The Immune Response to SARS-CoV-2 in the Context of Aging and Viral Evolution

Abstract

Coronavirus disease 2019 (COVID-19) was declared a pandemic by the World Health Organization in March 2020. The rapid spread of the virus, SARS-CoV-2, necessitated prompt development of vaccines, therapeutics, and a more comprehensive understanding of the virus’ biology. To aid in the early investigation of SARS-CoV-2, we aimed to generate a new transgenic mouse model that better recapitulates features of SARS-CoV-2 infection in humans. We demonstrate that reducing the hACE2 transgene in the K18-hACE2 transgenic mouse alleviates neuroinvasion and reduces the mortality rate of SARS-CoV-2 infection. One year after the emergence of SARS-CoV-2, viral variants evolved that challenged the existing population immunity induced by natural infection and vaccination. Improving our understanding of how the immune system adapts to the evolution of SARS-CoV-2 is crucial for developing protective vaccines. This dissertation explores this topic from two perspectives: 1) Investigating whether the immunity generated by the ancestral SARS-CoV-2 vaccinations in older adults can provide effective immune responses against new viral variants and 2) understanding the contribution of each component of the memory immune response in immune imprinting induced by ancestral vaccination.