Systems biological assessment of innate responses to vaccination

ABSTRACT - Project 1 In the current proposal, we will use systems biological approaches to address two fundamental issues in vaccinology. The first issue concerns the immunology of COVID-19 vaccines, which utilize novel platforms (mRNA) or adjuvants (Matrix M used in the Novavax vaccine). The second issue is related to the role of the microbiome on vaccine immunity. With respect to the first issue, despite the rapid development of COVID- 19 vaccines, there is a paucity of understanding about the mechanisms by which they induce innate and adaptive responses. Furthermore, the nature of the immune response induced by mRNA vaccines in special populations such as those with serious allergies is unknown. It is conceivable that in such populations, a predisposition towards Th2 responses, could alter the quality of the immune response. Interestingly, there have been reports of rare but severe allergic reactions to vaccination, in individuals with an atopic background. Therefore, we will assess immunity to the BNT162b2 vaccine atopic versus healthy subjects. In the case of the Matrix-M adjuvanted recombinant COVID-19 vaccine developed by Novavax, there is a paucity of understanding of innate immune mechanisms stimulated by the saponin-based Matrix-M adjuvant. We will analyze samples collected from a Novavax sponsored clinical trial of their investigational subunit COVID-19 vaccine in South African adults. The second theme of the proposal is focused on the impact of the microbiome on immunity to vaccination in healthy adults. Our recent work involving antibiotics driven ablation of the microbiota has highlighted an important role for the microbiome in modulating immune responses to vaccination with the seasonal influenza vaccine. However, the immune response against seasonal influenza vaccine in adults represents a recall response, because of prior exposure to influenza. The impact of the microbiome on a primary immune response, such as the response to rabies vaccination, is unknown. These issues will be addressed in the following specific aims: Aim 1: Systems biological assessment of innate responses to vaccination against COVID-19. Sub-aim 1a: Multi-omics assessment of innate responses to the BNT162b2 mRNA vaccine in atopic vs. healthy adults. Sub-aim 1b: Multi-omics assessment of innate responses to the Novavax COVID-19 vaccine. Aim 2: Systems biological assessment of the impact of the microbiota on innate immunity to rabies vaccination.