Adjuvant, mimicry and booster requirements for shepherding the development of neutralizing antibodies to the high-mannose patch on HIV-1

The HIV-1 envelope spike (Env) bears a cluster of oligomannose-type glycans that is a target for broadly neutralizing antibodies (bnAbs). However, while nAbs to this cluster, dubbed the high-mannose patch (HMP), are known to develop in at least some HIV-infected individuals, past attempts to elicit similar antibodies by immunization have been largely unsuccessful. Most previous approaches have involved presenting clusters of natural or synthetic high-mannose glycans on the surface of carrier proteins. The difficulty in eliciting high-mannose-targeting nAbs by immunization is believed to relate, at least in part, to the ‘self’ nature of the targeted glycans. The approach that we are pursuing is based on the scientific premise that antigenic mimicry of mammalian host structures can stimulate cross-reactive antibodies if such mimics are presented in the proper ‘foreign’ milieu. Our overarching hypothesis is that, upon immunization, an antigenic mimic of mammalian oligomannose will more readily elicit antibodies that bind the HMP than native or synthetic oligomannose. In our progress report, we show that a CRM197-conjugate of our lead oligomannose mimetic is bound with high avidity by various HMP-specific bnAbs as well as their germline precursors. Furthermore, human antibody transgenic mice immunized with this neoglycoconjugate yield antibodies that bind recombinant HIV-1 SOSIP trimers, albeit only when the conjugate is formulated in the TLR4-stimulating Th1-adjuvant GLA-SE. We expect our findings to help sharpen our strategy and critically inform the pursuit of future preclinical studies. Results from this research could inform other HIV vaccine design strategies also.