during the Omicron period. Low neutralizing antibody responses against the Omicron variant have been observed in individuals receiving two doses of CoronaVac [18] [19] [20] and three doses of CoronaVac. 18 ,21 A BNT162b2 booster dose has been shown to increase neutralizing antibodies against Omicron compared to a primary series of CoronaVac, 18 ,21 and to a higher level than individuals who received a primary series of BNT162b2. 20 The protection against severe disease for inactivated vaccines observed in this study speaks to the gaps in understanding of correlates of protection against severe disease, with a decoupling between measured neutralizing antibodies and clinical protection. This disparity has been observed for the primary series of CoronaVac, with moderate-to-high levels of protection against severe disease maintained beyond six months 5 despite the lack of detectable neutralizing antibodies during this period. 22

Our findings on the effectiveness against severe Covid-19 of homologous and heterologous booster doses during the Delta period is consistent with a previous test-negative study in Brazil 5 and with a cohort study from Chile conducted during the same period. 23 For the Omicron period, our estimates are consistent with an ecological study from Hong Kong regarding the effectiveness of a primary vaccination with CoronaVac. 12 However, our estimates of vaccine effectiveness against severe disease for a homologous booster are lower than reported the study in Hong Kong. The differences in study design, previous attack rate in the population, time of follow-up, non-pharmaceutical interventions in place during the Omicron outbreak in Hong Kong, and limited sample size for severe disease in the Hong Kong study could explain these differences. 12 . CC-BY-NC-ND 4.0 International license It is made available under a 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 April 1, 2022. ; https://doi.org/10.1101/2022.03.30.22273193 doi: medRxiv preprint There was evidence for waning of effectiveness against mild disease for homologous and heterologous boosters, and against severe disease for a homologous booster dose after three months during the Omicron period. This finding is consistent with numerous studies of primary series vaccination, [4] [5] [6] and with more recent studies of booster dose effectiveness over time. 7, 24 Such studies should be interpreted with caution, as known biases in study designs can lead to the appearance of waning, 10,25,26 particularly due to the accrual of undetected infections in unvaccinated individuals. In this study, we attempted to mitigate this bias by estimating relative VE over time since booster dose administration. However, depletion of susceptible individuals who have received a primary series could still lead to apparent waning, and studies designed to identify and mitigate such biases should be prioritized to estimate the extent and timescale of waning effectiveness.

There are several strengths of our study. We used a nationwide database resulting in a large sample size and geographical coverage. We applied a matched test-negative design, including matching by time of epidemic and each one of 5,570 Brazilian municipalities. Finally, the timing of the booster campaign in Brazil together with the size and extent of the Omicron epidemic afforded us an opportunity to analyze a large population with three vaccine doses during an Omicron-dominated period, providing effectiveness estimates with relatively high precision even in age subgroups and over time.

Some limitations should be acknowledged. The data available for this study was collected as part of Brazil's passive surveillance efforts for Covid-19, so important covariates may be missing or incomplete. The distribution of RT-PCR tests and antigen tests, which have significantly different sensitivity, changed over the course of the study period, which could have led to a decrease in . CC-BY-NC-ND 4.0 International license It is made available under a 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 April 1, 2022. ; https://doi.org/10.1101/2022.03.30.22273193 doi: medRxiv preprint estimated VE during the Omicron period through misclassification. However, a sensitivity analysis restricted to RT-PCR tests produced similar results. In addition, the test-negative controls may have been different during the Omicron and Delta periods, which could explain some of the difference in VE estimates. In particular, a higher proportion of controls were hospitalized or died during the Delta period (Table 1) , implying either that other pathogens with severe outcomes were circulating during that period, or that less testing was being done in the outpatient setting during the Delta period. Finally, differences in effectiveness and waning patterns by age could be driven by other factors, including occupational exposure (e.g., health care workers) and personal risk mitigation behavior.

Overall, we found that primary vaccination with two doses of the CoronaVac vaccine provided 50-60% effectiveness against severe Covid-19 outcomes during the Omicron epidemic in Brazil, although effectiveness against symptomatic disease was close to zero. While a homologous booster afforded little additional protection, a heterologous booster dose of BNT162b2 restored high effectiveness against severe Covid-19, and moderate effectiveness against symptomatic disease up to three months.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 

We declare no competing interests.

