Immunodominance is a poor predictor of vaccine-induced T follicular helper cell quality

BACKGROUND: Rational engineering of vaccine immunogens to focus B cell responses on potently neutralising epitopes is a promising approach to improve the potency, breadth and durability of viral vaccines. Such strategies, however, can compromise vaccine immunogenicity through the unintended exclusion of CD4+ T cell epitopes, which are critical for the development of T follicular helper (TFH) cells and to support high affinity antibody production. METHODS: Using a prototypic influenza haemagglutinin (HA) stem immunogen lacking effective CD4+ T cell help in C57BL/6 mice, we interrogated the minimal requirements for T cell help needed to drive serological responses to vaccination. FINDINGS: We find that priming of naïve CD4+ T cells is markedly efficient, however the immunodominance of a given CD4+ T cell epitope is not predictive of the propensity to provide high quality help to antigen-specific B cells. In the context of soluble antigens, provision of a single MHC class II epitope is sufficient to drive robust germinal centre responses and serum IgG titres. However not all CD4+ epitopes provide equivalent levels of B cell help, despite priming comparable numbers of antigen-specific CD4+ T cells. Finally, we show multimerizing and arraying antigens on nanoparticle scaffolds unlocks highly subdominant, near-undetectable CD4+ T cell helper responses to support a T-dependent antibody response. INTERPRETATION: Our findings emphasise the importance of CD4+ T cell help for programming robust and durable humoural immunity, and provide crucial insights to guide the rational incorporation of favourable T cell epitopes into vaccines. FUNDING: The study was funded by the NHMRC.