Elicitation of Robust Tier 2 Neutralizing Antibody Responses in Nonhuman Primates by HIV Envelope Trimer Immunization Using Optimized Approaches

Abstract

SummaryThe development of stabilized recombinant HIV envelope trimers that mimic the virion surface molecule has increased enthusiasm for a neutralizing antibody (nAb)-based HIV vaccine. However, there is limited experience with recombinant trimers as immunogens in nonhuman primates, which are typically used as a model for humans. 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. 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. We identified immunogens that minimized non-neutralizing V3 responses and demonstrated that continuous immunogen delivery could enhance nAb responses. nAb responses were strongly associated with germinal center reactions, as assessed by lymph node fine needle aspiration. This study provides a framework for preclinical and clinical vaccine studies targeting nAb elicitation.

Development of broadly neutralizing antibodies in HIV-1 infected elite neutralizers

“…This observation is consistent with the likelihood that bNAb epitopes are conserved for functional reasons, with escape likely requiring compensatory mutations [97, 110], and suggests that slower viral escape supports the development of bNAbs through prolonged exposure to antigen [96, 97, 110, 111]. This hypothesis is further supported by the demonstration in vaccine studies that extended antigen availability enhances germinal center activity and resulting neutralizing Ab responses [112, 113]. …”

“…However, during infection bNAbs develop in a highly competitive environment, and immunization studies showed that autologous neutralizing titers were not enhanced by reduction of V3 responses [113, 134]. Additionally, two elegant studies recently showed that most GCs retain substantial clonal diversity during affinity maturation of complex antigens [135, 136].…”

Efficacious Vaccine against Heroin Contaminated with Fentanyl

“…We have observed this phenomenon for several antidrug vaccines, including a fentanyl vaccine, 7 an oxycodone vaccine, 14 and a methamphetamine vaccine, 8 and this may be the result of a shortened vaccination schedule. 15 Antibody titers detected in the admixture were approximately half the level detected in the individual Her-KLH vaccine, as predicted based on the amount of Her-KLH immunoconjugate employed in each group (Table 1), but antibody affinity remained at similar levels. This trend was also observed for fentanyl antibodies in the admixture vaccine group by week 5 (Table 2).…”

Germinal center enhancement by extended antigen availability

“…Sporadic studies more than a decade ago found that controlled release of antigen over a longer period of time could result in stronger immune responses than conventional bolus injections [9–11]. More recent studies have revisited this concept with substantial success [12–14]. Here we describe several mechanisms through which sustained antigen availability may modulate the GC response to enhance the humoral response.…”

“…Indeed, continuous antigen release over 1–2 weeks using osmotic pumps in mice resulted in higher frequencies of GC Tfh, Tfh and GC B cells [12]. Strikingly, non-human primates (NHPs) immunized with HIV Env via two week osmotic pumps had dramatically increased autologous HIV nAbs compared to animals given a conventional bolus immunization [14]. Furthermore, HIV nAbs also developed in osmotic pump immunized animals more rapidly than conventional animals, suggesting that extended antigen release can accelerate the generation of GC B cells capable of neutralizing HIV.…”