Immune history influences SARS-CoV-2 booster impacts: the role of efficacy and redundancy

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 the updated vaccine formulations at the population level. While bivalent formulations have higher efficacy in vaccine trials, translating these findings to real-world effectiveness is challenging due to the 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. Using two complementary mathematical models that capture host demographics and immune histories over time, we investigated the potential impacts of bivalent and monovalent boosters in low– and middle-income countries (LMICs). These models allowed us to test the role of natural immunity and cross-protection in determining the optimal booster strategy. Our results show that to avert deaths from a new variant in populations with high immune history, it is more important that a booster is implemented than which booster is implemented (bivalent vs. monovalent). However, in populations with low preexisting immunity, bivalent boosters can become optimal. These findings suggest that for many LMICs – where acquiring a new vaccine stock may be economically prohibitive – monovalent boosters can still be implemented as long as pre-existing immunity is high. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded by the World Health Organization. The authors would like to thank the Biocluster at the Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, for providing access to the computing resources. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: We used publicly available data to parameterize our model simulations. All data sources are listed as references in the manuscript. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study will be provided at a public repository upon publication in a journal.