A Next-Generation Adenoviral Vaccine Elicits Mucosal and Systemic Immunogenicity and Reduces Viral Shedding after SARS-CoV-2 Challenge in Nonhuman Primates.

As new SARS-CoV-2 variants continue to emerge and impact communities worldwide, next-generation vaccines that enhance protective mucosal immunity may have a significant impact on productive infection and transmission. We have developed recombinant non-replicating adenovirus serotype 5 (rAd5) vaccines delivered by mucosal administration that express both target antigen and a novel molecular adjuvant within the same cell. Here, we describe the immunogenicity of three unique SARS-CoV-2 rAd5 vaccine candidates and their efficacy following viral challenge in non-human primates (NHPs). Intranasal immunization with rAd5 vaccines expressing Wuhan, or Beta variant spike alone, or Wuhan spike and nucleocapsid elicited strong antigen-specific serum IgG and IgA with neutralizing activity against multiple variants of concern (VOC). Robust cross-reactive mucosal IgA was detected after a single administration of rAd5, which showed strong neutralizing activity against multiple VOC. Additionally, mucosal rAd5 vaccination increased spike-specific IFN-γ producing circulating T-cells. Upon Beta variant SARS-CoV-2 challenge, all the vaccinated NHPs exhibited significant reductions in viral load and infectious particle shedding in both the nasal passages and lower airways. These findings demonstrate that mucosal rAd5 immunization is highly immunogenic, confers protective cross-reactive antibody responses in the circulation and mucosa, and reduces viral load and shedding after SARS-CoV-2 challenge.

Hyaluronan synthesis inhibition impairs antigen presentation and delays transplantation rejection.

A coat of pericellular hyaluronan surrounds mature dendritic cells (DC) and contributes to cell-cell interactions. We asked whether 4-methylumbelliferone (4MU), an oral inhibitor of HA synthesis, could inhibit antigen presentation. We find that 4MU treatment reduces pericellular hyaluronan, destabilizes interactions between DC and T-cells, and prevents T-cell proliferation in vitro and in vivo. These effects were observed only when 4MU was added prior to initial antigen presentation but not later, consistent with 4MU-mediated inhibition of de novo antigenic responses. Building on these findings, we find that 4MU delays rejection of allogeneic pancreatic islet transplant and allogeneic cardiac transplants in mice and suppresses allogeneic T-cell activation in human mixed lymphocyte reactions. We conclude that 4MU, an approved drug, may have benefit as an adjunctive agent to delay transplantation rejection.