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Effectiveness of an Inactivated SARS-CoV-2 Vaccine in Chile. BACKGROUND: Mass vaccination campaigns to prevent coronavirus disease 2019 (Covid-19) are occurring in many countries; estimates of vaccine effectiveness are urgently needed to support decision making. A countrywide mass vaccination campaign with the use of an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine (CoronaVac) was conducted in Chile starting on February 2, 2021. METHODS: We used a prospective national cohort, including participants 16 years of age or older who were affiliated with the public national health care system, to assess the effectiveness of the inactivated SARS-CoV-2 vaccine with regard to preventing Covid-19 and related hospitalization, admission to the intensive care unit (ICU), and death. We estimated hazard ratios using the extension of the Cox proportional-hazards model, accounting for time-varying vaccination status. We estimated the change in the hazard ratio associated with partial immunization (≥14 days after receipt of the first dose and before receipt of the second dose) and full immunization (≥14 days after receipt of the second dose). Vaccine effectiveness was estimated with adjustment for individual demographic and clinical characteristics. RESULTS: The study was conducted from February 2 through May 1, 2021, and the cohort included approximately 10.2 million persons. Among persons who were fully immunized, the adjusted vaccine effectiveness was 65.9% (95% confidence interval [CI], 65.2 to 66.6) for the prevention of Covid-19 and 87.5% (95% CI, 86.7 to 88.2) for the prevention of hospitalization, 90.3% (95% CI, 89.1 to 91.4) for the prevention of ICU admission, and 86.3% (95% CI, 84.5 to 87.9) for the prevention of Covid-19-related death. CONCLUSIONS: Our results suggest that the inactivated SARS-CoV-2 vaccine effectively prevented Covid-19, including severe disease and death, a finding that is consistent with results of phase 2 trials of the vaccine. (Funded by Agencia Nacional de Investigación y Desarrollo and others.).

We used a prospective observational cohort at the national level. The study cohort included participants 16 years of age or older who were affiliated with Fondo Nacional de Salud (FONASA), the national public health insurance program, which includes approximately 80% of the Chilean population. A detailed description of the vaccination campaign is provided in the Supplementary Appendix. Eligibility criteria included an age of 16 years or more, affiliation with FONASA, and receipt of at least one dose of the CoronaVac vaccine between February 2 and May 1, 2021, or no receipt of any Covid-19 vaccination. We excluded participants with a probable or confirmed SARS-CoV-2 infection, as assessed by reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay or antigen testing, on or before February 2, 2021, and persons who had received at least one dose of the BNT162b2 vaccine. We did not focus on the effectiveness of the BNT162b2 vaccine because these estimates have been provided elsewhere.15,17 We focused on the results regarding the CoronaVac vaccine because they are the mainstay of the vaccination strategy in Chile. However, we provide estimates of the effectiveness of the BNT162b2 vaccine in the Supplementary Appendix as a validation of the procedures used here.

estimates have been provided elsewhere.15,17 We focused on the results regarding the CoronaVac vaccine because they are the mainstay of the vaccination strategy in Chile. However, we provide estimates of the effectiveness of the BNT162b2 vaccine in the Supplementary Appendix as a validation of the procedures used here. All persons 16 years of age or older are eligible to receive the vaccine, according to the national vaccination schedule. We classified participants into three groups: those who were not vaccinated, those who were partially immunized (≥14 days after receipt of the first vaccine dose and before receipt of the second dose), and those who were fully immunized (≥14 days after receipt of the second dose). The study team was entirely responsible for the design of the study and for the collection and analysis of the data. The authors vouch for the accuracy and completeness of the data. The first, second, and last authors wrote the first draft of the manuscript.

