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AIDS and other acquired immunodeficiencies
Published in Gabriel Virella, Medical Immunology, 2019
John W. Sleasman, Gabriel Virella
Vaccines to prevent acquisition have been an even greater challenge. Recombinant viral particles made by inserting HIV glycoprotein genes in vaccinia virus or canary poxvirus genomes, for example, have been shown to induce neutralizing antibodies in both human and nonhuman primates. A vaccine trial testing a strategy to prime with a canary pox vector and three genetically engineered HIV genes (env, gag, and pol) termed ALVAC HIV (vCP1521), followed by a boost with an engineered gp120 protein (AIDSVAX B/E) has shown promise for providing protection to humans. Correlates of protection mapped to antibodies to variable regions 1 (V1) and 2 (V2). These studies provide promising evidence that an effective vaccine could be developed.
Strategies for inducing effective neutralizing antibody responses against HIV-1
Published in Expert Review of Vaccines, 2019
Iván del Moral-Sánchez, Kwinten Sliepen
Gp120-based immunogens are being applied in a number of strategies. First, as gp120 monomers, but these immunogens usually do not induce Abs that neutralize Tier 2 strains [56]. This was confirmed when some of the participants in the Phase I Vaxgen AIDSVAX clinical trial became infected despite having developed NAb titres against the lab-adapted strains [56]. The lack of neutralization of Tier 2 strains is possibly because gp120 monomers do not engage the precursors of bNAbs nor does gp120 recapitulate the structure of the complete Env trimer. The gp120 monomer displays epitopes on the non-neutralizing face of Env and the neutralizing epitopes present on gp120, such as the CD4 binding site, can be engaged from many angles of approach [57–59]. On viral Env, the same non-neutralizing epitopes are occluded and the possible angles of approach for the same neutralizing epitopes are much more restricted [58,60,61]. The second gp120-based immunogens are truncated gp120 monomers that lack non-NAb epitopes, such as the inner domains [62–64] or the V3 loop [65]. However, gp120 monomers without these immunogenic non-neutralizing epitopes have only elicited binding Abs or Tier 1 NAbs. Third, gp120 outer domains (eOD) have been engineered that interact with specific precursor B cell receptors [66,67]. These promising immunogens are now being applied in immunization strategies aimed at activating inferred germline versions of bNAbs and are discussed in detail later (see section 7: ‘Targeting the precursors of bNAb producing B cells’).
Prophylactic HIV vaccine: vaccine regimens in clinical trials and potential challenges
Published in Expert Review of Vaccines, 2020
Punnee Pitisuttithum, Mary Anne Marovich
Based on the efficacy results of the RV144 regimen, a separate follow-on ‘booster’ study, RV305, recruited (N = 162) HIV-negative RV144 vaccine recipients who were vaccinated 6–8 years earlier. Participants were boosted with either RV144 ALVAC-HIV (vCP1521) + AIDSVAX B/E or ALVAC-HIV alone or AIDSVAX B/E alone at 0 and 6 months after their last RV144 vaccination (6–8 years prior). In the RV305 study, boosting with AIDSVAX B/E + ALVAC-HIV or AIDSVAX B/E alone generated significantly higher neutralizing antibody responses. IgG titers against gp70 V1V2 92TH023 at week 2 compared favorably with the responses at 2 weeks after the last RV144 vaccination (GMT 14069 vs 999, respectively; P < 0.001), while boosting with ALVAC-HIV alone showed negligible antibody responses [16]. However, the antibody titers and CD4 functionality scores plateaued after the 6-month boosters (gp70 V1V2 92TH023 binding IgG titers 14069 vs 3052 and CD4 functionality score 0.1 vs 0.058 at week 2 and week 26, respectively, in RV305 ALVAC-HIV+AIDSVAX B/E treated group) and no significant CD8 functionality score elevation was observed [16]. Interestingly, the RV305 study showed boosting of HIV envelope CD4 binding site antibodies with long variable heavy third complementary determining region [17]. The next follow-on study, RV306 [18], was a prospective comparison between the original RV144 vaccine regimen and the RV144 vaccine regimen + three different types of boosters (ALVAC-HIV vaccine + AIDSVAX B/E vaccine or ALVAC-HIV vaccine alone or AIDSVAX B/E alone) given at three different intervals: 12, 15, or 18 months after the last RV144 regimen vaccination in HIV uninfected low-risk Thai adults. Initial results showed that longer intervals between boosts (either month 15 or 18) were better than boosting at month 12 Lancet HIV (in press). Improved immune responses with longer boost intervals are consistent with other clinical trials including DNA-based influenza vaccines and the RTS/S malaria vaccine [19,20]. The latter study, using delayed (0,1,2 vs 0,1,7* months) fractional dose (20%) boosting showed increased protection in the human challenge model along with dramatic increases in somatic hypermutation and avidity of antibody responses [20].