We studied two trimer platforms, the SOSIP and native-flexible linker (NFL) platforms ( Sharma et al., 2015). To optimize the induction of autologous tier 2 nAb responses by native-like trimer immunizations, we investigated a number of parameters, including immunization route, dose, and timing of immunizations. Most worrisome was the observation that only a fraction of the monkeys developed nAbs, raising concerns about whether Env trimers will elicit tier 2 nAbs in humans ( Havenar-Daughton et al., 2017, Sanders and Moore, 2017). Tier 2 nAb titers were primarily reported after 6–12 months of immunizations, and titers were relatively low. However, there have been concerns about the limitations of such results. Three RM studies using trimeric Env immunogens reported the induction of autologous tier 2 nAbs ( Havenar-Daughton et al., 2016, Hessell et al., 2016, Sanders et al., 2015), and two of these studies used SOSIP trimer designs ( Havenar-Daughton et al., 2016, Sanders et al., 2015). NHPs, and specifically rhesus macaques (RMs), are often argued to be the most appropriate pre-clinical model for HIV vaccine studies because of the close genetic relatedness of NHPs to humans. Indeed, native-like Env trimers have successfully induced tier 2 nAbs in small animal models ( de Taeye et al., 2016, Feng et al., 2016, McCoy et al., 2016, Sanders et al., 2015) and less reproducibly in nonhuman primates (NHPs) ( Havenar-Daughton et al., 2016, Sanders et al., 2015). The generation of molecules that more faithfully mimic the spike, particularly the SOSIP trimer ( Binley et al., 2000, Sanders et al., 2002, Sanders and Moore, 2017, Sanders et al., 2013), has opened up new opportunities for the induction of tier 2 nAbs.
The failure to induce tier 2 nAb responses has been associated with differences between the presentation of critical epitopes on the immunogens used and their presentation on the native Env spike. The latter neutralize only lab-adapted and very easy-to-neutralize HIV strains, which are not representative of most viruses circulating in humans ( Mascola et al., 2005). These trials mostly utilized monomeric Env gp120 or poor gp140 mimics of native Env spikes, which resulted in the generation of non-neutralizing or tier 1 nAbs only. All human HIV vaccine trials to date have failed to induce tier 2 nAbs ( Haynes et al., 2012, Mascola and Montefiori, 2010). The surface HIV envelope (Env) spike, which consists of a heterotrimer of composition (gp120) 3(gp41) 3, is the sole target of HIV nAbs. However, the induction of nAbs to circulating HIV (so-called tier 2 viruses) through immunization has proven very difficult. Successful vaccines to viral pathogens rely heavily on the induction of neutralizing antibody (nAb) responses for host protection ( Plotkin, 2010). This study provides a framework for preclinical and clinical vaccine studies targeting nAb elicitation.
nAb responses were strongly associated with germinal center reactions, as assessed by lymph node fine needle aspiration. We identified immunogens that minimized non-neutralizing V3 responses and demonstrated that continuous immunogen delivery could enhance nAb responses. A bilateral, adjuvanted, subcutaneous immunization protocol induced reproducible tier 2 nAb responses after only two immunizations 8 weeks apart, and these were further enhanced by a third immunization with BG505 SOSIP trimer. Here, we tested multiple immunogens and immunization strategies head-to-head to determine their impact on the quantity, quality, and kinetics of autologous tier 2 nAb development. However, there is limited experience with recombinant trimers as immunogens in nonhuman primates, which are typically used as a model for humans.
The development of stabilized recombinant HIV envelope trimers that mimic the virion surface molecule has increased enthusiasm for a neutralizing antibody (nAb)-based HIV vaccine.
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