All persons 16 years of age or older are eligible to receive the vaccine, according to the national vaccination schedule. We classified participants into three groups: those who were not vaccinated, those who were partially immunized (≥14 days after receipt of the first vaccine dose and before receipt of the second dose), and those who were fully immunized (≥14 days after receipt of the second dose). The study team was entirely responsible for the design of the study and for the collection and analysis of the data. The authors vouch for the accuracy and completeness of the data. The first, second, and last authors wrote the first draft of the manuscript. We estimated vaccine effectiveness using four primary outcomes: laboratory-confirmed Covid-19, hospitalization for Covid-19, admission to the ICU for Covid-19, and Covid-19–related death. For all the outcomes, we considered the time from the beginning of follow-up (February 2, 2021) to the onset of symptoms as the end point. Vaccine-effectiveness estimates regarding Covid-19 cases included the more severe outcomes. All suspected cases of Covid-19 in Chile are notified to health authorities by means of an online platform and are confirmed by laboratory testing. In our study, cases of Covid-19 and related deaths were those in persons with laboratory-confirmed infection, which corresponds to code U07.1 in the International Classification of Diseases, 10th Revision.

n Chile are notified to health authorities by means of an online platform and are confirmed by laboratory testing. In our study, cases of Covid-19 and related deaths were those in persons with laboratory-confirmed infection, which corresponds to code U07.1 in the International Classification of Diseases, 10th Revision. We controlled for several patient characteristics that could confound the association between vaccination and outcomes, including age, sex, region of residence, income, nationality, and whether the patient had underlying conditions that have been associated with severe Covid-19. These conditions included chronic kidney disease, diabetes, cardiovascular disease, stroke, chronic obstructive pulmonary disease, hematologic disease, autoimmune disease, human immunodeficiency virus infection, and Alzheimer’s disease and other dementias.4,33-35

nditions that have been associated with severe Covid-19. These conditions included chronic kidney disease, diabetes, cardiovascular disease, stroke, chronic obstructive pulmonary disease, hematologic disease, autoimmune disease, human immunodeficiency virus infection, and Alzheimer’s disease and other dementias.4,33-35 Our analysis was broadly based on the analytic methods of Thompson et al.17 for estimating vaccine effectiveness in the United States. We determined vaccine effectiveness by estimating the hazard ratio between the vaccinated and unvaccinated groups. On the basis of the observed information regarding the time to symptom onset from February 2, 2021, we estimated hazard ratios using the extension of the Cox proportional-hazards model, which allowed us to account for a time-varying vaccination status of the persons in the study. We evaluated the robustness of the model assumptions by fitting a stratified version of the extended Cox proportional-hazards model using the available predictors. Inference was based on a partial likelihood approach (Section S2).17 We estimated the change in the hazard associated with partial immunization and full immunization, and both time-to-event analyses were performed separately. Because the immunity status induced by the CoronaVac vaccine is unknown during the 13 days between vaccine administration and partial or full immunization, those periods were excluded from the at-risk person-time in our analyses.17

zation and full immunization, and both time-to-event analyses were performed separately. Because the immunity status induced by the CoronaVac vaccine is unknown during the 13 days between vaccine administration and partial or full immunization, those periods were excluded from the at-risk person-time in our analyses.17 We estimated the vaccine effectiveness as 1 minus the corresponding hazard ratio, obtained from a model including the previously described covariates, which was expressed as a percentage. We also provide the results with adjustment for the effect of sex and age only. To evaluate whether our effectiveness results were affected by potentially different access to health care between vaccinated persons and unvaccinated persons and according to the age distribution, we performed subgroup analyses involving the subgroup of persons with access to RT-PCR or antigen testing for SARS-CoV-2 and subgroups of persons 60 years of age or older and persons 16 to 59 years of age. Statistical analyses were conducted with the use of the survival package of R software, version 4.0.5.36,37