We thank the Pan American Health Organization for its support. . CC-BY-NC-ND 4.0 International license It is made available under a 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 April 1, 2022. . CC-BY-NC-ND 4.0 International license It is made available under a 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 April 1, 2022. ; https://doi.org/10.1101/2022.03.30.22273193 doi: medRxiv preprint Figure 1 . Times series of Covid-19 cases and Covid-19 hospital admissions or deaths, variants of concern prevalence and vaccination coverage in Brazil from Sep 2021 to Mar 2022.

Daily prevalence of SARS-CoV-2 variants among genotyped isolates were obtained from the GISAID (global initiative on sharing avian influenza data) database (extraction on 18 March 2022). Green represents Delta prevalence, pink area represents Omicron prevalence and gray area represents others. Second dose coverage includes a single dose of Ad26.COV2.S. MA -moving averages.

. CC-BY-NC-ND 4.0 International license It is made available under a 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 April 1, 2022. . CC-BY-NC-ND 4.0 International license It is made available under a 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 April 1, 2022. . CC-BY-NC-ND 4.0 International license It is made available under a 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 April 1, 2022. . CC-BY-NC-ND 4.0 International license It is made available under a 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 April 1, 2022. . CC-BY-NC-ND 4.0 International license It is made available under a 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 April 1, 2022. 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 April 1, 2022. ; https://doi.org/10.1101/2022.03.30.22273193 doi: medRxiv preprint eTable 7. Vaccine effectiveness of homologous and heterologous booster relative to those at least 180 days after the second dose of a primary series of CoronaVac during the Omicron period, from the sensitivity analysis including RT-PCR SARS-CoV-2 tests only . CC-BY-NC-ND 4.0 International license It is made available under a 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 April 1, 2022. 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 April 1, 2022. . CC-BY-NC-ND 4.0 International license It is made available under a 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 April 1, 2022. . CC-BY-NC-ND 4.0 International license It is made available under a 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 April 1, 2022. . CC-BY-NC-ND 4.0 International license It is made available under a 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 April 1, 2022. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 1, 2022. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 1, 2022. ; https://doi.org/10.1101/2022.03.30.22273193 doi: medRxiv preprint

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Effectiveness of the CoronaVac vaccine in older adults during a gamma variant associated epidemic of covid-19 in Brazil: test negative case-control study

Association Between 3 Doses of mRNA COVID-19 Vaccine and Symptomatic Infection Caused by the SARS-CoV-2 Omicron and Delta Variants

Vaccine effectiveness of heterologous CoronaVac plus BNT162b2 in Brazil

Waning of BNT162b2 Vaccine Protection against SARS-CoV-2 Infection in Qatar

Covid-19 Vaccine Effectiveness against the Omicron (B.1.1.529) Variant

Strategic Advisory Group of Experts on Immunization -SAGE (WHO). Highlights from the Meeting of the Strategic Advisory Group of Experts (SAGE) on Immunization

Effect of mRNA Vaccine Boosters against SARS-CoV-2 Omicron Infection in Qatar

Duration of effectiveness of vaccines against SARS-CoV-2 infection and COVID-19 disease: results of a systematic review and meta-regression

Omicron thwarts some of the world's most-used COVID vaccines

Vaccine effectiveness of two and three doses of BNT162b2 and CoronaVac against COVID-19 in Hong Kong

Epidemiologic Surveillance Guide. National Emergency of Public Health Concern due to the COVID-19 disease

Effectiveness of Covid-19 Vaccines in Ambulatory and Inpatient Care Settings

Theoretical Basis of the Test-Negative Study Design for Assessment of Influenza Vaccine Effectiveness

R: A language and environment for statistical computing

Austria: R Foundation for Statistical Computing

Neutralizing antibodies against the SARS-CoV-2 Omicron variant BA.1 following homologous and heterologous CoronaVac or BNT162b2 vaccination

Neutralization of Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Variant by Sera From BNT162b2 or CoronaVac Vaccine Recipients. Clinical Infectious Diseases systems**, n (%) 17564 (25.4) 11866 (17.2) and RT-PCR testing, median (p25-p75)