Non-human Primate Challenge Studies Research Articles

Assessing the safety and pharmacokinetics of the anti-HIV monoclonal antibody CAP256V2LS alone and in combination with VRC07-523LS and PGT121 in South African women: study protocol for the first-in-human CAPRISA 012B phase I clinical trial

IntroductionNew HIV prevention strategies are urgently required. The discovery of broadly neutralising antibodies (bNAbs) has provided the opportunity to evaluate passive immunisation as a potential prevention strategy and facilitate vaccine...

Prospects for a Globally Effective HIV-1 Vaccine.

A globally effective vaccine strategy must cope with the broad genetic diversity of HIV and contend with multiple transmission modalities. Understanding correlates of protection and the role of diversity in limiting protective vaccines with those correlates is key. RV144 was the first HIV-1 vaccine trial to demonstrate efficacy against HIV-1 infection. A correlates analysis comparing vaccine-induced immune responses in vaccinated-infected and vaccinated-uninfected volunteers suggested that IgG specific for the V1V2 region of gp120 was associated with reduced risk of HIV-1 infection and that plasma Env IgA was directly correlated with infection risk. RV144 and recent non-human primate (NHP) challenge studies suggest that Env is essential and perhaps sufficient to induce protective antibody responses against mucosally acquired HIV-1. Whether RV144 immune correlates can apply to different HIV vaccines, to populations with different modes and intensity of transmission, or to divergent HIV-1 subtypes remains unknown. Newer prime-boost mosaic and conserved sequence immunization strategies aiming at inducing immune responses of greater breadth and depth as well as the development of immunogens inducing broadly neutralizing antibodies should be actively pursued. Efficacy trials are now planned in heterosexual populations in southern Africa and men who have sex with men in Thailand. Although NHP challenge studies may guide vaccine development, human efficacy trials remain key to answer the critical questions leading to the development of a global HIV-1 vaccine for licensure.

Lessons from the RV144 Thai phase III HIV-1 vaccine trial and the search for correlates of protection.

RV144 remains the only HIV-1 vaccine trial to demonstrate efficacy against HIV-1 acquisition. The prespecified analysis of immune correlates of risk showed that antibodies directed against the V1V2 region of gp120, in particular the IgG1 and IgG3 subclass mediating antibody-dependent cell-mediated cytotoxicity, seem to play a predominant role in protection against HIV-1 acquisition and that plasma envelope (Env)-specific IgA antibodies were directly correlated with risk. RV144 and recent nonhuman primate challenge studies suggest that Env is essential, and perhaps sufficient, to induce protective antibody responses against mucosal HIV-1 acquisition. Follow-up clinical trials are ongoing to further dissect the immune responses elicited by the RV144 ALVAC-HIV and AIDSVAX® B/E regimen. The study of gp120 Env immunogens and immune correlates of risk has resulted in the development of improved antigens. Whether the RV144 immune correlates of risk will generalize to other populations vaccinated with similar immunogens with different modes and intensity of transmission remains to be demonstrated. Efficacy trials are now planned in heterosexual populations in southern Africa and men who have sex with men in Thailand.

Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial

Observational data and non-human primate challenge studies suggest that cell-mediated immune responses might provide control of HIV replication. The Step Study directly assessed the efficacy of a cell-mediated immunity vaccine to protect against HIV-1 infection or change in early plasma HIV-1 levels. We undertook a double-blind, phase II, test-of-concept study at 34 sites in North America, the Caribbean, South America, and Australia. We randomly assigned 3000 HIV-1-seronegative participants by computer-generated assignments to receive three injections of MRKAd5 HIV-1 gag/pol/nef vaccine (n=1494) or placebo (n=1506). Randomisation was prestratified by sex, adenovirus type 5 (Ad5) antibody titre at baseline, and study site. Primary objective was a reduction in HIV-1 acquisition rates (tested every 6 months) or a decrease in HIV-1 viral-load setpoint (early plasma HIV-1 RNA measured 3 months after HIV-1 diagnosis). Analyses were per protocol and modified intention to treat. The study was stopped early because it unexpectedly met the prespecified futility boundaries at the first interim analysis. This study is registered with ClinicalTrials.gov, number NCT00095576. In a prespecified interim analysis in participants with baseline Ad5 antibody titre 200 or less, 24 (3%) of 741 vaccine recipients became HIV-1 infected versus 21 (3%) of 762 placebo recipients (hazard ratio [HR] 1.2 [95% CI 0.6-2.2]). All but one infection occurred in men. The corresponding geometric mean plasma HIV-1 RNA was comparable in infected male vaccine and placebo recipients (4.61 vs 4.41 log(10) copies per mL, one tailed p value for potential benefit 0.66). The vaccine elicited interferon-gamma ELISPOT responses in 75% (267) of the 25% random sample of all vaccine recipients (including both low and high Ad5 antibody titres) on whose specimens this testing was done (n=354). In exploratory analyses of all study volunteers, irrespective of baseline Ad5 antibody titre, the HR of HIV-1 infection between vaccine and placebo recipients was higher in Ad5 seropositive men (HR 2.3 [95% CI 1.2-4.3]) and uncircumcised men (3.8 [1.5-9.3]), but was not increased in Ad5 seronegative (1.0 [0.5-1.9]) or circumcised (1.0 [0.6-1.7]) men. This cell-mediated immunity vaccine did not prevent HIV-1 infection or reduce early viral level. Mechanisms for insufficient efficacy of the vaccine and the increased HIV-1 infection rates in subgroups of vaccine recipients are being explored.