We estimated vaccine effectiveness using four primary outcomes: laboratory-confirmed Covid-19, hospitalization for Covid-19, admission to the ICU for Covid-19, and Covid-19–related death. For all the outcomes, we considered the time from the beginning of follow-up (February 2, 2021) to the onset of symptoms as the end point. Vaccine-effectiveness estimates regarding Covid-19 cases included the more severe outcomes. All suspected cases of Covid-19 in Chile are notified to health authorities by means of an online platform and are confirmed by laboratory testing. In our study, cases of Covid-19 and related deaths were those in persons with laboratory-confirmed infection, which corresponds to code U07.1 in the International Classification of Diseases, 10th Revision. We controlled for several patient characteristics that could confound the association between vaccination and outcomes, including age, sex, region of residence, income, nationality, and whether the patient had underlying conditions that have been associated with severe Covid-19. These conditions included chronic kidney disease, diabetes, cardiovascular disease, stroke, chronic obstructive pulmonary disease, hematologic disease, autoimmune disease, human immunodeficiency virus infection, and Alzheimer’s disease and other dementias.4,33-35

Our analysis was broadly based on the analytic methods of Thompson et al.17 for estimating vaccine effectiveness in the United States. We determined vaccine effectiveness by estimating the hazard ratio between the vaccinated and unvaccinated groups. On the basis of the observed information regarding the time to symptom onset from February 2, 2021, we estimated hazard ratios using the extension of the Cox proportional-hazards model, which allowed us to account for a time-varying vaccination status of the persons in the study. We evaluated the robustness of the model assumptions by fitting a stratified version of the extended Cox proportional-hazards model using the available predictors. Inference was based on a partial likelihood approach (Section S2).17 We estimated the change in the hazard associated with partial immunization and full immunization, and both time-to-event analyses were performed separately. Because the immunity status induced by the CoronaVac vaccine is unknown during the 13 days between vaccine administration and partial or full immunization, those periods were excluded from the at-risk person-time in our analyses.17

Figure 1 shows the flow diagram of the study cohort. Of the 11,820,292 persons 16 years of age or older who were affiliated with FONASA, 10,187,720 were eligible for inclusion in the study. Table 1 shows the descriptive statistics for the approximately 10.2 million participants included in the study cohort. There were significant differences according to geographic region, sex, age, income group, nationality, and presence of underlying medical conditions, both in the incidence of Covid-19 and according to vaccination status (unvaccinated, vaccinated with only one dose, or vaccinated with two doses). Laboratory confirmation of infection was by RT-PCR assay in 98.1% of the cases and by antigen testing in 1.9%. Figure 2A shows the rapid rollout of the vaccination campaign, which started on February 2, 2021. Details of the vaccination campaign are provided in Section S1 and Figures S5 through S8. Figure 2B shows the crude cumulative incidence of Covid-19 during the study period among persons who had received one or two doses of vaccine or were unvaccinated. There were approximately 615 million person-days in the unvaccinated group, 70 million person-days in the partially immunized group, and 92 million person-days in the fully immunized group during the study period (Table 2). We documented 218,784 cases of Covid-19, as well as 22,866 hospitalizations, 7873 ICU admissions, and 4042 deaths.

mately 615 million person-days in the unvaccinated group, 70 million person-days in the partially immunized group, and 92 million person-days in the fully immunized group during the study period (Table 2). We documented 218,784 cases of Covid-19, as well as 22,866 hospitalizations, 7873 ICU admissions, and 4042 deaths. We estimated that the vaccine effectiveness among partially immunized persons (14 to 28 days after receipt of the first dose) was 15.5% (95% CI, 14.2 to 16.8) for the prevention of Covid-19 and 37.4% (95% CI, 34.9 to 39.9) for the prevention of hospitalization, 44.7% (95% CI, 40.8 to 48.3) for the prevention of admission to the ICU, and 45.7% (95% CI, 40.9 to 50.2) for the prevention of Covid-19–related death. In the fully immunized group, the estimated adjusted vaccine effectiveness was 65.9% (95% CI, 65.2 to 66.6) for the prevention of Covid-19 and 87.5% (95% CI, 86.7 to 88.2) for the prevention of hospitalization, 90.3% (95% CI, 89.1 to 91.4) for the prevention of ICU admission, and 86.3% (95% CI, 84.5 to 87.9) for the prevention of Covid-19–related death (Table 2). The vaccine-effectiveness estimates in the stratified model were consistent with these results.

