Vaccine effectiveness of CanSino (Adv5-nCoV) COVID-19 vaccine among childcare workers – Mexico, March–December 2021

Abstract Background Beginning in March 2021, Mexico vaccinated childcare workers with a single-dose CanSino Biologics (Adv5-nCoV) COVID-19 vaccine. Although CanSino is currently approved for use in 10 Latin American, Asian, and European countries, little information is available about its vaccine effectiveness (VE). Methods We evaluated CanSino VE within a childcare worker cohort that included 1,408 childcare facilities. Participants were followed during March–December 2021 and tested through SARS-CoV-2 RT-PCR or rapid antigen test if they developed any symptom compatible with COVID-19. Vaccination status was obtained through worker registries. VE was calculated as 100% × (1−hazard ratio for SARS-CoV-2 infection in fully vaccinated vs. unvaccinated participants), using an Andersen-Gill model adjusted for age, sex, state, and local viral circulation. Results The cohort included 43,925 persons who were mostly (96%) female with a median age of 32 years; 37,646 (86%) were vaccinated with CanSino. During March–December 2021, 2,250 (5%) participants had laboratory-confirmed COVID-19, of whom 25 were hospitalized and 6 died. Adjusted VE was 20% (95% CI = 10–29%) against illness, 76% (42–90%) against hospitalization, and 94% (66–99%) against death. VE against illness declined from 48% (95% CI = 33–61) after 14–60 days following full vaccination to 20% (95% CI = 9–31) after 61–120 days. Conclusions CanSino vaccine was effective at preventing COVID-19 illness and highly effective at preventing hospitalization and death. It will be useful to further evaluate duration of protection and assess the value of booster doses to prevent COVID-19 and severe outcomes.

Notificación en Línea para la Vigilancia Epidemiológica (SINOLAVE) national surveillance system and 1 death certificates. For patients who were hospitalized or who died, IMSS staff also gathered information 2 about underlying health conditions including physician-diagnosed diabetes, high blood pressure, 3 cardiovascular disease, obesity, chronic kidney disease, chronic obstructive pulmonary disease, 4 pregnancy, or cancer from SINOLAVE. 5

Statistical Analysis 6
We restricted our vaccine effectiveness analyses to participants who contributed person-time 7 during March 30, 2021, the date when CanSino vaccine had been available for ≥14 days to childcare 8 workers at IMSS, to December 31, 2021, the latest available data for the ongoing cohort. We also 9 restricted our analysis to persons aged ≥18 years, the age of eligibility to the CanSino vaccine. We 10 excluded cohort participants who reported a laboratory-confirmed COVID-19 illness prior to March 30, 11 2021 (n=1,074), were vaccinated with COVID-19 vaccine products other than CanSino (n=11,415) and 12 developed COVID-19 within 13 days after vaccination with CanSino (n=69), resulting in 43,925 included 13 cohort participants. We then classified participants into fully vaccinated with CanSino (≥14 days after 14 receipt of CanSino vaccine) or unvaccinated. As in other vaccine effectiveness analyses, we considered 15 the 13 days between vaccination and full vaccination as excluded person-time [13]. 16 We estimated vaccine effectiveness for three outcomes: laboratory-confirmed COVID-19 illness, 17 COVID-19-associated hospitalization, and COVID-19-associated death. Participant characteristics were 18 first compared by vaccination status using Chi-square tests to explore propensity to vaccination. We 19 then calculated the rolling 7-day daily incidence of laboratory-confirmed COVID-19 by vaccination 20 status. We assessed which SARS-CoV-2 variant represented >50% of SARS-CoV-2 sequences during the 21 study period using data submitted from Mexico to the Global Initiative on Sharing Avian Influenza Data 22 [14]. We classified June 29-December 19 as B.1.617.2 (Delta) variant predominance based on 1 GISAID data. 2 Hazard ratios and 95% confidence intervals for outcomes in fully vaccinated participants, as 3 compared with unvaccinated participants, were estimated with the Andersen-Gill extension of the Cox 4 proportional hazards model, which accounted for time-varying vaccination status (i.e., persons could 5 contribute both unvaccinated and fully vaccinated person time). Unadjusted vaccine effectiveness was 6 calculated with the following formula: 100% × (1−hazard ratio). An adjusted vaccine effectiveness model 7 included a priori characteristics that could confound the association between vaccination and outcomes, 8 namely age, sex, and the state in which the childcare center was located, in addition to local viral 9 circulation, which was the weekly percentage positive of SARS-CoV-2 tests performed in the state, 10 obtained via the Mexico Dirección General de Epidemiología public COVID-19 data dashboard [15]. We 11 stratified vaccine effectiveness by days since full vaccination, and also calculated vaccine effectiveness 12 prior to and during Delta variant predominance in Mexico. We did not calculate vaccine effectiveness 13 post-Delta predominance due to limited follow-up time available (2 weeks). As a sensitivity analysis, we 14 stratified vaccine effectiveness estimates by type of laboratory test used for confirmation (rapid antigen 15 test vs. RT-PCR). All analyses were conducted with SAS software, version 9.4 (SAS Institute). 16 This IMSS-funded vaccine evaluation occurred within the context of emergency response and 17 used anonymized workplace surveillance data. IMSS determined that the evaluation was a non-research, 18 public health surveillance activity that was exempt from institutional review board approval because 19 data collection and illness tracking were a requirement for working in these childcare centers during the 20 pandemic. 21 Cohort participants were primarily female (96%) and aged 18-49 years (90%) with a median age 2 of 32 years (interquartile range [IQR] = 26-41) ( Table 1). Among all 43,925 cohort participants, 37,646 3 (86%) were vaccinated with CanSino. We observed differences in age and geographic site, both in 4 frequency of laboratory-confirmed illness and vaccination status, and also observed differences in sex by 5 vaccination status ( Table 1 and Supplementary Table 1). Among persons who were hospitalized, 18 6 (72%) reported at least one underlying medical condition, including all 6 (100%) patients who died 7 Table 2). 8

