Progress with induction of HIV broadly neutralizing antibodies in the Duke Consortia for HIV/AIDS Vaccine Development

Abstract

Purpose of review: Design of an HIV vaccine that can induce broadly neutralizing antibodies (bnAbs) is a major goal. However, HIV bnAbs are not readily made by the immune system. Rather HIV bnAbs are disfavored by a number of virus and host factors. The purpose of the review is to discuss recent progress made in the design and use of immunogens capable of inducing HIV bnAbs in the Duke Consortia for HIV/AIDS Vaccine Development.

Recent findings: New immunogens capable of binding with high affinity to unmutated common ancestors (UCAs) of bnAb B cell lineages have been designed and strategies for stabilization of HIV Env in its prefusion state are being developed. Success is starting to be translated from preclinical studies of UCA-targeting immunogens in animals, to success of initiating bnAb lineages in humans.

Summary: Recent progress has been made in both immunogen design and in achieving bnAb B cell lineage induction in animal models and now in human clinical trials. With continued progress, a practical HIV/AIDS vaccine may be possible. However, host constraints on full bnAb maturation remain as potential roadblocks for full maturation of some types of bnAbs.

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FIGURE 1

Modified mRNA HIV-1 vaccine immunogen design strategy. Modified mRNAs are designed and produced for screening for adequate in vitro expression, followed by encapsulation in ionizable LNPs for in vivo immunization studies. If immunogenicity is acceptable at appropriate doses in mice or macaques, the mRNA can be down-selected for manufacture. If immunogenicity is not acceptable, redesign of the mRNA is necessary (dotted line). LNPs, lipid nanoparticles.

FIGURE 2

The Duke CHAVD Clinical Trials Planned Portfolio. For CD4BS bnAb induction, we have two clinical trials planned, one with protein (HVTN 309) and one as mRNA/LNPs encoding transmembrane stabilized gp160 Envs (HVTN 312). Both the protein and the mRNA/LNP versions are of the VH1–46-type of CD4 mimicking CD4BS bnAb designed for the CH235 bnAb lineage. For V3-glycan bnAb induction, again, we have two clinical trials planned, one as protein (HVTN 307) and one as mRNA/LNP. Since a key limiting factor in inducing V3-glycan bnAbs is the dearth of bnAb precursors of this type, we have designed a priming immunogen that binds to three different V3 glycan lineage UCAs. Similarly, for V2-glycan bnAb induction, mRNAs are being designed that bind to multiple UCAs. Finally for MPER bnAb induction, in the HVTN 133 clinical trial we have used repetitive immunizations with an MPER peptide-liposome formulation. bnAb, broadly neutralizing antibody, LNP, lipid nanoparticles; UCA, unmutated common ancestor.

FIGURE 3

Immunogen combinations undergoing testing for induction of proximal and distal gp41 bnAbs. Panel a shows the MPER peptide-liposome used in HVTN 133 that induced heterologous neutralizing antibodies targeting the proximal MPER region. Boosts such priming have been designed to trigger both proximal and distal MPER epitopes. Panel b shows the HVTN 133 prime immunogen with boosts of mRNAs designed as transmembrane expressing modified mRNAs or transmembrane gp150  or gp160 trimers. Panel c shows the same boosts being primed by mRNAs that encode a protein or proteins that recognize both proximal and distal MPER bnAb precursors. bnAb, broadly neutralizing antibody; MPER, membrane proximal external region.