Host Genetic Variation Impacts SARS-CoV-2 Vaccination Response in the Diversity Outbred Mouse Population

Abstract

The COVID-19 pandemic led to the rapid and worldwide development of highly effective vaccines against SARS-CoV-2. However, there is significant individual-to-individual variation in vaccine efficacy due to factors including viral variants, host age, immune status, environmental and host genetic factors. Understanding those determinants driving this variation may inform the development of more broadly protective vaccine strategies. While host genetic factors are known to impact vaccine efficacy for respiratory pathogens such as influenza and tuberculosis, the impact of host genetic variation on vaccine efficacy against COVID-19 is not well understood. To model the impact of host genetic variation on SARS-CoV-2 vaccine efficacy, while controlling for the impact of non-genetic factors, we used the Diversity Outbred (DO) mouse model. We found that DO mice immunized against SARS-CoV-2 exhibited high levels of variation in vaccine-induced neutralizing antibody responses. While the majority of the vaccinated mice were protected from virus-induced disease, similar to human populations, we observed vaccine breakthrough in a subset of mice. Importantly, we found that this variation in neutralizing antibody, virus-induced disease, and viral titer is heritable, indicating that the DO serves as a useful model system for studying the contribution of genetic variation of both vaccines and disease outcomes.

Keywords: Diversity Outbred; SARS-CoV-2; host genetic diversity; vaccination.

Figure 1

Grouping of Diversity Outbred mice in families. Diversity Outbred mice were separated into different families based on autosomal distance to determine how closely related they are to one another. Each color represents a distinct family of DO mice. The large cluster of green represents mice where no family member could be matched.

Figure 2

Vaccination response in Diversity Outbred mice is variable, but mostly protective following SARS-CoV-2 challenge. (A) Neutralizing antibody titers against MA10 in DO mice from post-boost sera between controls and S2P-vaccinated mice. Neutralization was measured using a virus expressing nanoluciferase and presenting 50% reciprocal inhibitory concentration (IC50). An IC50 above 50 indicates positive neutralization activity. (B) Lung viral titers after MA10 challenge in DO mice mock-vaccinated with PBS or spike protein vaccine with Sigma adjuvant (RIBI). Viral titers were measured through plaque assay quantified as PFU/lung lobe. (C) Weight loss in PBS mock-vaccinated or spike protein-vaccinated with Sigma adjuvant-RIBI DO mice after MA10 challenge, measured over the course of 4 days. Weight loss percentage was determined based on starting weights prior to infection. (D) Distributions of weight loss at day four in DO mice vaccinated with PBS mock vaccination or the spike protein vaccine with Sigma adjuvant-RIBI. Frequency in distributions indicates number of mice for each corresponding weight loss percent. The Kolmogorov–Smirnov test was used to differentiate between control and S2P groups, control: p < 2.2⁻¹⁶, S2P: p < 2.2⁻¹⁶.

Figure 3

Genetic diversity contributes to vaccination and virus induced disease phenotypes. (A) Neutralizing antibody titers measured from serum harvested three weeks post-boost vaccination titers. Neutralization at 50% reciprocal inhibitory concentration (IC50) plotted by family grouping. (B) Weight loss across PBS-vaccinated DO mice families measured four days post-MA10 challenge. (C) Lung viral titer by family measured from S2P-vaccinated mice challenged with MA10 4 days post-infection. Each color and shape indicates a different family.

Figure 4

Vaccination is broadly protective in genetically paired mice post-infection. (A) Differences in percent weight loss at day 4 between paired mice, based on genetic relatedness, vaccinated with either PBS (control) vaccination or S2P + RIBI. (B) Differences in lung viral load measured in pfu/mL between genetic pairs of mice vaccinated with PBS (control) or S2P + RIBI. Pairs were challenged with MA10 at the same time to measure the degree of protection in mice.