DISCUSSION 19
Our evaluation of the real-world effectiveness of the CanSino vaccine in Mexico suggests that 20 most IMSS-affiliated childcare workers sought CanSino vaccines and had a 20% reduction in risk of 21 COVID-19 illness, as well as a 76% reduction in risk of COVID-19-associated hospitalization and 94% Our evaluation demonstrated noteworthy strengths or IMSS's worker surveillance and vaccine 6 rollout in Mexico. We followed nearly 44,000 childcare workers during 2021 which allowed us to 7 prospectively monitor COVID-19 illness development and ascertain hospitalization and death. High 8 vaccination coverage (86%) among this cohort was facilitated by Mexico's vaccination rollout through an 9 existing universal vaccination program; assessments of previous pandemics demonstrate that countries 10 that have existing immunization programs are more likely to rapidly benefit from pandemic vaccines 11 than countries without such programs [32]. 12 However, our study also had important limitations. Cohort members were predominantly 13 female (96%) with a median age of 32 years, and findings may not be generalizable to other populations. 14 Sparse outcomes, particularly hospitalizations and deaths, reduced the precision of vaccine 15 effectiveness estimates. Additionally, a large proportion of workers with symptoms compatible with 16 COVID-19 were tested through rapid antigen tests rather than through the more sensitive RT-PCR assays 17 [33]; however, results of our sensitivity analysis indicated that estimates were comparable for overall 18 and RT-PCR-only test results. Key data about SARS-CoV-2 infection and COVID-19 illness (including 19 presence of symptoms, laboratory result, and vaccination status) were derived in many instances 20 through self-report, although these were verified by official sources whenever possible. Finally, data on 21 underlying medical conditions were only available for persons who were hospitalized or who died and 22 could not be evaluated as a covariate in vaccine effectiveness models. Individuals with underlying 23 conditions may have sought vaccination earlier than those without conditions, potentially causing 24 A C C E P T E D M A N U S C R I P T differential risk from waning protection during the Delta wave in this population. As this was an 1 observational study, unmeasured and residual confounding might have also been present. 2

CONCLUSION 3
Our evaluation suggests that CanSino vaccine was effective, particularly for severe outcomes; 4 vaccination reduced the risk of COVID-19 illness among childcare workers by 20% and reduced risk of 5 COVID-19-associated hospitalization and death by 76% and 94%, respectively. Like most COVID-19 6 vaccine products, vaccine effectiveness waned substantially during the first 4 months after 7 administration, suggesting the value of administering booster doses to persons who received a single 8 dose of CanSino vaccine, using either homologous or heterologous schedules. Additional vaccine 9 effectiveness evaluations are warranted following Omicron SARS-CoV-2 variant predominance 10 throughout Mexico and possible booster doses received by cohort participants. 11

ACKNOWLEDGMENTS 12
We thank the childcare workers and supervisors who participated in the COVID-19 surveillance 13 and their families, who made this evaluation possible. We would also like to thank Jonathan Peralta 14 Álvarez for development of the database, Jaime Israel Pérez Mora for data processing, Daniel (Young) 15 Yoo for assistance with mathematical modeling, and Drs. Alicia Fry and Michael Jhung for expert review.  This evaluation has been funded through the IMSS, Government of Mexico. 22

Conflict of interest 23
None of the coauthors have conflicts of interest to declare. 24