Durability of BNT162b2 vaccine against hospital and emergency department admissions due to the omicron and delta variants in a large health system in the USA: a test-negative case–control study

and laboratory results have suggested that T-cell epitopes have remained mostly unaltered for the omicron variant.

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The relationship between cell-mediated immunity and protection against severe infection, however, needs more research. It is also likely that trained innate immunity has an important role in durable protection, particularly against severe infection. Unrelated live attenuated vaccines and adjuvanted vaccines can provide sustained protection against heterologous infections and severe outcomes, including COVID-19, possibly through induction of trained innate immunity, which mRNA vaccines also induce.

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and with preliminary studies showing waning effectiveness against the omicron variant and symptomatic SARS-CoV-2 infection.

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After a third dose, effectiveness against emergency department admission increased to 84% (95% CI 80–87) for the delta variant and 77% (72–81) for the omicron variant. Waning of immunity against emergency department admission after three doses was moderate for the delta variant but was more pronounced for the omicron variant, falling to 53% (36–66) at 3 months or more after the third dose. This finding is consistent with early reports from the UK Health Security Agency suggesting that even after three doses, vaccine effectiveness against symptomatic SARS-CoV-2 infection due to the omicron variant wanes rapidly.

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Age-stratified analyses showed that effectiveness was generally higher in adults aged 65 years and older. However, this finding might reflect enhanced risk-mitigating behaviours, especially among vaccinated people in this age group, or the potential dilution of vaccine effectiveness among adults younger than 65 years.

in the omicron era three doses appear to be necessary to achieve high levels of protection against severe COVID-19 outcomes. These findings are consistent with laboratory data reporting that neutralising antibody concentrations not only improved after a third dose (compared to after two doses) but also that the breadth of coverage against variants of concern seemed to increase.

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however, continual evaluation of booster strategies will be needed in the future. Preliminary data from Israel have shown improved protection against SARS-CoV-2 infection with the omicron variant and severe COVID-19 in individuals who received a fourth dose of BNT162b2 compared to those who had received only three doses at least 4 months ago.

However, data describing the durability of additional booster doses (beyond the third dose) are needed.

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Furthermore, although we attempted to control for previous SARS-CoV-2 infection, we were not able to assess previous infections among those who do not seek testing at KPSC. If undocumented previous infection was more likely in unvaccinated individuals, for example, this could contribute to underestimation of vaccine effectiveness, which might be more likely in the omicron era. In addition to using a time window where the omicron variant accounted for at least 95% of all new incident cases, we identified omicron cases based on SARS-CoV-2 samples with SGTF on the Thermo Fisher TaqPath assay. This approach could have led to misclassification of some samples. Misclassification, however, occurred in less than 1% of samples tested on ThermoFisher in our small validation study that compared PCR results to those from whole-genome sequencing. It is possible that some emergency department or hospital admissions were “with COVID-19” rather than “for COVID-19.” This could lead to spurious findings of waning against severe outcomes if in fact vaccine breakthroughs were only incidental infections among patients admitted to hospital for something other than COVID-19. This could explain why we found higher effectiveness estimates in adults aged 65 years and older (who are likely to be admitted to hospital for and have more severe COVID-19) compared to those aged 18–64 years who might be more likely to have incidental positivity for the omicron variant. By restricting our analysis to patients with a diagnosis of an acute respiratory infection, we attempted to mitigate this potential bias. However, it remains possible (especially in the emergency department setting) that milder COVID-19 or incidental SARS-CoV-2 infection was included in our analysis, which is likely to bias vaccine effectiveness estimates downwards, especially for the omicron variant given its milder clinical presentation and higher levels of antibody escape. Moreover, it is possible that hospital admission practices changed during our study period. For example, if larger numbers of less severe patients were admitted during the omicron wave, as was reported by the CDC,

this could also bias vaccine effectiveness estimates for the omicron variant downwards. Finally, given the study period, effectiveness estimates 3 months or more after the booster dose are likely to represent findings for individuals who first received booster doses, and additional follow-up will be needed to understand the effectiveness of booster doses over time in the general population and at different stages of the pandemic. Due to limitations in sample size, we were unable to assess long-term durability of the third dose or to provide vaccine effectiveness estimates specific to age groups or high-risk groups. Furthermore, due to the rapid influx of at-home antigen tests and increasing variation in clinic-based testing practices, we were not able to assess vaccine effectiveness against symptomatic or asymptomatic SARS-CoV-2 infection not requiring hospital or emergency department admission.