Development of soluble and membrane bound immunogens to shepherd HIV-1 MPER specific BCR maturation

The quest for a broadly protective vaccine against Influenza has been stymied in part to the antigenic diversity of the flu virus, and in part due to pre-existing, non-protective immunity from past exposures, so called immunological imprinting. Further complicating the elicitation of broadly protective antibodies against Influenza is that the most highly immunodominant regions of hemagglutinin tend to be in regions of high antigenic variability, which generally only result in strain specific or seasonal responses [1]. In recent years, multiple groups have isolated antibodies directed towards highly conserved regions of hemagglutinin located in the stem [2-4], including towards the newly identified anchor epitope, which is analogous to the membrane proximal external region (MPER) of the HIV-1 envelope protein. These broadly neutralizing anchor antibodies have exhibited the ability to bind and neutralize H1, H2 and H5 viruses [5, 6]. Thus, anchor bnAbs are an attractive class of antibodies for passive infusion or vaccine elicitation, either in isolation or in concert with other epitopes where they would likely enhance protection breadth. Though the stem region of hemagglutinin tends to be more conserved, the recessed and immunologically subdominant nature of the epitope restricts the frequency of these responses, however the development of epitope scaffold immunogens could overcome these barriers for antibody access. Rigorous prior research has demonstrated (i) germline targeting epitope scaffolds can elicit highly specific antibodies against HIV in both preclinical and clinical models [7-11]; (ii) influenza neutralizing antibodies are influenza correlates of protection [12-14]; and (iii) tuning Influenza humoral responses towards conserved regions can improve cross strain reactivity of elicited responses [6, 15]. This project seeks to develop immunogens that present the anchor epitope in a native-like context with the aim of eliciting anchor class antibodies.