Several countries have authorised or begun using a booster vaccine dose against COVID-19. Policy makers urgently need evidence of the effectiveness of additional vaccine doses and its clinical spectrum for individuals with complete primary immunisation schedules, particularly in countries where the primary schedule used inactivated SARS-CoV-2 vaccines.
Using individual-level data, we evaluated a prospective, observational, national-level cohort of individuals (aged ≥16 years) affiliated with the Fondo Nacional de Salud insurance programme in Chile, to assess the effectiveness of CoronaVac (Sinovac Biotech), AZD1222 (Oxford-AstraZeneca), or BNT162b2 (Pfizer-BioNTech) vaccine boosters in individuals who had completed a primary immunisation schedule with CoronaVac, compared with unvaccinated individuals. Individuals administered vaccines from Feb 2, 2021, to the prespecified study end date of Nov 10, 2021, were evaluated; we excluded individuals with a probable or confirmed SARS-CoV-2 infection (RT-PCR or antigen test) on or before Feb 2, 2021, and individuals who had received at least one dose of any COVID-19 vaccine before Feb 2, 2021. We estimated the vaccine effectiveness of booster doses against laboratory-confirmed symptomatic COVID-19 (symptomatic COVID-19) cases and COVID-19 outcomes (hospitalisation, admission to the intensive care unit [ICU], and death We used inverse probability-weighted and stratified survival regression models to estimate hazard ratios, accounting for time-varying vaccination status and adjusting for relevant demographic, socioeconomic, and clinical confounders. We estimated the change in hazard from unvaccinated status to vaccinated status associated with the primary immunisation series and a booster vaccine.
11 174 257 individuals were eligible for this study, among whom 4 127 546 completed a primary immunisation schedule (two doses) with CoronaVac and received a booster dose during the study period. 1 921 340 (46·5%) participants received an AZD1222 booster, 2 019 260 (48·9%) received a BNT162b2 booster, and 186 946 (4·5%) received a homologous booster with CoronaVac. We calculated an adjusted vaccine effectiveness (weighted stratified Cox model) in preventing symptomatic COVID-19 of 78·8% (95% CI 76·8–80·6) for a three-dose schedule with CoronaVac, 96·5% (96·2–96·7) for a BNT162b2 booster, and 93·2% (92·9–93·6) for an AZD1222 booster. The adjusted vaccine effectiveness against COVID-19-related hospitalisation, ICU admission, and death was 86·3% (83·7–88·5), 92·2% (88·7–94·6), and 86·7% (80·5–91·0) for a homologous CoronaVac booster, 96·1% (95·3–96·9), 96·2% (94·6–97·3), and 96·8% (93·9–98·3) for a BNT162b2 booster, and 97·7% (97·3–98·0), 98·9% (98·5–99·2), and 98·1% (97·3–98·6) for an AZD1222 booster.
Our results suggest that a homologous or heterologous booster dose for individuals with a complete primary vaccination schedule with CoronaVac provides a high level of protection against COVID-19, including severe disease and death. Heterologous boosters showed higher vaccine effectiveness than a homologous booster for all outcomes, providing additional support for a mix-and-match approach.
Agencia Nacional de Investigación y Desarrollo through the Fondo Nacional de Desarrollo Científico y Tecnológico, Millennium Science Initiative Program, and Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias.
COVID-19 vaccines are now an essential component of the pandemic response to reduce disease burden and allow a safer reopening of society and economic recovery. 23 effective COVID-19 vaccines have been approved for use since the first vaccine tested in a large randomised clinical trial was approved in the UK on Dec 2, 2020,
and several new vaccines are in the final testing stage. The efficacy, effectiveness, and safety profiles of numerous vaccine platforms are well supported by large-scale efficacy trials or observational studies. Many countries are currently running mass vaccination campaigns.
