Enhanced: The Need for a Global HIV Vaccine Enterprise

Klausner, Richard D.; Fauci, Anthony S.; Corey, Lawrence; Nabel, Gary J.; Gayle, Helene; Berkley, Seth; Haynes, Barton F.; Baltimore, David; Collins, Chris; Douglas, R. Gordon; Esparza, José; Francis, Donald P.; Ganguly, Nirmal Kumar; Gerberding, Julie L.; Johnston, Margaret I.; Kazatchkine, Michel D.; McMichael, Andrew J.; Makgoba, M. W.; Pantaleo, Giuseppe; Piot, Peter; Shao, Yiming; Tramont, Edmund C.; Varmus, Harold; Wasserheit, Judith N.

doi:10.1126/science.1086916

Cited by 179 publications

(89 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The rgp120 human Phase III trial was not successful, suggesting that rgp120s may not be viable vaccine candidates in and of themselves (12). However, that rgp120 BaL alone can induce antibodies that neutralize ϳ60% of subtype B HIV-1 isolates provides a beach head from which to work to improve the immunogenicity.…”

Section: Discussionmentioning

confidence: 99%

Immunogenicity of Constrained Monoclonal Antibody A32-Human Immunodeficiency Virus (HIV) Env gp120 Complexes Compared to That of Recombinant HIV Type 1 gp120 Envelope Glycoproteins

Liao

Alam

Mascola

et al. 2004

J Virol

Self Cite

View full text Add to dashboard Cite

One strategy for the generation of broadly reactive neutralizing antibodies (NA) against human immunodeficiency virus type 1 (HIV-1) primary isolates is to use immunogens that have constrained HIV-1 envelope gp120 conformations reflective of triggered envelope on the surface of virions. A major change in gp120 following binding to CD4 is the enhanced exposure of the CCR5 binding site. One inducer of CCR5 binding site epitopes on gp120 is the human anti-gp120 monoclonal antibody, A32. We have made cross-linked A32-rgp120 89.6 and A32-rgp120 BaL complexes and have compared their immunogenicities to those of uncomplexed recombinant gp120 BaL (rgp120 BaL ) and rgp120 89.6 . A32-rgp120 89.6 and A32-rgp120 BaL complexes had stable induced CCR5 binding site expression compared to that of uncomplexed rgp120s. However, the A32-rgp120 complexes had similar capacities in guinea pigs for induction of NA against HIV-1 primary isolates versus that of rgp120 alone. A32-rgp120 89.6 induced antibodies that neutralized 6 out of 11 HIV-1 isolates, while rgp120 89.6 alone induced antibodies that neutralized 4 out of 11 HIV-1 isolates. A32-rgp120 BaL complexes induced antibodies that neutralized 4 out of 14 HIV-1 isolates while, surprisingly, non-cross-linked rgp120 BaL induced antibodies that neutralized 9 out of 14 (64%) HIV-1 isolates. Thus, stable enhanced expression of the coreceptor binding site on constrained gp120 is not sufficient for inducing broadly neutralizing anti-HIV-1 NA. Moreover, the ability of HIV-1 rgp120 BaL to induce antibodies that neutralized ϳ60% of subtype B HIV-1 isolates warrants consideration of using HIV-1 BaL as a starting point for immunogen design for subtype B HIV-1 experimental immunogens.The design of immunogens that will neutralize a broad spectrum of human immunodeficiency virus type 1 (HIV-1) primary isolates is a high priority for development of a practical HIV-1 vaccine. Following binding of virion gp120 to cellular CD4, the HIV-1 envelope undergoes conformational changes that result in exposure of the coreceptor binding site leading to virion-host cell fusion (1, 24).One potential strategy for inducing broadly reactive neutralizing antibodies (NA) is to construct immunogens that are constrained and reflect wild-type fusion intermediate Env forms, with the hope of stably exposing conserved immunogenic epitopes that otherwise would not be readily available for antibody induction. An alternative strategy for selection of Env immunogens is to select the best envelopes from among many screened for their ability to induce antibodies that broadly neutralize HIV-1 primary isolates.In this work we describe the immunogenicity of recombinant HIV-1 gp120s complexed with the CD4 mimic, monoclonal antibody (MAb) A32. Like CD4, MAb A32 induces expression of the CCR5 binding site on rgp120, but unlike CD4, MAb A32 does not bind at the CD4 binding site (26). Thus, MAb A32 has a potential advantage over CD4 in a constrained Env complex in that A32-rgp120 complexes have exposed CD4 binding sites. Here we show ...

show abstract

Section: Discussionmentioning

confidence: 99%

Immunogenicity of Constrained Monoclonal Antibody A32-Human Immunodeficiency Virus (HIV) Env gp120 Complexes Compared to That of Recombinant HIV Type 1 gp120 Envelope Glycoproteins

