Daniel C Douek | Search PubMed

PubMed2026

IgA is necessary and sufficient to prevent norovirus infection in mice.

Human norovirus is the leading cause of viral gastroenteritis, yet effective vaccines and therapeutics remain elusive. Using murine norovirus as a model, we found that mucosal immunoglobulin A (IgA) is both necessary and sufficient for protection against infection, whereas CD8+ T cells are dispensable. Robust intestinal IgA production requires at least 4 weeks of enteric infection, consistent with kinetics of human norovirus RNA clearance. Systemic vaccination elicits high titers of neutralizing serum IgG but fails to prevent enteric norovirus infection, phenocopying a recent human norovirus vaccine failure. In contrast, prophylactic delivery of dimeric anti-norovirus IgA via mRNA lipid nanoparticles confers sterilizing immunity. Together, these findings define a critical role for mucosal IgA in norovirus protection and identify IgA-based treatments as a therapeutic approach for human norovirus.

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PubMed2025

Passive infusion of an S2-Stem broadly neutralizing antibody protects against SARS-CoV-2 infection and lower airway inflammation in rhesus macaques.

The continued evolution of SARS-CoV-2 variants capable of subverting vaccine and infection-induced immunity suggests the advantage of a broadly protective vaccine against betacoronaviruses (β-CoVs). Recent studies have isolated monoclonal antibodies (mAbs) from SARS-CoV-2 recovered-vaccinated donors capable of neutralizing many variants of SARS-CoV-2 and other β-CoVs. Many of these mAbs target the conserved S2 stem region of the SARS-CoV-2 spike protein, rather than the receptor binding domain contained within S1 primarily targeted by current SARS-CoV-2 vaccines. One of these S2-directed mAbs, CC40.8, has demonstrated protective efficacy in small animal models against SARS-CoV-2 challenge. As the next step in the pre-clinical testing of S2-directed antibodies as a strategy to protect from SARS-CoV-2 infection, we evaluated the in vivo efficacy of CC40.8 in a clinically relevant non-human primate model by conducting passive antibody transfer to rhesus macaques (RM) followed by SARS-CoV-2 challenge. CC40.8 mAb was intravenously infused at 10mg/kg, 1mg/kg, or 0.1 mg/kg into groups (n = 6) of RM, alongside one group that received a control antibody (PGT121). Viral loads in the lower airway were significantly reduced in animals receiving higher doses of CC40.8. We observed a significant reduction in inflammatory cytokines and macrophages within the lower airway of animals infused with 10mg/kg and 1mg/kg doses of CC40.8. Viral genome sequencing demonstrated a lack of escape mutations in the CC40.8 epitope. Collectively, these data demonstrate the protective efficiency of broadly neutralizing S2-targeting antibodies against SARS-CoV-2 infection within the lower airway while providing critical preclinical work necessary for the development of pan-β-CoV vaccines.

Animals↗