Evidence before this study
We searched PubMed and medRxiv for research articles, with no language restrictions, using the search terms (“COVID-19” OR “SARS-CoV-2” OR “2019-nCoV” OR “coronavirus”) AND (“vaccine” OR “vaccination”) AND (“third dose” OR “booster”). We searched for studies published between Dec 1, 2020, and Dec 10, 2021. We identified five original clinical studies on the effectiveness of booster doses for SARS-CoV-2 vaccines. Four studies from Israel examined the effectiveness of a third dose of Pfizer-BioNTech’s mRNA vaccine BNT162b2 compared with the primary vaccination series. One study estimated a 70–84% reduction in the probability of testing positive for SARS-CoV-2 infection among individuals who had received a third dose, but did not examine other outcomes. Another study found that the infection rate in the booster group was lower by a factor of 11·3 for confirmed infection and by a factor of 19·5 for severe illness, but did not adjust for comorbidities. The third study found a 90% lower COVID-19 related mortality rate among participants with a third dose. The fourth study estimated that the vaccine effectiveness of a third dose of BNT162b2 was 93% against hospital admission, 92% against severe disease, and 81% against death. Additionally, a preprint study found that, compared with demographically and clinically matched individuals with two doses, the effectiveness of a third dose in preventing SARS-CoV-2 infection and hospitalisation was 46% and 47%, respectively, for BNT162b2, and 47% and 50%, respectively, for Moderna’s mRNA-1273 vaccine. All available evidence relates to mRNA vaccines. We found no studies examining the effectiveness of a homologous or heterologous booster dose for individuals with a complete primary vaccination schedule with an inactivated SARS-CoV-2 vaccine.
Added value of this study
Our study estimates the effectiveness of a homologous or heterologous booster dose for individuals with a complete primary vaccination schedule with an inactivated SARS-CoV-2 vaccine (CoronaVac), which is among the world’s most widely used COVID-19 vaccines. Specifically, we used a prospective national cohort of 11·2 million people aged 16 years or older to assess the effectiveness of CoronaVac, AZD1222, or BNT162b2 vaccine boosters in individuals who had completed their primary immunisation schedule with CoronaVac. We assessed vaccine effectiveness against symptomatic COVID-19 and COVID-19 outcomes (hospitalisation, admission to the intensive care unit, and death) between treated individuals (three doses) and non-treated individuals (unvaccinated), adjusting for known demographic, socioeconomic, and clinical confounders by inverse probability of treatment weighting. We found that a homologous or heterologous booster dose significantly increased vaccine effectiveness against COVID-19 and COVID-19 outcomes.
Implications of all the available evidence
COVID-19 vaccines are an essential component of the pandemic response to reduce disease burden. However, increasing evidence suggests that vaccine protection against COVID-19 might be decreasing over time or have lower effectiveness against the delta variant (B.1.617.2). The decrease in vaccine protection is particularly worrying for inactivated vaccines, which offer lower protection than other vaccine technologies. Considering this emerging evidence, several countries have authorised or begun using a third dose. Our results suggest that a homologous or heterologous booster dose for individuals with a complete primary vaccination schedule with CoronaVac provides a high level of protection against COVID-19, including severe disease and death, with the heterologous boosters offering higher protection than the homologous booster.
Although the correlates of protection from COVID-19 vaccines are not fully understood,
research has shown a time-dependent decrease in humoral immune responses after vaccination with any vaccine against SARS-CoV-2,
which might parallel decreasing protection against infection and disease. Research suggests that this decrease also occurs for the CoronaVac inactivated SARS-CoV-2 vaccine produced by Sinovac Biotech.
Additionally, increasing reports are describing breakthrough infections among vaccinated individuals.
Recent research has shown that vaccine effectiveness might weaken over time, particularly for symptomatic illness.
These studies examined data for Pfizer-BioNTech’s mRNA vaccine (BNT162b2), and Oxford-AstraZeneca’s ChAdOx1 nCov-19 vaccine (AZD1222). Whether protection against more severe disease has also decreased is unknown. A potential decrease in vaccine protection is particularly worrying for inactivated vaccines, which offer lower protection than other vaccine technologies, and account for about half the COVID-19 vaccine doses delivered globally thus far.