d 87.5% (95% CI, 86.7 to 88.2) for the prevention of hospitalization, 90.3% (95% CI, 89.1 to 91.4) for the prevention of ICU admission, and 86.3% (95% CI, 84.5 to 87.9) for the prevention of Covid-19–related death (Table 2). The vaccine-effectiveness estimates in the stratified model were consistent with these results. We estimated that the adjusted vaccine effectiveness in the subgroup of fully immunized persons 60 years of age or older was 66.6% (95% CI, 65.4 to 67.8) for the prevention of Covid-19 and 85.3% (95% CI, 84.3 to 86.3) for the prevention of hospitalization, 89.2% (95% CI, 87.6 to 90.6) for the prevention of ICU admission, and 86.5% (95% CI, 84.6 to 88.1) for the prevention of Covid-19–related death (Table 3). Vaccine-effectiveness estimates among persons 16 to 59 years of age are provided in Table S3.

and 85.3% (95% CI, 84.3 to 86.3) for the prevention of hospitalization, 89.2% (95% CI, 87.6 to 90.6) for the prevention of ICU admission, and 86.5% (95% CI, 84.6 to 88.1) for the prevention of Covid-19–related death (Table 3). Vaccine-effectiveness estimates among persons 16 to 59 years of age are provided in Table S3. To address a potential concern that the observed vaccine effectiveness may have been driven by health care access, we conducted an analysis in the subgroup of persons who had undergone testing with an RT-PCR assay (98.1%) or antigen test (1.9%) during the analysis period. The results, conditional on whether testing was performed, showed larger effects for vaccination than when we included the complete cohort. Among fully immunized persons in this subgroup, the adjusted vaccine effectiveness was 72.9% (95% CI, 72.3 to 73.4) for the prevention of Covid-19 and 89.2% (95% CI, 88.5 to 89.8) for the prevention of hospitalization, 91.6% (95% CI, 90.5 to 92.5) for the prevention of ICU admission, and 87.8% (95% CI, 86.2 to 89.2) for the prevention of Covid-19–related death (Table S4).

Figure 1 shows the flow diagram of the study cohort. Of the 11,820,292 persons 16 years of age or older who were affiliated with FONASA, 10,187,720 were eligible for inclusion in the study. Table 1 shows the descriptive statistics for the approximately 10.2 million participants included in the study cohort. There were significant differences according to geographic region, sex, age, income group, nationality, and presence of underlying medical conditions, both in the incidence of Covid-19 and according to vaccination status (unvaccinated, vaccinated with only one dose, or vaccinated with two doses). Laboratory confirmation of infection was by RT-PCR assay in 98.1% of the cases and by antigen testing in 1.9%. Figure 2A shows the rapid rollout of the vaccination campaign, which started on February 2, 2021. Details of the vaccination campaign are provided in Section S1 and Figures S5 through S8. Figure 2B shows the crude cumulative incidence of Covid-19 during the study period among persons who had received one or two doses of vaccine or were unvaccinated.

