DISCUSSION
We found that during a delta-predominant period in Azerbaijan, point estimates suggest that primary series CoronaVac vaccine protected nearly 1 in 3 HCWs against COVID-19, but this finding was not statistically significant. Our findings are the first to describe COVID-19 VE in the South Caucasus region—an area of the WHO European region that continues to have much lower rates of vaccination compared to Western and Central Europe . As of November 2022, less than half to the adult population (48%) in Azerbaijan had completed primary series vaccination for COVID-19, and less than 10% had completed a booster dose.
Our primary course Coronavac VE point estimates of 29%, and 37% when we excluded participants who had previous PCR-confirmed infection, are similar to previous studies of Coronac VE against symptomatic infection and all infections. A study of HCWs in Turkey without previous infection, the only published study of CoronaVac VE in the European Region of WHO, found that adjusted two-dose VE against SARS-CoV-2 infection was 39% (HR 0.61, 95% CI 0.46–0.80) during a period of alpha variant circulation. That same study reported an unadjusted two-dose CoronaVac VE of 48% (95% CI 29–61%) against symptomatic infection. Studies outside of the European region that have evaluated two-dose CoronaVac VE during periods of predominant delta circulation showed a range of results that varied in part according to time since vaccination. A study from Brazil that included individuals who were 60-179 days and >180 days after their second dose found two-dose VE against symptomatic disease of 37.6% (36.1-39.1) and 34% (32.3-35.7), respectively, in a delta-predominant period. In contrast, two studies from Asia found higher two-dose VE against illness and infection during periods of delta-predominant circulation, but these studies included individuals who had mostly been recently vaccinated. A study from Thailand that used the test-negative design reported two-dose CoronaVac effectiveness of 60% (95% CI, 49–69) against infection; vaccinated participants in that study had received their last dose a mean of 81 days (Range: 60-91 days) prior to the analysis period. A study related to an outbreak of SARS-CoV-2-delta variant in China reported two-dose CoronaVac VE against illness of 73.0 (95% CI 22.3–90.6) among individuals who had mostly received their second vaccine dose within the previous three months.
Primary series VE against infection during delta-predominant periods has been shown to be mostly higher for mRNA and viral vector vaccines compared to Coronavac. However, against omicron, two-dose VE against has been much lower against symptomatic infection, and, to a lesser extent, severe disease, across vaccine products. Booster doses have been shown to increase protection against both mild and severe COVID-19 illness from delta and omicron. In Azerbaijan, booster doses were recommended for HCWs from September 2021. Both Coronavac and Cominarty (Pfizer/Biontech) have been offered, without a preferential recommendation. To date, few studies have evaluated VE of a heterologous booster compared to a homologous booster following primary series vaccination with Coronavac. In Brazil, during an Omicron-predominant period, for individuals who had received tprimary series CoronaVac, heterologous booster with Cominarty had higher VE than homologous booster with CoronaVac against both symptomatic infection [56.8% (56.3-57.3) vs. -2.9% (-5.2–0.6)] and severe disease [86% (84.5-87.4) vs. 73.6% (63.9-80.7)] for those vaccinated 8-59 days prior to the analysis period. Differences persisted for those boosted >59 days prior. However, in Hong Kong, also during a period of Omicron BA.2 circulation, VE against mortality and severe complications was mostly similar for individuals who had received a primary series of CoronaVac followed by Cominarty a booster compared to those who had received three doses of CoronaVac. Both studies showed increased VE against all endpoints for booster doses compared to primary series. In Azerbaijan, where less than 10% of the adult population has received a booster vaccine., conveying the important benefits of booster doses to the public is critical.
Our study population likely had high rates of previous infection at enrolment. Because vaccination with inactivated vaccine leads to seroconversion in both anti-spike and anti-nucleocapsid antibody tests, we could not use antibody testing to determine previous infection among participants who had been vaccinated prior to enrolment. However, 69% of unvaccinated HCWs who did not report a previous infection were seropositive by at least one of the two antibody tests at enrolment, and these findings likely reflect the extent of previous infection in the overall study population. Despite more than two of every three participants likely having been previously infected, we still found some benefit, albeit not statistically significant, to primary series vaccination with CoronaVac. The added benefit of primary COVID-19 vaccination and booster doses in previously infected individuals (hybrid immunity) has been widely demonstrated in other studies.
In our study we found a trend towards decreased VE among participants for whom more than 5 months had passed since their second CoronaVac vaccine. Waning VE with increased time since COVID-19 vaccination has been described for CoronaVac and other COVID-19 vaccines., The waning effectiveness of primary series vaccination again underscores the importance of booster doses to increase protection.
Our study has a number of strengths. Because we enrolled and systematically followed a discrete cohort of HCWs, we were able to obtain data about vaccination status, SARS-CoV-2 test results, and clinical outcomes, information which would not have been discernible from routinely collected data. The protocol was followed rigorously; participants completed more than 95% of weekly symptom questionnaires during the study period. Only 34 (2%) participants were lost to follow-up. Finally, the use of serology at enrolment allowed us to estimate the prevalence of prior infections among unvaccinated participants, and also provided information on seroconversion rates of HCWs who received the inactivated CoronaVac vaccine.
Our study also has some limitations. The study was not powered to estimate VE against severe outcomes like hospitalization and death – critical endpoints for vaccine evaluation. The study may have suffered from selection bias since enrolment was voluntary. In our study, while there were no differences in age and sex between unvaccinated and vaccinated participants, there were more unvaccinated physicians at the end of the study period. In addition, few participants remained unvaccinated at the end of the study, and these unvaccinated participants may differ from vaccinated participants in ways that we did not measure, including likelihood of exposure to SARS-CoV-2 and other parameters. More unvaccinated participants (40%) than vaccinated participants (6%) had a PCR-confirmed SARS-CoV-2 infection prior to enrolment – likely the result of the Azerbaijan MoH recommendation to defer vaccinated in individuals who had been infected with SARS-CoV-2. While differential rates of previous infection in the two arms could bias VE estimates, we accounted for this difference by including only participants eligible for vaccination, according to the recommendations, and including previous SARS-CoV-2 infection as a confounding variable. Finally, because of the relatively low number of events, the relatively low amount of person-time among unvaccinated participants, and the relatively low VE, our VE estimates had wide confidence intervals.
In conclusion, during a period of mainly delta circulation in Baku, Azerbaijan, we found that primary series CoronaVac VE protected approximately one in three HCWs against symptomatic PCR-confirmed infection, although the results were not statistically significant. HCWs in our cohort had high rates of previous infection and had mostly receive their second vaccine three months previously. These findings reaffirm previous findings about the limited durability of protection of primary series CoronaVac and other vaccines in preventing symptomatic infection, and thus should provide further support for the consideration of booster doses. Our findings also support the utility of COVID-19 vaccination even among individuals who have been previously infected, a policy that is currently promoted in Azerbaijan and elsewhere, and that will be critical to continue as more of the population in Azerbaijan and globally has experienced at least one COVID-19 infection. As this is an ongoing cohort study, future analyses will evaluate VE in the context of booster doses and omicron infection in Azerbaijan.