Most of these countries have restricted vaccine boosters to people at high risk of SARS-CoV-2 infection or related complications, including older adults, health-care workers, and individuals with underlying health conditions. Other countries that have relied on inactivated vaccines, including Cambodia, Chile, Uruguay, Thailand, and Turkey, are offering homologous and heterologous booster doses to individuals immunised with primary inactivated SARS-CoV-2 vaccines schedules.
Policy makers urgently need evidence of the effectiveness of vaccine boosters against severe disease for individuals who have completed their primary immunisation schedules. Existing evidence for the effectiveness of boosters is limited to mRNA vaccines.
On Aug 11, 2021, the Ministry of Health began administering a booster dose for individuals fully vaccinated with CoronaVac. CoronaVac has been the campaign’s backbone, with 20·5 million (59·0%) of all doses administered (n=34·8 million doses) being CoronaVac as of Nov 16, 2021. Pfizer-BioNTech’s BNT162b2 vaccine represents 10·6 million (30·5%) doses, Oxford-AstraZeneca’s AZD1222 vaccine represents 3·1 million (8·8%) doses, and CanSino Biologics’ Ad5-nCoV vaccine represents 0·57 million (1·7%) doses Nov 16, 2021.
and provide essential information on homologous and heterologous vaccine booster schedules.
Table 1Characteristics of the study cohort of FONASA affiliates, Feb 2 to Nov 10, 2021
The 13 days between vaccine administration and partial or full immunisation were excluded from the at-risk person-time. We show the results for the standard and stratified versions of the extended Cox hazards model with inverse probability of treatment weighting, and without weighting as a robustness check.
suggesting that a three-dose schedule should be considered for primary immunisation with inactivated vaccines.
Another study found that the rate of infection in the booster group was lower by a factor of 11·3 for confirmed infection and by a factor of 19·5 for severe illness, but did not adjust for clinical confounders.
A third study found a 90% lower COVID-19-related mortality rate among participants with a third vaccine dose.
The fourth study found that the effectiveness of the third dose of BNT162b2 was 93% (95% CI 88–97) against hospitalisation, 92% (82–97) against severe COVID-19, and 81% (59–97) against COVID-19-related death.
A preprint study in the USA found lower risk of infection and hospitalisation with a third dose of BNT162b2 (46% and 47%, respectively) or Moderna’s mRNA-1273 (47% and 50%).
Although not directly comparable, our vaccine effectiveness estimates against COVID-19-related hospitalisation, ICU admission, and deaths for the third dose of BNT162b2 are higher than estimates in the USA,
but similar to those in Israel considering estimated CIs.
Our results suggest that a three-dose vaccination schedule for CoronaVac, one of the most commonly used COVID-19 vaccines globally,
substantially increases protection against severe illness. However, protection is significantly higher for individuals who receive a heterologous vaccine booster compared with a homologous booster with CoronaVac. Our data are consistent with a recent study in Brazil showing that homologous and heterologous (BNT162b2 and AZD1222) boosters following a two-dose CoronaVac vaccination schedule were safe and substantially enhanced humoral immune responses.
However, anti-spike IgG responses at day 28 were superior in all heterologous regimens compared with homologous regimens, suggesting enhanced protection. Our results for heterologous vaccine booster schedules with BNT162b2 and AZD1222 booster doses also show encouraging results for individuals with a complete primary immunisation schedule with CoronaVac, providing additional support for using a mix-and-match approach. These findings might be crucial for policymakers, particularly in low-resource settings.
although there is no consensus on the speed of this decrease, and whether protection against severe COVID-19 also decreases. Although the priority should be to ensure that vulnerable individuals across the globe are vaccinated, particularly considering that some COVID-19 vaccines probably provide enough protection against severe disease for the most prevalent SARS-CoV-2 lineages,
our results suggest that booster doses substantially increase vaccine effectiveness for a CoronaVac primary series. These results are consistent with evidence for BNT162b2 in Israel.