HIV DNA Vaccination: Advances and Experiences

The world is in dire need of a vaccine against HIV. Several approaches for vaccine development have been taken to eradicate this deadly virus. DNA vaccines in particular are being considered as prime candidates for this task. The ease with which they can be molecularly manipulated, compounded by their immunogenicity, safety, and simple and reproducible manufacture, have put DNA vaccines in the vaccine spotlight. Co-transfection of plasmids encoding HIV antigens, with those having the potential to veer the immune response in the desired direction (cytokines, chemokines, and co-stimulatory molecules), have shown promise. In addition, manipulation of codons of the HIV structural genes in the plasmid, to alter the dependence on rev have shown promising results. DNA vaccines are proving their efficacy in challenge studies in non-human primates. The first generation of DNA vaccines seem to be well tolerated in humans. In addition to being safe, they were also found to be immunogenic. Improving on these initial clinical studies may deliver a safe and effective DNA vaccine for HIV-1.

First updated and revised survey of worldwide HIV and SIV vaccine challenge studies in nonhuman primates: Progress in first and second order studies

Journal of Medical PrimatologyVolume 22, Issue 2-3 p. 203-235 Article First updated and revised survey of worldwide HIV and SIV vaccine challenge studies in nonhuman primates: Progress in first and second order studies Jonathan T. Warren, Corresponding Author Jonathan T. Warren n/a@dne.dne The EMMES Corporation, Potomac, MD, U.S.A.Jonathan T. Warren, Ph.D., The EMMES Corporation, 11325 Seven Locks Rd., Suite 214, Potomac, MD 20854 U.S.A.Search for more papers by this authorMariam Dolatshahi, Mariam Dolatshahi The EMMES Corporation, Potomac, MD, U.S.A.Search for more papers by this author Jonathan T. Warren, Corresponding Author Jonathan T. Warren n/a@dne.dne The EMMES Corporation, Potomac, MD, U.S.A.Jonathan T. Warren, Ph.D., The EMMES Corporation, 11325 Seven Locks Rd., Suite 214, Potomac, MD 20854 U.S.A.Search for more papers by this authorMariam Dolatshahi, Mariam Dolatshahi The EMMES Corporation, Potomac, MD, U.S.A.Search for more papers by this author First published: 01 February 1993 https://doi.org/10.1111/j.1600-0684.1993.tb00661.xCitations: 4Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume22, Issue2-3February-May 1993Pages 203-235 RelatedInformation

Worldwide survey of AIDS vaccine challenge studies in nonhuman primates: Vaccines associated with active and passive immune protection from live virus challenge

An AIDS Vaccine Surveillance System (AVSS) was designed and implemented to track the rapidly growing international database supporting the development of promising AIDS vaccines. Both preclinical nonhuman primate (NHP) and clinical human trials are tracked by the AVSS. This report presents summary data generated from the AVSS on the NHP AIDS vaccine/live virus challenge studies only. Summary data on more than 100 preclinical HIV/SIV vaccines are presented within the framework of 1) 13 arbitrary Vaccine Types, 2) studies grouped by animal model (i.e., chimpanzee/HIV-1, and macaque/SIV, HIV-2), and 3) immunization approach (i.e., active and passive). Systematic and timely presentations of these summary data, both here and in future reports, aim to promote a clearer understanding of both earlier and more recent preclinical AIDS vaccine developments.