There were approximately 615 million person-days in the unvaccinated group, 70 million person-days in the partially immunized group, and 92 million person-days in the fully immunized group during the study period (Table 2). We documented 218,784 cases of Covid-19, as well as 22,866 hospitalizations, 7873 ICU admissions, and 4042 deaths. We estimated that the vaccine effectiveness among partially immunized persons (14 to 28 days after receipt of the first dose) was 15.5% (95% CI, 14.2 to 16.8) for the prevention of Covid-19 and 37.4% (95% CI, 34.9 to 39.9) for the prevention of hospitalization, 44.7% (95% CI, 40.8 to 48.3) for the prevention of admission to the ICU, and 45.7% (95% CI, 40.9 to 50.2) for the prevention of Covid-19–related death. In the fully immunized group, the estimated adjusted vaccine effectiveness was 65.9% (95% CI, 65.2 to 66.6) for the prevention of Covid-19 and 87.5% (95% CI, 86.7 to 88.2) for the prevention of hospitalization, 90.3% (95% CI, 89.1 to 91.4) for the prevention of ICU admission, and 86.3% (95% CI, 84.5 to 87.9) for the prevention of Covid-19–related death (Table 2). The vaccine-effectiveness estimates in the stratified model were consistent with these results.

We provide estimates of the effectiveness of administration of the CoronaVac vaccine in a countrywide mass vaccination campaign for the prevention of laboratory-confirmed Covid-19 and related hospitalization, admission to the ICU, and death. Among fully immunized persons, the adjusted vaccine effectiveness was 65.9% for Covid-19 and 87.5% for hospitalization, 90.3% for ICU admission, and 86.3% for death. The vaccine-effectiveness results were maintained in both age-subgroup analyses, notably among persons 60 years of age or older, independent of variation in testing and independent of various factors regarding vaccine introduction in Chile.

19 and 87.5% for hospitalization, 90.3% for ICU admission, and 86.3% for death. The vaccine-effectiveness results were maintained in both age-subgroup analyses, notably among persons 60 years of age or older, independent of variation in testing and independent of various factors regarding vaccine introduction in Chile. The vaccine-effectiveness results in our study are similar to estimates that have been reported in Brazil for the prevention of Covid-19 (50.7%; 95% CI, 35.6 to 62.2), including estimates of cases that resulted in medical treatment (83.7%; 95% CI, 58.0 to 93.7) and estimates of a composite end point of hospitalized, severe, or fatal cases (100%; 95% CI, 56.4 to 100).27 The large confidence intervals for the trial in Brazil reflect the relatively small sample (9823 participants) and the few cases detected (35 cases that led to medical treatment and 10 that were severe). However, our estimates are lower than the vaccine effectiveness recently reported in Turkey (83.5%; 95% CI, 65.4 to 92.1),27,28 possibly owing to the small sample in that phase 3 clinical trial (10,029 participants in the per-protocol analysis), differences in local transmission dynamics, and the predominance of older adults among the fully or partially immunized participants in our study. Overall, our results suggest that the CoronaVac vaccine had high effectiveness against severe disease, hospitalizations, and death, findings that underscore the potential of this vaccine to save lives and substantially reduce demands on the health care system.

the fully or partially immunized participants in our study. Overall, our results suggest that the CoronaVac vaccine had high effectiveness against severe disease, hospitalizations, and death, findings that underscore the potential of this vaccine to save lives and substantially reduce demands on the health care system. Our study has at least three main strengths. First, we used a rich administrative health care data set, combining data from an integrated vaccination system for the total population and from the Ministry of Health FONASA, which covers approximately 80% of the Chilean population. These data include information on laboratory tests, hospitalization, mortality, onset of symptoms, and clinical history in order to identify risk factors for severe disease. Information on region of residence also allowed us to control for differences in incidence across the country. We adjusted for income and nationality, which correlate with socioeconomic status in Chile and are thus considered to be social determinants of health. The large population sample allowed us to estimate vaccine effectiveness both for one dose and for the complete two-dose vaccination schedule. It also allowed for a subgroup analysis involving adults 60 years of age or older, a subgroup that is at higher risk for severe disease3 and that is underrepresented in clinical trials. Second, data were collected during a rapid vaccination campaign with high uptake and during a period with one of the highest community transmission rates of the pandemic, which allowed for a relatively short follow-up period and for estimation of the prevention of at least four essential outcomes: Covid-19 cases and related hospitalization, ICU admission, and death. Finally, Chile has the highest testing rates for Covid-19 in Latin America, universal health care access, and a standardized, public reporting system for vital statistics, which limited the number of undetected or unascertained cases and deaths.14

