Testing Whether Higher Contact Among the Vaccinated Can Be a Mechanism for Observed Negative Vaccine Effectiveness

Evidence from early observational studies suggested negative vaccine effectiveness (${V}_{Eff}$) for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant. Since true ${V}_{Eff}$ is unlikely to be negative, we explored how differences in contact among vaccinated persons (e.g., potentially from the implementation of vaccine mandates) could lead to observed negative ${V}_{Eff}$. Using a susceptible-exposed-infectious-recovered (SEIR) transmission model, we examined how vaccinated-contact heterogeneity, defined as an increase in the contact rate only between vaccinated individuals, interacted with 2 mechanisms of vaccine efficacy: vaccine efficacy against susceptibility ($V{E}_S$) and vaccine efficacy against infectiousness ($V{E}_I$), to produce underestimated and in some cases, negative measurements of ${V}_{Eff}$. We found that vaccinated-contact heterogeneity led to negative estimates when $V{E}_I$, and especially $V{E}_S$, were low. Moreover, we determined that when contact heterogeneity was very high, ${V}_{Eff}$ could still be underestimated given relatively high vaccine efficacies (0.7), although its effect on ${V}_{Eff}$ was strongly reduced. We also found that this contact heterogeneity mechanism generated a signature temporal pattern: The largest underestimates and negative measurements of ${V}_{Eff}$ occurred during epidemic growth. Overall, our research illustrates how vaccinated-contact heterogeneity could have feasibly produced negative measurements during the Omicron period and highlights its general ability to bias observational studies of ${V}_{Eff}$.