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Multi-Envelope HIV-1 Vaccine Development: Two Targeted Immune Pathways, One Desired Protective Outcome.

ABSTRACT: In 2016, there were more than 30 million individuals living with HIV-1, ?1.8 million new HIV-1 infections, and ?1 million HIV-1-related deaths according to UNAIDS ( unaids.org ). Hence, a preventive HIV-1 vaccine remains a global priority. The variant envelopes of HIV-1 present a significant obstacle to vaccine development and the vaccine field has realized that immunization with a single HIV-1 envelope protein will not be sufficient to generate broadly neutralizing antibodies. Here we describe two nonmutually exclusive, targeted pathways with which a multi-envelope HIV-1 vaccine may generate protective immune responses against variant HIV-1. Pathways include (i) the induction of a polyclonal immune response, comprising a plethora of antibodies with subset-reactive and cross-reactive specificities, together able to neutralize diverse HIV-1 (termed Poly-nAb in this report) and (ii) the induction of one or a few monoclonal antibodies, each with a broadly neutralizing specificity (bnAb). With each pathway in mind, we describe challenges and strategies that may ultimately support HIV-1 vaccine success.

SUBMITTER: Hurwitz JL

PROVIDER: S-EPMC5915263 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Multi-Envelope HIV-1 Vaccine Development: Two Targeted Immune Pathways, One Desired Protective Outcome.

Hurwitz Julia L JL Bonsignori Mattia M

Viral immunology 20180109 2

In 2016, there were more than 30 million individuals living with HIV-1, ∼1.8 million new HIV-1 infections, and ∼1 million HIV-1-related deaths according to UNAIDS ( unaids.org ). Hence, a preventive HIV-1 vaccine remains a global priority. The variant envelopes of HIV-1 present a significant obstacle to vaccine development and the vaccine field has realized that immunization with a single HIV-1 envelope protein will not be sufficient to generate broadly neutralizing antibodies. Here we describe ...[more]

PMID: 29315059

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Project description:Lentiviral Envelope (Env) antigenic variation and related immune evasion present major hurdles to effective vaccine development. Centralized Env immunogens that minimize the genetic distance between vaccine proteins and circulating viral isolates are an area of increasing study in HIV vaccinology. To date, the efficacy of centralized immunogens has not been evaluated in the context of an animal model that could provide both immunogenicity and protective efficacy data. We previously reported on a live-attenuated (attenuated) equine infectious anemia (EIAV) virus vaccine, which provides 100% protection from disease after virulent, homologous, virus challenge. Further, protective efficacy demonstrated a significant, inverse, linear relationship between EIAV Env divergence and protection from disease when vaccinates were challenged with viral strains of increasing Env divergence from the vaccine strain Env. Here, we sought to comprehensively examine the protective efficacy of centralized immunogens in our attenuated vaccine platform. We developed, constructed, and extensively tested a consensus Env, which in a virulent proviral backbone generated a fully replication-competent pathogenic virus, and compared this consensus Env to an ancestral Env in our attenuated proviral backbone. A polyvalent attenuated vaccine was established for comparison to the centralized vaccines. Additionally, an engineered quasispecies challenge model was created for rigorous assessment of protective efficacy. Twenty-four EIAV-naïve animals were vaccinated and challenged along with six-control animals six months post-second inoculation. Pre-challenge data indicated the consensus Env was more broadly immunogenic than the Env of the other attenuated vaccines. However, challenge data demonstrated a significant increase in protective efficacy of the polyvalent vaccine. These findings reveal, for the first time, a consensus Env immunogen that generated a fully-functional, replication-competent lentivirus, which when experimentally evaluated, demonstrated broader immunogenicity that does not equate to higher protective efficacy.

Dataset Information

Multi-Envelope HIV-1 Vaccine Development: Two Targeted Immune Pathways, One Desired Protective Outcome.

Publications

Multi-Envelope HIV-1 Vaccine Development: Two Targeted Immune Pathways, One Desired Protective Outcome.

Similar Datasets

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