Liao

Alam

Mascola

et al. 2004

J Virol

Self Cite

View full text Add to dashboard Cite

show abstract

“…While the first HIV vaccines to reach phase III clinical trials, AIDSVAX B/B [3] and B/E [4], were found to be inefficacious, these large-scale efforts demonstrate the feasibility of conducting safe and ethical human trials of HIV vaccines [5]. With growing international advocacy [6] and increased leadership and coordination of vaccine development efforts through the new Global HIV Vaccine Enterprise [7], HIV vaccine research has gained substantial momentum. Nevertheless, the advent of HIV vaccines will not ensure their acceptability.…”

Section: Introductionmentioning

confidence: 99%

HIV vaccine acceptability among communities at risk: The impact of vaccine characteristics

Newman

Duan²,

Lee³

et al. 2006

Vaccine

View full text Add to dashboard Cite

HIV vaccines offer the best long-term hope of controlling the AIDS pandemic; yet, the advent of HIV vaccines will not ensure their acceptability. We conducted a cross-sectional survey (n = 143), incorporating conjoint analysis, to assess HIV vaccine acceptability among participants recruited using multi-site (n = 9), venue-based sampling in Los Angeles. We used a fractional factorial experimental design to construct eight hypothetical HIV vaccines, each with seven dichotomous attributes. The acceptability of each vaccine was assessed individually and then averaged across participants. Next, the impact of each attribute on vaccine acceptability was estimated for each participant using ANOVA and then analyzed across participants. Acceptability of the eight hypothetical HIV vaccines ranged from 33.2 (S.D. 34.9) to 82.2 (S.D. 31.3) on a 0-100 scale; mean = 60.0 (S.D. 21.9). Efficacy had the greatest impact on acceptability (22.7; CI: 18.5-27.1; p < 0.0001), followed by cross-clade protection (12.5; CI: 8.7-16.3, p < 0.0001), side effects (11.5; CI: 7.4-15.5; p < 0.0001), and duration of protection (6.1; CI: 3.2-9.0; p < .0001). Route of administration, number of doses and cost were not significant. Low acceptability of "partial efficacy" vaccines may present obstacles to future HIV vaccine dissemination. Educational and social marketing interventions may be necessary to ensure broad HIV vaccine uptake.

show abstract

“…Indeed, comprehensive identification of genes involved in SIV control using functional genomics would likely require hundreds of animals with defined SIV pathogenesis and unprecedented cooperation among the many investigators possessing samples from these animals. Inspiration for this ambitious undertaking can be drawn from other large-scale collaborative efforts recently initiated to answer fundamental questions about HIV and SIV pathogenesis (3,13,14).…”

Section: An Unresolved Question Is Whether Differences In Mamu-b*17-rmentioning

confidence: 99%

Control of Simian Immunodeficiency Virus SIVmac239 Is Not Predicted by Inheritance of Mamu-B * 17 -Containing Haplotypes

Wojcechowskyj

Yant

Wiseman

et al. 2007

J Virol

View full text Add to dashboard Cite

It is well established that host genetics, especially major histocompatibility complex (MHC) genes, are important determinants of human immunodeficiency virus disease progression. Studies with simian immunodeficiency virus (SIV)-infected Indian rhesus macaques have associated Mamu-B*17 with control of virus replication. Using microsatellite haplotyping of the 5-Mb MHC region, we compared disease progression among SIVmac239-infected Indian rhesus macaques that possess Mamu-B*17-containing MHC haplotypes that are identical by descent. We discovered that SIV-infected animals possessing identical Mamu-B*17-containing haplotypes had widely divergent disease courses. Our results demonstrate that the inheritance of a particular Mamu-B*17-containing haplotype is not sufficient to predict SIV disease outcome.

show abstract

Enhanced: The Need for a Global HIV Vaccine Enterprise

Cited by 179 publications

References 1 publication

Immunogenicity of Constrained Monoclonal Antibody A32-Human Immunodeficiency Virus (HIV) Env gp120 Complexes Compared to That of Recombinant HIV Type 1 gp120 Envelope Glycoproteins

Immunogenicity of Constrained Monoclonal Antibody A32-Human Immunodeficiency Virus (HIV) Env gp120 Complexes Compared to That of Recombinant HIV Type 1 gp120 Envelope Glycoproteins

HIV vaccine acceptability among communities at risk: The impact of vaccine characteristics

Control of Simian Immunodeficiency Virus SIVmac239 Is Not Predicted by Inheritance of Mamu-B * 17 -Containing Haplotypes

Contact Info

Product

Resources

About