Effectiveness of first-generation severe acute respiratory syndrome coronavirus 2 mRNA vaccines against the Omicron variant.

The emergence of novel variants, the relatively quickly waning immunity following vaccination, and the possibility of reinfection following recovery, have together made the effectiveness of the different SARS-CoV-2 vaccines a "moving target". This necessitates a constant reevaluation of vaccine effectiveness (VE) to better inform public policy.

In this issue of Clinical Microbiology and Infection, Robilotti et al. estimate the effectiveness of a third dose of a SARS-CoV-2 mRNA vaccine against infection, compared to two vaccine doses, in a cohort of healthcare workers from a tertiary medical center in New York during a period dominated by the Omicron variant. Compared to individuals vaccinated twice, they found a modest VE of 33% (95% CI: 29-38%) in HCWs who received three doses of the mRNA vaccines. In those previously infected, the effect was similar, with a VE of 34% (95% CI: 7-41%). The authors additionally describe the clinical course of breakthrough infections, finding the majority to be mild.

The authors' results add to an existing body of literature regarding the effectiveness of the first generation of mRNA vaccines against the Omicron variant. For the primary series of the BNT162b2 vaccine, Andrews et al. estimate a VE of 65% soon after the second dose, later waning to 9%. For the third dose, they estimate a VE against symptomatic disease of 67% soon after boosting, later waning to 54%. Numbers were similar for the mRNA-1273 vaccine [1]. Asking a similar question, Link-Gelles et al. estimate a VE of 47% for recent two-dose vaccination of either the BNT162b2 or the mRNA-1273 vaccine against emergency department and urgent care visits due to Covid-19, later waning to 39%. VE against hospitalization was better at 68% soon after vaccination, later waning to 61%. Protection after the third dose was improved, while protection against the BA.2 subvariant was not as good [2].

Estimates of the effectiveness of the fourth dose (compared to persons receiving only three doses) against Omicron were similarly not as high as with previous variants. For example, Grewal et al. estimate a VE of 19%, 31%, and 40% against infection, symptomatic disease, and more severe outcomes, respectively [3] for the mRNA-1273 vaccine. Regev-Yochay et al. estimate a VE of 30% and 43% for the BNT162b2 vaccine, with somewhat lower estimates for the mRNA-1273 vaccine [4].

There is variance in the different estimates, as would be expected considering the different circumstances under which each was derived (including different populations, study designs, vaccination regimens, etc.). Despite this variability, there is an evident trend of reduced VE of the mRNA vaccines, both the primary series and the boosters, against the Omicron variant (compared to previous variants) that further wanes over time. The vaccines also present a trend of improved protection against more severe outcomes. These trends, together with the Omicron's variant increased propensity to cause reinfections in those previously infected with previous variants, explains the infection surges observed worldwide, including in countries with high vaccine coverage. It should also be noted that the above-mentioned vaccine effectiveness estimates were derived during periods in which the BA.1 and BA.2 were the predominant sub-variants of Omicron. Today, with the increasing spread of the subvariant BA.5, effectiveness might be different.

While the relatively better effectiveness of the vaccines for severe disease from the Omicron variant is encouraging, as is the apparent inherent lower virulence of the Omicron variant [5], attaining high protection against infection is still important in order to reduce the amount of community transmission of SARS-CoV-2 and specifically to protect vulnerable populations that are at increased risk for severe disease if infected. The new generation of Omicron-specific vaccines that are currently undergoing clinical trials [6] may provide this needed protection against infections. Indeed, early evidence suggests they elicit a more vigorous immune response against the now-dominant Omicron variant [7].

The quick pace in which the Covid-19 pandemic changes, including the changes in the landscape of variants and the introduction of novel mitigation technologies, including vaccines and treatments, emphasize the need for continuous research efforts to evaluate the effectiveness of these technologies. The work by Robilotti et al., along with the other studies cited in this commentary, provided quick and important evidence regarding the effectiveness of the mRNA vaccines against the Omicron variant. This was possible due to the increasing availability of observational data repositories that include Covid-19 data and the increasing experience of various research groups in using them to study causal effects in a reliable and timely manner. Using these resources, the medical community should focus on addressing the most pressing research questions still remaining open– estimating the clinical effectiveness of the novel Omicron-specific vaccines and understanding the long-term effects of Omicron-variant infections, even mild ones. In parallel, and at least until the effectiveness of omicron-specific vaccines is convincingly proven, societal protection of vulnerable populations must remain a priority.

Transparency declaration

ND reports institutional grants to the Clalit Research Institute from Pfizer outside the submitted work and unrelated to COVID-19, with no direct or indirect personal benefits. NB reports institutional grants to Sheba Medical Center from Pfizer and Moderna outside the submitted work. This study did not receive external funding.

Authors' contribution

Both authors participated in the writing and editing of this commentary.