An HIV gp120-CD4 Immunogen Does Not Elicit Autoimmune Antibody Responses in Cynomolgus Macaques

Schwartz, Jennifer A.; Prado, Ilia; Misamore, Johnathan; Weiss, Deborah; Francis, Jesse; Pal, Ranajit; Huaman, Maria Cecilia; Cristillo, Anthony D.; Lewis, George K.; Gallo, Robert C.; DeVico, Anthony L.; Fouts, Timothy

doi:10.1128/cvi.00115-16

Cited by 7 publications

(8 citation statements)

References 84 publications

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“…The total plasmablasts were also not affected by the mucosal vaccine (Supplemental Figure 3C). In the present study, no antibodies were detected against CD4, as shown in Supplemental Figure 2A, consistent with the observations that rhFLSC did not raise anti-CD4 autoantibodies in any previous macaque studies, including a formal immunotoxicological study published by Schwartz et al (18). Other components, e.g., MVA, did not contain any xeno antigens.…”

Section: C and D)supporting

confidence: 93%

Mucosal vaccine efficacy against intrarectal SHIV is independent of anti-Env antibody response

Sui¹,

Lewis²,

Wang³

et al. 2019

Journal of Clinical Investigation

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Section: C and D)supporting

confidence: 93%

Mucosal vaccine efficacy against intrarectal SHIV is independent of anti-Env antibody response

Sui¹,

Lewis²,

Wang³

et al. 2019

Journal of Clinical Investigation

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“…Such development raises the question of the potential immunogenicity of this class of compound, a point of concern that is subject of future studies. It is worth noting, however, that immunization with multiple high doses of a chimeric antigen comprising gp120 linked to CD4 sequences did not elicit detectable autoantibody reactivity with cell surface CD4, despite a robust response to the antigen 56 .…”

Section: Discussionmentioning

confidence: 94%

CD4-mimetic sulfopeptide conjugates display sub-nanomolar anti-HIV-1 activity and protect macaques against a SHIV162P3 vaginal challenge

Ariën

Baleux

Desjardins

et al. 2016

Sci Rep

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The CD4 and the cryptic coreceptor binding sites of the HIV-1 envelope glycoprotein are key to viral attachment and entry. We developed new molecules comprising a CD4 mimetic peptide linked to anionic compounds (mCD4.1-HS12 and mCD4.1-PS1), that block the CD4-gp120 interaction and simultaneously induce the exposure of the cryptic coreceptor binding site, rendering it accessible to HS12- or PS1- mediated inhibition. Using a cynomolgus macaque model of vaginal challenge with SHIV162P3, we report that mCD4.1-PS1, formulated into a hydroxyethyl-cellulose gel provides 83% protection (5/6 animals). We next engineered the mCD4 moiety of the compound, giving rise to mCD4.2 and mCD4.3 that, when conjugated to PS1, inhibited cell-free and cell-associated HIV-1 with particularly low IC50, in the nM to pM range, including some viral strains that were resistant to the parent molecule mCD4.1. These chemically defined molecules, which target major sites of vulnerability of gp120, are stable for at least 48 hours in conditions replicating the vaginal milieu (37 °C, pH 4.5). They efficiently mimic several large gp120 ligands, including CD4, coreceptor or neutralizing antibodies, to which their efficacy compares very favorably, despite a molecular mass reduced to 5500 Da. Together, these results support the development of such molecules as potential microbicides.

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“…This latter relationship is in accordance with other nonhuman primate studies of HIV vaccine concepts linking protection with Fc-mediated effector functions (see for examples [30] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46] . FLSC-vaccinated animals did not exhibit autoreactive anti-CD4 autoantibodies or other detectable alterations in circulating CD4 + T cells [47] . A recent study showed that rhFLSC could be used as a component of a vaccination regimen that afforded protection in macaques via trained immunity [48] .…”

Section: Introductionmentioning

confidence: 85%

Safety and immunogenicity of an HIV-1 gp120-CD4 chimeric subunit vaccine in a phase 1a randomized controlled trial

Chua

Davis

Husson

et al. 2021

Vaccine

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A major challenge for HIV vaccine development is to raise anti-envelope antibodies capable of recognizing and neutralizing diverse strains of HIV-1. Accordingly, a full length single chain (FLSC) of gp120-CD4 chimeric vaccine construct was designed to present a highly conserved CD4-induced (CD4i) HIV-1 envelope structure that elicits cross-reactive anti-envelope humoral responses and protective immunity in animal models of HIV infection. IHV01 is the FLSC formulated in aluminum phosphate adjuvant. We enrolled 65 healthy adult volunteers in this first-in-human phase 1a randomized, double-blind, placebo-controlled study with three dose-escalating cohorts (75 µg, 150 µg, and 300 µg doses). Intramuscular injections were given on weeks 0, 4, 8, and 24. Participants were followed for an additional 24 weeks after the last immunization. The overall incidence of adverse events (AEs) was not significantly different between vaccinees and controls. The majority (89%) of vaccine-related AE were mild. The most common vaccine-related adverse event was injection site pain. There were no vaccine-related serious AE, discontinuation due to AE, intercurrent HIV infection, or significant decreases in CD4 count. By the final vaccination, all vaccine recipients developed antibodies against IHV01 and demonstrated anti-CD4i epitope antibodies. The elicited antibodies reacted with CD4 non-liganded Env antigens from diverse HIV-1 strains. Antibody-dependent cell-mediated cytotoxicity against heterologous infected cells or gp120 bound to CD4+ cells was evident in all cohorts as were anti-gp120 T -cell responses. IHV01 vaccine was safe, well tolerated, and immunogenic at all doses tested. The vaccine raised broadly reactive humoral responses against conserved CD4i epitopes on gp120 that mediates antiviral functions.

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An HIV gp120-CD4 Immunogen Does Not Elicit Autoimmune Antibody Responses in Cynomolgus Macaques

Cited by 7 publications

References 84 publications

Mucosal vaccine efficacy against intrarectal SHIV is independent of anti-Env antibody response

Mucosal vaccine efficacy against intrarectal SHIV is independent of anti-Env antibody response

CD4-mimetic sulfopeptide conjugates display sub-nanomolar anti-HIV-1 activity and protect macaques against a SHIV162P3 vaginal challenge

Safety and immunogenicity of an HIV-1 gp120-CD4 chimeric subunit vaccine in a phase 1a randomized controlled trial

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