Streptococcus pyogenes pharyngitis elicits diverse antibody responses to key vaccine antigens influenced by the imprint of past infections.

Knowledge gaps regarding human immunity to Streptococcus pyogenes have impeded vaccine development. To address these gaps and evaluate vaccine candidates, we established a human challenge model of S. pyogenes pharyngitis. Here, we analyse antibody responses in serum and saliva against 19 antigens to identify characteristics distinguishing 19 participants who developed pharyngitis and 6 who did not. We show that pharyngitis elicits serum IgG responses to key vaccine antigens and a muted mucosal IgA response, whereas IgG responses are minimal and IgA responses more pronounced in participants without pharyngitis. Serum IgG responses to pharyngitis in adult participants resemble those in children and are inversely correlated with the magnitude of pre-existing responses. While a straightforward correlate of protection is not evident, baseline antibody signatures distinguish clinical and immunological outcomes following experimental challenge. This highlights the influence of a complex humoral imprint from previous exposure, relevant for interpreting immunogenicity in forthcoming vaccine trials.