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