s: Covid-19 cases and related hospitalization, ICU admission, and death. Finally, Chile has the highest testing rates for Covid-19 in Latin America, universal health care access, and a standardized, public reporting system for vital statistics, which limited the number of undetected or unascertained cases and deaths.14 Our study has several limitations. First, as an observational study, it is subject to confounding. To account for known confounders, we adjusted the analyses for relevant variables that could affect vaccine effectiveness, such as age, sex, underlying medical conditions, region of residence, and nationality. The risk of misclassification bias that would be due to the time-dependent performance of the SARS-CoV-2 RT-PCR assay is relatively low, because the median time from symptom onset to testing in Chile is approximately 4 days (98.1% of the tests were RT-PCR assays). In this 4-day period, the sensitivity and specificity of the molecular diagnosis of Covid-19 are high.38 However, there may be a risk of selection bias. Systematic differences between the vaccinated and unvaccinated groups, such as health-seeking behavior or risk aversion, may affect the probability of exposure to the vaccine and the risk of Covid-19 and related outcomes.39,40 However, we cannot be sure about the direction of the effect. Persons may be hesitant to get the vaccine for various reasons, including fear of side effects, lack of trust in the government or pharmaceutical companies, or an opinion that they do not need it, and they may be more or less risk-averse. Vaccinated persons may compensate by increasing their risky behavior (Peltzman effect).40 We addressed potential differences in health care access by restricting the analysis to persons who had undergone diagnostic testing, and we found results that were consistent with those of our main analysis.

or less risk-averse. Vaccinated persons may compensate by increasing their risky behavior (Peltzman effect).40 We addressed potential differences in health care access by restricting the analysis to persons who had undergone diagnostic testing, and we found results that were consistent with those of our main analysis. Second, owing to the relatively short follow-up in this study, late outcomes may not have yet developed in persons who were infected near the end of the study, because the time from symptom onset to hospitalization or death can vary substantially.3,15 Therefore, effectiveness estimates regarding severe disease and death, in particular, should be interpreted with caution. Third, during the study period, ICUs in Chile were operating at 93.5% of their capacity on average (65.7% of the patients had Covid-19).32 If fewer persons were hospitalized than would be under regular ICU operation, our effectiveness estimates for protection against ICU admission might be biased downward, and our effectiveness estimates for protection against death might be biased upward (e.g., if patients received care at a level lower than would usually be received during regular health system operation).

regular ICU operation, our effectiveness estimates for protection against ICU admission might be biased downward, and our effectiveness estimates for protection against death might be biased upward (e.g., if patients received care at a level lower than would usually be received during regular health system operation). Fourth, although the national genomic surveillance for SARS-CoV-2 in Chile has reported the circulation of at least two viral lineages considered to be variants of concern, P.1 and B.1.1.7 (or the gamma and alpha variants, respectively),41 we lack representative data to estimate their effect on vaccine effectiveness (Table S2). Results from a test-negative design study of the effectiveness of the CoronaVac vaccine in health care workers in Manaus, Brazil, where the gamma variant is now predominant, showed that the efficacy of at least one dose of the vaccine against Covid-19 was 49.6% (95% CI, 11.3 to 71.4).30 Although the vaccine-effectiveness estimates in Brazil are not directly comparable with our estimates owing to differences in the target population, the vaccination schedule (a window of 14 to 28 days between doses is recommended in Brazil42), and immunization status, they highlight the importance of continued vaccine-effectiveness monitoring. Overall, our study results suggest that the CoronaVac vaccine was highly effective in protecting against severe disease and death, findings that are consistent with the results of phase 2 trials23,24 and with preliminary efficacy data.27,28