key: cord-0807300-9ov4w48q authors: Bello-Chavolla, O. Y.; Antonio-Villa, N. E.; Valdes-Ferrer, S. I.; Fermin-Martinez, C. A.; Fernandez-Chirino, L.; Ramirez-Garcia, D.; Mancilla-Galindo, J.; Kammar-Garcia, A.; Avila-Funes, J. A.; Zuniga-Gil, C. H.; Garcia-Grimshaw, M.; Ceballos-Liceaga, S. E.; Carbajal-Sandoval, G.; Montes-Gonzalez, J. A.; Zaragoza-Jimenez, C. A.; Garcia-Rodriguez, G.; Cortes-Alcala, R.; Reyes-Teran, G.; Lopez-Gatell, H.; Gutierrez-Robledo, L. M. title: Effectiveness of a nation-wide COVID-19 vaccination program in Mexico date: 2022-04-05 journal: nan DOI: 10.1101/2022.04.04.22273330 sha: 5dbe758a28f87ff7389ea529a683f138a805c0b6 doc_id: 807300 cord_uid: 9ov4w48q BACKGROUND: Vaccination has been effective in ameliorating the impact of COVID-19. However, estimation of vaccine effectiveness (VE) is still unavailable for some widely used vaccines and underrepresented groups. Here, we report on the effectiveness of a nation-wide COVID-19 vaccination program in Mexico. METHODS: We used a test-negative design within a national COVID-19 surveillance system to assess VE of the BNT162b2, mRNA-12732, Gam-COVID-Vac, Ad5-nCoV, Ad26.COV2.S, ChAdOx1 and CoronaVac vaccines, against SARS-CoV-2 infection, COVID-19 related hospitalization and death for adults [≥]18 years in Mexico. VE was estimated using Cox proportional hazard models considering time-varying vaccination status in partial and fully vaccinated individuals compared to unvaccinated adults, adjusted by age, sex, comorbidities and municipality. We also estimated VE for adults [≥]60 years, for cases with diabetes and comparing periods with predominance of variants B.1.1.519 and B.1.617.2. RESULTS: We assessed 793,487 vaccinated compared to 4,792,338 unvaccinated adults between December 24th, 2020, and September 27th, 2021. VE against SARS-CoV-2 infection was highest for fully vaccinated individuals with mRNA-12732 (91.5%, 95%CI 90.3-92.4) and Ad26.COV2.S (82.2%, 95%CI 81.4-82.9), whereas for COVID-19 related hospitalization were BNT162b2 (84.3%, 95%CI 83.6-84.9) and Gam-COVID-Vac (81.4% 95%CI 79.5-83.1) and for mortality BNT162b2 (89.8%, 95%CI 89.2-90.2) and mRNA-12732 (93.5%, 95%CI 86.0-97.0). VE for all evaluated vaccines was reduced for adults [≥]60 years, people with diabetes, and in periods of Delta variant predominance. CONCLUSIONS: All evaluated vaccines were effective against SARS-CoV-2 infection and COVID-19 related hospitalization and death. Mass vaccination campaigns with multiple vaccine products are feasible and effective to maximize vaccination coverage. 3 . 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 5, 2022. ; https://doi.org/10.1101/2022.04.04.22273330 doi: medRxiv preprint Coronavirus Disease (COVID- 19) has imposed a significant public health challenge worldwide. In Mexico, mitigation of COVID-19 has imposed a significant challenge due to the large impact of cardio-metabolic diseases and long-standing socio-demographic and healthcare inequalities in the region [1] [2] [3] . The most significant contributing factor to decreasing the impact of COVID-19 has been the availability of vaccines to prevent symptomatic and severe forms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections 4, 5 . Available COVID-19 vaccines are effective in preventing symptomatic SARS-CoV-2 infection and COVID-19 related hospitalization and death 6-12 . Despite the availability or randomized clinical trials to inform vaccine efficacy, populationbased studies to estimate vaccine effectiveness are required to evaluate and inform future vaccine rollouts, assess and prioritize eligibility for vaccine boosters and reduce vaccine hesitancy 13 . 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 5, 2022. ; https://doi.org/10.1101/2022.04.04.22273330 doi: medRxiv preprint who may benefit from prioritization for booster allocation, are often underrepresented in clinical trials; evaluating effectiveness for COVID-19 vaccines in these groups remains a public health priority 27 . In this study, we sought to provide the first nation-wide evaluation for the effectiveness of nationally available COVID-19 vaccines for SARS-CoV-2 infections and COVID-19 hospitalization and death, and the impact of circulating variants, older age and comorbidities in modifying effectiveness for COVID-19 vaccines implemented within the Mexican vaccination program during 2020-2021. We conducted a retrospective national cohort, using a test-negative design to evaluate vaccine effectiveness for nationally available COVID- 19 26, 27 . Mexico approached its vaccination strategy by incorporating multiple vaccine products to maximize national vaccination coverage. SARS-CoV-2 vaccines which were applied 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 5, 2022. We calculated vaccine effectiveness (VE) based on three primary outcomes: 1) SARS-CoV-2 infections including both symptomatic and asymptomatic individuals, which considered laboratory confirmed SARS-CoV-2 infections with either rapid antigen test or RT-PCR. All diagnostic tests used to identify SARS-CoV-2 infections were certified by COFEPRIS and identified as per WHO recommendations 31 . 2) COVID-19 related hospitalization and 3) COVID-19 related death. We also further stratified VE based the following criteria: . 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. 2) Age strata -Given underrepresentation of older adults in vaccine clinical trials and observed inequities on the impact of COVID-19 on this population in Mexico 2 , we evaluated VE using 60 years as the cut-off for age. 3) Comorbidities -Prevalence of diabetes and obesity in Mexican population are high and the impact of their impact on the course of the COVID-19 pandemic in Mexico have been widely reported 1, 33, 34 . To this end, we also evaluated vaccine effectiveness for individuals with diabetes and, secondarily, obesity. VE was estimated using a Cox proportional hazard regression model, which accounts for the time-varying covariate of time from beginning of follow-up until vaccination, as previously described 26, 35 . The model is presented as follows: Exposure time was calculated from December 24 th , 2020, until the onset of each evaluated outcome or until last follow-up, whichever occurred first. Vaccination status will be evaluated as a time-dependent covariate for each evaluated vaccine, calculated as the . 