The role of the mRNA-based or Newcastle disease virus (NDV)-based vaccine platform in mucosal B cell priming and recirculation - PROJECT SUMMARY The experiences and lessons learned from the COVID-19 pandemic geared our interests towards investigating the mechanism of action of different vaccine platforms and vaccination strategies that aim to induce long-lasting protective systemic and mucosal immune responses to prevent disease and transmission via the mucosal route. Dr. Weina Sun co-developed a Newcastle disease virus vector (NDV)-based COVID-19 vaccine that can be used either as an injectable inactivated whole virion vaccine or a live intranasal vaccine, the latter of which can elicit mucosal immune responses as a “stand-alone” vaccine platform. In naïve mice, a 2-dose regimen of intranasal NDV-based vaccine induced a high level of mucosal IgA antibodies. In mice that were pre- vaccinated with mRNA-LNP COVID-19 vaccines via the intramuscular route, a third intranasal NDV booster also substantially enhanced nasal wash antigen-specific IgA. By closely examining samples obtained from different anatomical mucosal sites in mRNA-LNP vaccinated mice without the NDV booster, spike-specific IgA were detected in nasal wash, intestinal lavage as well as vaginal lavage, among which Intestinal lavage contained the highest levels of IgA. Dr. Jennifer Gommerman is an immunologist with special interests studying mucosal B lymphocytes. In humans, she developed methods to detect salivary antibodies. While SARS-CoV-2 infection induces high levels of spike-specific salivary IgG and IgA, salivary IgG are also abundantly found after intramuscular 2-dose mRNA vaccinations. Intriguingly, some of the mRNA-vacccinated individuals developed and maintained modest salivary secretory-IgA that were resistence to decay after a 2-dose mRNA vaccine. Given that both in mice and humans, mucosal antigen-specific IgA were detected after mRNA-LNP vaccination, we hypothesize that mRNA-LNP vaccines can prime de novo mucosal B cells that are close to the administration sites, which are able to recirculate to other mucosal surfaces. Consequently, a further mucosal booster vaccine, such as the intranasal live NDVvaccine, would be able to recall pre-exisiting memory B cell responses. We will follow two specific aims to test our hypothesis, utilizing mRNA-LNP vaccine and NDV vaccine encoding the spike of Beta variant as a proof of concept: (Aim 1) To examine temporal and spatial dynamics of antigen-specific IgA and IgG secreting B cells in the mucosa-associated lymphoid tissues after mRNA and NDV vaccination in mice. (Aim 2) To track circulation of antigen-specific mucosal B cells in photoconvertible Kikume mice after mRNA prime followed by NDV vaccination or infection by flowcytometry. The proposed work entails innovative approaches and mouse models to test our hypothesis. We believe the outcomes of the study can inform the mechanism of action of not only mRNA-based and NDV-based SARS-CoV-2 vaccines, but also the same types of vaccines against other respiratory or enteric viral pathogens, in which mucosal antibody responses plays a critical role to mitigate virus infection and transmission.
