Assessing Intranasal M Protein–Based Vaccines Against Streptococcus pyogenes: Serotype-Specific Constructs and Mucosal Immunity in a B6HLA Mouse Model

Streptococcus pyogenes is a Gram-positive, human-specific pathogen that colonizes the skin and upper respiratory tract, causing various invasive diseases including bacteremia and toxic shock syndrome. The M protein, a prominent virulence factor that enables resistance to phagocytosis and complement-mediated killing, represents an attractive vaccine target. This study investigated whether intranasal immunization with recombinant M proteins from serotypes M12, M3, and M18—with or without alum adjuvant—could protect transgenic B6HLA mice from nasopharyngeal challenge. Despite modest increases in serum IgG titers, particularly for full-length and conserved-region M12 constructs and M3 with alum, none of these formulations significantly reduced S. pyogenes burden. Robust mucosal IgA responses were not induced in most vaccination groups, and even those with detectable IgA did not improve opsonophagocytic clearance in vitro. Our findings highlight the challenges of eliciting strong mucosal immunity against S. pyogenes using M protein constructs with alum, suggesting future work should explore alternative adjuvants, delivery routes, or prime-boost strategies.