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.