Rolling out booster vaccine doses parallel to primary immunisation campaigns might become a powerful strategy to reduce SARS-CoV-2 infections and mitigate its consequences. Our results are aligned with the recommendation of WHO’s Strategic Advisory Group of Experts, to provide a third dose to people aged 60 years or older,
without neglecting primary immunisation coverage also recommended by WHO.
The main strengths of our study include the use of a diverse cohort of 11·2 million individuals, with combined vaccination and administrative health-care data and representing about 80% of the Chilean population. We collected data on demographic variables, residence, income, nationality, and comorbidities, in addition to data on testing, health-care use, vital statistics, and vaccination. The large sample size allowed us to non-parametrically estimate inverse probability of treatment weights and fit a stratified extended Cox proportional hazards model for the different outcomes of interest (given that each combination of predictors has a specific hazard function), adding robustness to our statistical approach. In addition, we assessed the performance of homologous and heterologous booster doses, which provides valuable evidence to policy makers globally, particularly for countries that have used CoronaVac and are considering booster doses. The availability of a diverse matrix of highly effective booster alternatives should avoid potential vaccine supply shortages, helping countries implement and sustain COVID-19 vaccination efforts over time.
We cannot be sure in which direction, if any, these systematic differences affect vaccine effectiveness estimates. For example, publicly reported effectiveness results for the CoronaVac vaccine in Chile during May, 2021, might have resulted in fully vaccinated people taking more risks for acquiring SARS-CoV-2 infection than unvaccinated individuals.
As we have described (appendix pp 3–6), the Chilean Ministry of Health organised a vaccination rollout through a publicly available vaccination schedule. In the current strategy, individuals need to attend the nearest vaccination site with a form of personal identification; no appointments are required. The risk for misclassification bias with the exposure or the outcomes is low. Chile has a single, electronic, and centralised immunisation registry, and SARS-CoV-2 testing is free and widely available.
the predominant circulating variant in Chile at the time of our analysis. We do not have representative data to estimate the true prevalence of these variants and their effect on vaccine effectiveness, which could be highly relevant to control the pandemic. A third limitation is that individuals younger than 55 years were not eligible for AZD1222 booster doses, so results cannot be directly compared among the different vaccines. Giving the AZD1222 boosters to older individuals at increased risk of COVID-19 and related outcomes might have resulted in lower estimated vaccine effectiveness compared with a situation in which all ages were eligible to receive AZD1222 boosters. A final limitation is that we estimated vaccine effectiveness within 3 months after the booster doses became available, but increasing evidence suggests that vaccine protection might decrease over time.
Overall, our results suggest that a homologous or heterologous booster vaccine dose for individuals with a complete primary vaccination schedule with CoronaVac results in a high level of protection against COVID-19, including severe disease and death. Heterologous boosters showed higher vaccine effectiveness than a homologous booster for all clinical outcomes considered, providing additional support for use of a mix-and-match approach.
AJ and RA conceived and designed the study. JRZ provided support for the study design and analytic approach. AJ, FP, TB, and RA managed and analysed the data. AJ, RA, and EU wrote the first draft of the manuscript. AJ, EU, JRZ, CG, AP, JA, KL, FP, TB, VV, MM, FL, IP, PL, PS, JCR, HGE, and RA, critically reviewed and edited the manuscript. AJ, RA, CG, AP, JA, KL, FP, TB, VV, MM, FL, IP, PL, PS, JCR, and HGE had full access to study data. VV, HGE, and RA had access to vaccine safety data. RA and HGE had access to genomic surveillance data. The author group was entirely responsible for study design, data collection, and data analysis. All authors vouch for the accuracy and completeness of the data and accept responsibility for publication.