C1q enables influenza hemagglutinin stem binding antibodies to block viral attachment and broadens the antibody escape repertoire.

Antigenic drift, the gradual accumulation of amino acid substitutions in the influenza virus hemagglutinin (HA) receptor protein, enables viral immune evasion. Antibodies (Abs) specific for the drift-resistant HA stem region are a promising universal influenza vaccine target. Although anti-stem Abs are not believed to block viral attachment, here we show that complement component 1q (C1q), a 460-kilodalton protein with six Ab Fc-binding domains, confers attachment inhibition to anti-stem Abs and enhances their fusion and neuraminidase inhibition. As a result, virus neutralization activity in vitro is boosted up to 30-fold, and in vivo protection from influenza PR8 infection in mice is enhanced. These effects reflect increased steric hindrance and not increased Ab avidity. C1q greatly expands the anti-stem Ab viral escape repertoire to include residues throughout the HA, some of which cause antigenic alterations in the globular region or modulate HA receptor avidity. We also show that C1q enhances the neutralization activity of non–receptor binding domain anti–SARS-CoV-2 spike Abs, an effect dependent on spike density on the virion surface. These findings demonstrate that C1q can greatly expand Ab function and thereby contribute to viral evolution and immune escape. Editor's summary: Antibodies (Abs) targeting the stem region of the influenza hemagglutinin (HA) receptor are a promising approach for a universal influenza (IAV) vaccine. The serum complement protein C1q is known to increase the functionality of antiviral Abs, but how C1q influences Ab-driven viral evolution is not understood. Kosik et al. found that C1q binding to HA stem-bound Ab sterically blocked IAV attachment and increased the frequency and diversity of escape mutations in the HA gene via amino acid substitutions. C1q enhanced virus neutralization mediated by anti-stem Abs, as well as non–RBD-specific anti–SARS-CoV-2 Abs. These findings show that C1q expands the viral escape repertoire while increasing virus neutralization. —Hannah Isles [ABSTRACT FROM AUTHOR]