The vaccine elicitation of broadly neutralizing responses is a central goal of HIV research. Recently， we elicited cross-clade neutralizing responses against the N terminus of the fusion peptide (FP)， a critical component of the HIV-entry machinery. While the consistency of the elicited cross-clade neutralizing responses was good in mice， it was poor in guinea pigs: after seven immunizations comprising either envelope (Env) trimer or FP coupled to a carrier， serum from only one of five animals could neutralize a majority of a cross-clade panel of 19 wild-type strains. Such a low response rate-only 20%-made increasing consistency an imperative. Here， we show that additional Env-trimer immunizations cou... More
The vaccine elicitation of broadly neutralizing responses is a central goal of HIV research. Recently， we elicited cross-clade neutralizing responses against the N terminus of the fusion peptide (FP)， a critical component of the HIV-entry machinery. While the consistency of the elicited cross-clade neutralizing responses was good in mice， it was poor in guinea pigs: after seven immunizations comprising either envelope (Env) trimer or FP coupled to a carrier， serum from only one of five animals could neutralize a majority of a cross-clade panel of 19 wild-type strains. Such a low response rate-only 20%-made increasing consistency an imperative. Here， we show that additional Env-trimer immunizations could boost broad FP-directed neutralizing responses in a majority of immunized animals. The first boost involved a heterologous Env trimer developed from the transmitted founder clade C strain of donor CH505， and the second boost involved a cocktail that combined the CH505 trimer with a trimer from the BG505 strain. After boosting， sera from three of five animals neutralized a majority of the 19-strain panel and serum from a fourth animal neutralized 8 strains. We demonstrate that cross-reactive serum neutralization targeted the FP by blocking neutralization with soluble fusion peptide. The FP competition revealed two categories of elicited responses: an autologous response to the BG505 strain of high potency (~10，000 ID50)， which was not competed by soluble FP， and a heterologous response of lower potency， which was competed by soluble FP. While the autologous response could increase rapidly in response to Env-trimer boost， the heterologous neutralizing response increased more slowly. Overall， repetitive Env-trimer immunizations appeared to boost low titer FP-carrier primed responses to detectable levels， yielding cross-clade neutralization. The consistent trimer-boosted neutralizing responses described here add to accumulating evidence for the vaccine utility of the FP site of HIV vulnerability.
