Poor vaccine responders mask the true trend in vaccine effectiveness against progression to severe disease.

Vaccines can reduce an individual's risk of infection and their risk of progression to severe disease given infection. The latter effect is less commonly estimated but is relevant for vaccine impact modeling and cost-effectiveness calculations. Using a motivating example from the COVID-19 literature, we note how vaccine effectiveness against progression to severe disease can appear to increase from below 0 % to over 70 % within 8 months. With true biological strengthening of this magnitude being unlikely, we use a mathematical modeling framework to identify parameter combinations where this phenomenon can occur. Fundamental features are an immunocompetent population with high initial protection against infection, contrasted with a vulnerable subpopulation with poor vaccine response against infection and progression. As a result, the earliest infections are among those with the weakest protection against severe disease. This work highlights methodological challenges in isolating a vaccine's effect on progression to severe disease after infection, and it signals the need for refined analytical methods to adjust for differences between the vaccinated infected and the unvaccinated infected populations.