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 (VEff) for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant. Since true VEff 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 VEff. 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 (VES) and vaccine efficacy against infectiousness (VEI), to produce underestimated and in some cases, negative measurements of VEff. We found that vaccinated-contact heterogeneity led to negative estimates when VEI, and especially VES, were low. Moreover, we determined that when contact heterogeneity was very high, VEff could still be underestimated given relatively high vaccine efficacies (0.7), although its effect on VEff was strongly reduced. We also found that this contact heterogeneity mechanism generated a signature temporal pattern: The largest underestimates and negative measurements of VEff 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 VEff.