AIDS Vaccine Evaluation Group Research Articles

What does the report of the USMHRP Phase III study in Thailand mean for HIV and for vaccine developers?

What does the report of the USMHRP Phase III study in Thailand mean for HIV and for vaccine developers?

Participant Retention in Clinical Trials of Candidate HIV Vaccines

: To determine predictors of loss to follow-up (LTFU) in trials of candidate HIV vaccines. : Data were obtained from trials of candidate preventive HIV vaccines conducted by the AIDS Vaccine Evaluation Group (AVEG) and HIV Network for Prevention Trials (HIVNET) that enrolled HIV-negative volunteers. Analytic models included multiple logistic regression and generalized estimating equations. : Of 3033 volunteers enrolled in 48 trials, 282 (9.3%) persons did not complete follow-up. In univariate analyses, age, trial duration, and number of immunizations were associated with LTFU. In a multivariate logistic model, age (per year) (adjusted odds ratio [AOR] = 0.96, 95% confidence interval [CI]: 0.95, 0.98) and study duration (per month) (AOR = 1.04, 95% CI: 1.01, 1.08) remained significantly associated with LTFU. : Younger age and increasing trial duration predicted LTFU. Limiting enrollment in trials of novel products to those less than 40 years of age may exclude participants shown to have improved retention. Trials should be designed to last only as long as required to address the scientific question. Retention efforts in future trials should especially address younger persons.

HIV Vaccines in Infants and Children

The interruption of HIV transmission from mother to child is important. Prevention strategies, including antiretroviral agents administered to the mother and/or child, can successfully prevent such transmission. Avoidance of breastfeeding or the administration of antiretroviral agents to the mother while she continues breastfeeding is another strategy. Based on the successful model of hepatitis B prevention by treatment of the newborn, research protocols have been designed to prevent mother-to-child transmission of HIV by the administration of passive HIV-specific antibody preparations and HIV vaccines to the mother and/or child. A number of animal studies using active and passive products have shown efficacy in similar settings, providing hope that a similar strategy will work in humans. Clinical trials conducted through the US National Institutes of Health AIDS Clinical Trials Programs have focused on such an approach. This article summarizes the results of a number of these trials, including AVEG (AIDS Vaccine Evaluation Group) 104, a phase I study of active immunization of HIV-infected pregnant women with an HIV gp120 subunit vaccine, and PACTG (Pediatrics AIDS Clinical Trial Group) 185, a phase III efficacy trial of HIV immunoglobulin administered to HIV-infected pregnant women and their newborns. A number of HIV vaccine trials have been performed in HIV-exposed and -infected children. These include PACTG 218, a vaccine immunotherapy phase I trial of HIV subunit vaccines administered to asymptomatic HIV-infected children, and two phase I vaccine trials in HIV-exposed children, PACTG 230 and 326. While the results of PACTG 230 were encouraging, the gp120 subunit vaccines were not capable of generating cytotoxic T-cell (CTL) responses. A subsequent phase I study, PACTG 326, utilized a canarypox vectored HIV vaccine (ALVAC vCP205, Sanofi Pasteur), which was previously shown to generate CTL responses in HIV-uninfected adults. The vaccines were safe but the immunogenicity was poor when compared with results of adult studies. Specifically, no antibody responses were found, lymphoproliferative responses to HIV-specific antigens were found in <50% of vaccinees, and CTL responses, modest in nature, were seen in approximately 50% of vaccinees.Future planned vaccine studies are focused on prime-boost approaches, using live recombinant vectors or DNA vaccines combined with subunit vaccines to stimulate both cellular and antibody responses. HIV vaccines may have special utility in newborns, in infants who continue to breastfeed, and in pre-adolescent children before they become sexually active. However, to date, candidate HIV vaccines capable of generating robust immunologic responses in these populations have been disappointing.

Foundations for a Phase III human immunodeficiency virus vaccine trial: A decade of Thai-U.S. Army collaborative research.

As part of the response of the Royal Thai Army to the outbreak of human immunodeficiency virus (HIV) in Thailand, a collaboration was established with the U.S. Army to jointly work toward the development of vaccines for the prevention of HIV infection. During the first decade of this collaboration, studies have been carried out in the diverse disciplines that are crucial to providing the foundations for efficacy trials of candidate HIV vaccines. Studies of host, pathogen, and vaccine interventions included studies of viral diversity, epidemiology, disease course, potential vaccine cohorts, and Phase I/II clinical trials. Collaborations were expanded to other Thai institutions and to overseas partners, resulting in the Thai AIDS Vaccine Evaluation Group. The efforts of these collaborations resulted in the development of candidate vaccines specifically designed for use in Thailand, and sequential evaluations that have lead to the threshold of the world's next and largest efficacy trial of HIV vaccines.

