Response to Comment: Absolute and Relative Vaccine Effectiveness of Primary and Booster Series of COVID-19 Vaccines Against COVID-19 Hospitalizations Open Access

We appreciate the comments [1] from Dr. Kleebayoon and Dr. Wiwanitkit regarding our manuscript, “Absolute and Relative Vaccine Effectiveness of Primary and Booster Series of COVID-19 Vaccines (mRNA and Adenovirus Vector) Against COVID-19 Hospitalizations in the United States, December 2021–April 2022” [2]. As they point out, real-world COVID-19 vaccine effectiveness (VE) studies such as ours often evaluate the impact of vaccination among those persons who seek medical attention (eg, outpatient, inpatient, or emergency department care) and test to diagnose severe acute respiratory syndrome coronavirus 2 infection during the course of medical care. Although it is true that asymptomatic and untested persons are not accounted for in our analysis, asymptomatic infection is not the outcome for which COVID-19 mRNA vaccine effectiveness is being evaluated; rather, we are specifically evaluating effectiveness against symptomatic infection requiring hospitalization. In VE studies conducted by our network, Investigating Respiratory Viruses in the Acutely Ill (IVY), all cases have symptomatic COVID-19 disease and a positive antigen or reverse-transcription polymerase chain reaction (RT-PCR) test, and all controls have a negative PCR test. Although initial enrollment is based on clinical test results, an additional respiratory specimen is collected for all enrolled participants and tested by RT-PCR at a central laboratory to confirm the patient's case or control status [3]. Thus, we are using rigorous methods to minimize misclassification of case versus control status.

We also appreciate the observation that people's immune systems appear to respond to COVID-19 vaccinations differently depending on genetic diversity. Although we do not collect detailed genetic information in our studies, we do assess for heterogeneity of vaccine effectiveness by conducting subgroup analyses defined by clinical characteristics, such as age groups, immunocompromised status, and presence of chronic medical conditions. We agree that additional, more sophisticated assessments of heterogeneity of COVID-19 vaccine effectiveness are needed. However, our findings of higher VE against hospitalized COVID-19 for a COVID-19 mRNA vaccine primary series plus booster compared with a primary series only ultimately reinforce the existing literature that provides strong evidence for effectiveness of these vaccines and support public health recommendations for booster vaccination.

The additional objective of the manuscript was to explain the concept of relative vaccine effectiveness (rVE) and facilitate its interpretation given increasing but heterogeneous usage in COVID-19 booster effectiveness studies. As noted above, we agree that contextual factors (eg, the outcome being evaluated) are important to interpreting rVE, but we believe that the way in which the rVE estimate is presented is also important. As used in most previous influenza and COVID-19 vaccine effectiveness studies, rVE can be a meaningful metric of the incremental benefit of a booster dose beyond a primary vaccine series. However, when rVE is used as simple ratio of disease risk in 2 different vaccinated groups (eg, primary series recipients and primary series plus booster recipients), which is increasingly common in an era of widespread COVID-19 vaccination coverage, the clinically relevant benefit of a booster dose can be difficult to determine. Although our study supported the benefit of a first booster dose versus a primary vaccine series alone, assessing the benefit of additional vaccine booster doses, especially amid other factors such as vaccine waning and virus evolution, will continue to be a complex task requiring careful presentation and interpretation of VE data.

We recommend that authors of future COVID-19 VE studies clearly define the way in which rVE is being calculated and reported, that is, as 1 minus the relative risk of infection for 2 different vaccine regimens (a proxy VE), versus the percentage change in the remaining risk (compared with being unvaccinated) after a primary series that is brought about by a booster dose, or after a primary series plus booster dose(s) that is brought about by a bivalent booster dose. Authors can also provide context of the trajectory of vaccine effectiveness in their respective locations and populations (eg, discussion of earlier VE studies using unvaccinated comparison groups), so that evidence of incremental gains in effectiveness can be better understood. Finally, we urge authors of forthcoming VE studies to be cautious in their messaging around rVE, particularly when comparing regimens in which the additional benefit may be modest, such as for a primary series plus 2 monovalent booster doses and a bivalent booster dose versus a primary series plus 2 monovalent booster doses. Phrasing such as “additional benefit” may be more appropriate than describing a specific percentage gain or increase in VE or other population-level impact.

Acknowledgments

Financial support. This work was supported by the US Centers for Disease Control and Prevention (Grants 75D30120F00002 and 75D30122C12914; to WHS).

References

Author notes