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SARS-CoV-2 vaccinations were initially shown to substantially reduce risk of severe disease and death. However, pharmacokinetic (PK) waning and rapid viral evolution degrade neutralizing antibody (nAb) binding titers, causing loss of vaccinal protection. Additionally, there is inter-individual heterogeneity in the strength and durability of the vaccinal nAb response. Here, we propose a personalized booster strategy as a potential solution to this problem. Our model-based approach incorporates inter-individual heterogeneity in nAb response to primary SARS-CoV-2 vaccination into a pharmacokinetic/pharmacodynamic (PK/PD) model to project population-level heterogeneity in vaccinal protection. We further examine the impact of evolutionary immune evasion on vaccinal protection over time based on variant fold reduction in nAb potency. Our findings suggest viral evolution will decrease the effectiveness of vaccinal protection against severe disease, especially for individuals with a less durable immune response. More frequent boosting may restore vaccinal protection for individuals with a weaker immune response. Our analysis shows that the ECLIA RBD binding assay strongly predicts neutralization of sequence-matched pseudoviruses. This may be a useful tool for rapidly assessing individual immune protection. Our work suggests vaccinal protection against severe disease is not assured and identifies a potential path forward for reducing risk to immunologically vulnerable individuals. 

The strategy of relying solely on current SARS-CoV-2 vaccines to halt SARS-CoV-2 transmission has proven infeasible. In response, many public-health authorities have advocated for using vaccines to limit mortality while permitting unchecked SARS-CoV-2 spread (“learning to live with the disease”). The feasibility of this strategy critically depends on the infection fatality rate (IFR) of SARS-CoV-2. An expectation exists that the IFR will decrease due to selection against virulence. In this work, we perform a viral fitness estimation to examine the basis for this expectation. Our findings suggest large increases in virulence for SARS-CoV-2 would result in minimal loss of transmissibility, implying that the IFR may vary freely under neutral evolutionary drift. We use an SEIRS model framework to examine the effect of hypothetical changes in the IFR on steady-state death tolls under COVID-19 endemicity. Our modeling suggests that endemic SARS-CoV-2 implies vast transmission resulting in yearly US COVID-19 death tolls numbering in the hundreds of thousands under many plausible scenarios, with even modest increases in the IFR leading to unsustainable mortality burdens. Our findings highlight the importance of enacting a concerted strategy and continued development of biomedical interventions to suppress SARS-CoV-2 transmission and slow its evolution.