DISCUSSION
This study found that the current bivalent vaccines were about 30% effective overall in protecting against infection with SARS-CoV-2, when the Omicron BA.4/BA.5 lineages were the predominant circulating strains. The magnitude of protection afforded by bivalent vaccination was similar to that estimated in a recent study using data from the Increasing Community Access to Testing (ICATT) national SARS-CoV-2 testing program [
16].
The strengths of our study include its large sample size, and its conduct in a healthcare system where a very early recognition of the critical importance of maintaining an effective workforce during the pandemic led to devotion of resources to have an accurate accounting of who had COVID-19, when COVID-19 was diagnosed, who received a COVID-19 vaccine, and when. The study methodology, treating bivalent vaccination as a time-dependent covariate, allowed for determining vaccine effectiveness in real time.
The study has several limitations. Individuals with unrecognized prior infection would have been misclassified as previously uninfected. Since prior infection protects against subsequent infection, such misclassification would have resulted in underestimating the protective effect of the vaccine. However, there is little reason to suppose that prior infections would have been missing in the bivalent vaccinated and non-vaccinated states at disproportionate rates. Those who chose to receive the bivalent vaccine might have been more worried about infection and might have been more likely to get tested when they had symptoms, thereby disproportionately detecting more incident infections among those who received the bivalent vaccine. This risk is mitigated by the time-dependent treatment of bivalent vaccination, because with such treatment, risk of disproportionate detection is actually in the opposite direction. If individuals received the bivalent vaccine thinking it would reduce their risk of infection, they would have been less inclined to get tested for the same symptoms after getting the vaccine (bivalent vaccinated state) than before getting the vaccine (non-bivalent vaccinated state), providing greater opportunity to detect infection in the non-boosted than the boosted state, thereby having the effect of overestimating vaccine effectiveness. Those who chose to get the bivalent vaccine were also more likely to have lower risk-taking behavior with respect to COVID-19, having the effect of a higher risk of COVID-19 in the non-boosted state (as those who chose not to get the bivalent vaccine, expectedly with higher risk-taking behavior, remained in the non-boosted state throughout the duration of the study), thereby again potentially overestimating vaccine effectiveness. The widespread availability of home testing kits might have reduced detection of incident infections. This potential effect should be somewhat mitigated in our healthcare cohort because one needs a NAAT to get paid time off, providing a strong incentive to get a NAAT if one tested positive at home. Even if one assumes that some individuals chose not to follow up on a positive home test result with a NAAT, it is very unlikely that individuals would have chosen to pursue NAAT after receiving the bivalent vaccine more so than before receiving the vaccine, at rates disproportionate enough to affect the study’s findings. We were unable to distinguish between symptomatic and asymptomatic infections, and had to limit our analyses to all detected infections. Variables that were not considered might have influenced the findings substantially. There were too few severe illnesses for the study to be able to determine if the vaccine decreased severity of illness. Our study of healthcare personnel included no children and few elderly subjects, and the majority would not have been immunocompromised. Lastly, during most of the study the circulating variants were those represented in the vaccine. It is not known if the vaccine will be equally effective when the strains circulating in the community are not those represented in the vaccine.
A possible explanation for a weaker than expected vaccine effectiveness is that a substantial proportion of the population may have had prior asymptomatic Omicron variant infection. About a third of SARS-CoV-2 infections have been estimated to be asymptomatic in studies that have been done in different places at different times [
17–
19]. If so, protection from the bivalent vaccine may have been masked because those with prior Omicron variant infection may have already been somewhat protected against COVID-19 by virtue of natural immunity. A seroprevalence study conducted by the CDC found that by February 2022, 64% of the 18-64 age-group population and 75% of children and adolescents had serologic evidence of prior SARS-CoV-2 infection [
20], with almost half of the positive serology attributed to infections that occurred between December 2021 and February 2022, which would have predominantly been Omicron BA.1/BA.2 lineage infections. With such a large proportion of the population expected to have already been previously exposed to the Omicron variant of SARS-CoV-2, there could be some concern that a substantial proportion of individuals may be unlikely to derive substantial benefit from a bivalent vaccine.
The evolution of the SARS-CoV-2 virus necessitates a more nuanced approach to assessing the potential impact of vaccination than when the original vaccines were developed. Additional factors beyond vaccine effectiveness need to be considered. The association of increased risk of COVID-19 with higher numbers of prior vaccine doses in our study, was unexpected. A simplistic explanation might be that those who received more doses were more likely to be individuals at higher risk of COVID-19. A small proportion of individuals may have fit this description. However, the majority of subjects in this study were generally young individuals and all were eligible to have received at least 3 doses of vaccine by the study start date, and which they had every opportunity to do. Therefore, those who received fewer than 3 doses (>45% of individuals in the study) were not those ineligible to receive the vaccine, but those who chose not to follow the CDC’s recommendations on remaining updated with COVID-19 vaccination, and one could reasonably expect these individuals to have been more likely to have exhibited higher risk-taking behavior. Despite this, their risk of acquiring COVID-19 was lower than those who received a larger number of prior vaccine doses. This is not the only study to find a possible association with more prior vaccine doses and higher risk of COVID-19. A large study found that those who had an Omicron variant infection after previously receiving three doses of vaccine had a higher risk of reinfection than those who had an Omicron variant infection after previously receiving two doses of vaccine [
21]. Another study found that receipt of two or three doses of a mRNA vaccine following prior COVID-19 was associated with a higher risk of reinfection than receipt of a single dose [
7]. We still have a lot to learn about protection from COVID-19 vaccination, and in addition to a vaccine’s effectiveness it is important to examine whether multiple vaccine doses given over time may not be having the beneficial effect that is generally assumed.
In conclusion, this study found an overall modest protective effect of the bivalent vaccine booster against COVID-19, among working-aged adults. The effect of multiple COVID-19 vaccine doses on future risk of COVID-19 needs further study.