Analyzing the Impact of Host Genetic Variation in SARS-CoV-2 and Influenza Adjuvanted Vaccination

The advent of vaccines for multiple infectious agents has prevented over 100 million deaths across the world and has also led to the near eradication of diseases. However, there is still considerable inter-individual variability in immune responses following vaccination. Host genetic differences are likely drivers of some of these differences affecting immune responses. The development of adjuvants to augment vaccine responses has proven effective, resulting in improved immune responses to overcome external factors influencing immune response but may not be able to overcome genetic host effects. Understanding how host genetic background modulates immune responses will aid the development of vaccines to provide protection. We used the Diversity Outbred (DO) and Collaborative Cross (CC) mouse model genetic reference populations (GRPs) to model human genetic variation and investigate how genetic variation impacts vaccine responses and protection following SARS-CoV-2 and influenza vaccination. In both cases, we demonstrated that variation in vaccine response is heritable, leading to a vast magnitude in antibody levels and protective neutralizing response. We used the DO for SARS-CoV-2 vaccination and found host genetic variation affects vaccine protection, resulting in breakthrough infections. In influenza vaccination, we identified quantitative trait loci (QTL) in the CC population regulating antibody response to influenza without adjuvant and adjuvanted influenza vaccination. Overall, this body of work highlights the importance of host genetic variation's influence on vaccine-induced immune response and shows the importance of GRPs as a model to study variation in vaccine response. Understanding the genetic factors and interactions contributing to vaccine response will improve vaccine design across different human populations.