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 5, 2022. ; https://doi.org/10.1101/2022.04.04.22273330 doi: medRxiv preprint 8 time from study entry to application of the first dose of any received vaccine. VE will be estimated for each evaluated vaccine product, where effectiveness is defined as 1 minus the hazard ratio of the resulting Cox model. For each comparison, each individual vaccine product was compared to unvaccinated population; this was also conducted for subgroup analyses for age, predominant circulating variant and comorbidities. We fitted all models for each vaccine product adjusted for age, sex, comorbidities and stratified per municipality of origin to account for region-level variation in pandemic dynamics, including all stratified analyses. All statistical analyses were conducted using R version 4.1.2. We evaluated 793,487 vaccinated persons aged 18 or older and with Detailed effectiveness for SARS-CoV-2 infection and COVID-19 related hospitalization and mortality are available in Table 1 and stratified by subgroups in Figure 3 . For the ChAdOx1 vaccine, effectiveness against SARS-CoV-2 infection in partially vaccinated individuals was 61.49% (95%CI 61.14-61.83), which increased in fully vaccinated individuals with a 2-dose regime to 80.79% (95%CI 80.43-81.14). Regarding . 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 5, 2022. Regarding the Ad5-nCoV vaccine, we observed an effectiveness for SARS-CoV-2 We also report on a reduction in VE against SARS-CoV-2 infection and COVID-19 related hospitalization and death for most evaluated vaccines in older adults and persons living with diabetes. Previous data had shown that waning of vaccine-induced immunity was associated with increased age and comorbidity 42 27 . Furthermore, by evaluating a national vaccination campaign which incorporated multiple vaccines we were able to assess the feasibility of incorporating multiple vaccines simultaneously to maximize vaccination coverage, which will also be helpful when evaluating policies to implement heterologous schemes for vaccine boosters in the future. Finally, by incorporating a time-varying component to the vaccination status, we were able to capture shifts in exposure risks through the follow-up time to allow for more precise estimates of vaccine effectiveness for all evaluated outcomes. We would also like to acknowledge some limitations which should be considered to adequately interpret our results. First, the SISVER dataset is a sentinel surveillance system, which is designed to evaluate high-risk symptomatic cases which are assessed and tested for COVID-19 31 ; because of its design, SISVER primarily identifies cases with moderate to severe COVID-19, which may skew our observations towards more severe cases and underrepresent mild and asymptomatic infections, which represent most SARS-CoV-2 cases; therefore, we are unable to distinguish VE in symptomatic versus asymptomatic SARS-CoV-2 infections 45 . This may also lead to a healthcare . 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 5, 2022. ; https://doi.org/10.1101/2022.04.04.22273330 doi: medRxiv preprint seeking bias, whereby identification of cases who did not seek testing or in-hospital care may be underrepresented in out estimation 27 . Second, information regarding vaccination status and date was collected during epidemiological characterization of SARS-CoV-2 cases and relies on accurate reporting by cases, which precludes precise evaluation of vaccine effectiveness waning through time, which should be evaluated in further studies. Third, estimates of hospitalization should be taken with caution, particularly considering the effect of hospital saturation in admittance of COVID-19 cases in Mexico during the second and third waves of the COVID-19 pandemic, which are included in the study 3 . Fourth, because vaccination roll-out in Mexico has been sequential and based on age categories, representation of vaccinated cases under 29 years has been low in comparison to the incidence of COVID-19 in this age group, which is heavily represented in the unvaccinated group. Even though all our models adjusted for age, the possibility of residual confounding in our estimations cannot be formally ruled out. Finally, because of the period we evaluated in our study, we were unable to estimate effectiveness during periods of increased circulation of the Omicron SARS-CoV-2 variant in Mexico, which had reported increased immune evasion and reduced VE for infection in different settings 46, 47 . 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 5, 2022. ; 16 COVID-19 vaccination policies in Mexico. Data analysis and interpretation was primarily conducted by members of the team independent of these duties. . 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 5, 2022. ; https://doi.org/10.1101/2022.04.04.22273330 doi: medRxiv preprint . 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 5, 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. 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 5, 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 5, 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 5, 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 5, 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. 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(which was not certified by peer review) The copyright holder for this preprint this version posted