Influence of immune history when choosing a SARS-CoV-2 booster strategy

Given the continued emergence of SARS-CoV-2 variants of concern as well as unprecedented vaccine development, it is crucial to understand the effect of updated vaccine formulations at the population level. While bivalent formulations developed during 2022 have had higher efficacy in vaccine trials, translating these findings to real-world effectiveness is challenging due to diversity in immune history, especially in settings with a high degree of natural immunity. Known socioeconomic disparities in key metrics such as vaccine coverage, social distancing, and access to healthcare have likely shaped the development and distribution of this immune landscape. Yet little has been done to investigate the impact of booster formulation in the context of host heterogeneity. Here, we present work undertaken in 2022-2023 to inform the World Health Organization's Immunization and Vaccines Related Implementation Research Advisory Committee (IVIR-AC), at a time when policymakers were considering optimal boosting strategies. Using two complementary mathematical models that capture host demographics and immune histories over time, we investigated the potential impacts of bivalent and monovalent boosters, inspired by disease dynamics in low- and middle-income countries (LMICs). These models allowed us to test the role of natural immunity and cross-protection in determining optimal booster strategy. Our results show that in hypothetical populations with high pre-existing immunity in the 2022-23 season, disease-related deaths from a new variant would be more sensitive to boosting/no boosting than booster formulation (bivalent vs. monovalent) - and if using bivalent formulations would result in delayed implementation compared to monovalent, it would almost always be better to implement monovalent immediately. However, deaths might be more sensitive to bivalent formulations in populations with low pre-existing immunity. These findings suggest that for many places where acquiring new vaccine stock may be economically prohibitive, monovalent boosters could still have been implemented where pre-existing immunity was high. While this analysis focuses on policy concerns in 2022, these results remain relevant now amidst ongoing questions about optimal booster formulation and timing to combat emerging transmission waves of COVID-19.