Thailand's Prime-Boost HIV Vaccine Phase III

The Thailand Ministry of Public Health will pursue the Prime-Boost HIV Vaccine Phase III Trial in Chon Buri and Rayong provinces, as planned. The Ministry and collaborating institutions remain confident in the scientific merit of the prime-boost vaccination concept and the combined immune response induced by ALVAC-HIV vCP1521 and AIDSVAX B/E, as demonstrated in Phase I and II safety and immunogenicity studies conducted in Thailand. The Ministry is aware of the comments made by 22 scientists in a recent Policy Forum in Science (D. R. Burton et al. , 16 Jan., p. [316][1]; see also the related Policy Forum on p. [961][2]). Although we welcome constructive input, we find the underlying premise of the Policy Forum flawed in that it uses data from efficacy trials of a single vaccine concept to predict the results of a prime-boost combination vaccine study. Only by conducting the trial will we be able to determine if the combination of two candidate vaccines will induce both cellular and humoral immunity and protect against HIV infection. Both the Screening Protocol and Vaccine Protocol of the Prime-Boost Study were reviewed and endorsed by Institutional Review Boards and Expert Committees in Thailand and the United States, and by the World Health Organization (WHO)/UN AIDS Programme (UNAIDS). Thailand's leading researchers, all of whom have international standing and extensive experience in AIDS vaccine studies, from the Faculty of Tropical Medicine, Mahidol University; the Armed Forces Research Institute of Medical Sciences, Medical Corps, Royal Thai Army; and the Thai AIDS Vaccine Evaluation Group, are involved in the conduct of this trial under the Ministry of Public Health. The Prime-Boost Study was carefully considered within multiple venues, including a special WHO/UNAIDS/Centers for Disease Control consultation on the impact of the lack of efficacy of the AIDSVAX trials in North America and Thailand, which concluded that “because of its independent scientific rationale,” it was appropriate to go forward with efficacy evaluation of the prime-boost combination. There is no such thing as wasting time or money in researching an AIDS vaccine. Regardless of the efficacy results, Thailand is benefiting from conducting this trial in several areas: Experience will be gained by its scientists and health workers, and its laboratory infrastructure and specimen archiving will be strengthened. Close collaboration has also been established with NGOs and community groups to plan and implement community engagement activities. Another important gain is the intensified HIV/AIDS awareness campaign around the trial, which directly benefits the local communities in Chon Buri and Rayong. Thailand intends to share knowledge and experience gained and lessons learned in conducting this large-scale community-based efficacy trial. Needless to say, if the vaccine is proven efficacious, other countries will benefit as well. The Ministry of Public Health will continue to strive to find the best preventive measure to stop the spread of HIV. It is the Ministry's responsibility to further reduce the yearly HIV infection rate in Thailand, which is currently 25,000. [1]: /lookup/doi/10.1126/science.1094620 [2]: /lookup/doi/10.1126/science.1096161

Safety profile of recombinant canarypox HIV vaccines

Attenuated poxviruses have been developed for use as candidate vaccine vectors. ALVAC, a strain of the Avipoxvirus canarypox, has been extensively evaluated as a vector for vaccines against the human immunodeficiency virus type 1 (HIV-1). This report presents the safety and reactogenicity data derived from 11 multicenter, randomized controlled trials of ALVAC-HIV vaccines conducted by the HIV Vaccine Trials Network (HVTN) and its predecessor, the AIDS Vaccine Evaluation Group (AVEG). Five different ALVAC vaccine constructs were tested among 1497 volunteers. Reactogenicity was similar for different ALVAC constructs. Local reactions of any grade to ALVAC vaccines were common. However, fewer than 2% of vaccinees had severe local responses, and less than 1% experienced severe local pain or tenderness. Systemic responses were mild and transient. As combination vaccine regimens are in common use, we also evaluated side effects of ALVAC vectors given in combination with a recombinant subunit protein. No significant differences were noted in the reactogenicity of ALVAC given with or without a recombinant envelope subunit vaccine. Black, non-Hispanic and male recipients of ALVAC-HIV reported less pain following vaccination than White, non-Hispanics and females, respectively. ALVAC-HIV vaccines are well tolerated at tested doses. The reactogenicity profiles are comparable to those reported for existing vaccines licensed for use among adults. Reactogenicity does not appear to be related to the number or type of inserted genes, and did not vary between different ALVAC constructs.

Long-term safety analysis of preventive HIV-1 vaccines evaluated in AIDS vaccine evaluation group NIAID-sponsored Phase I and II clinical trials

This report evaluates long-term safety data from 3189 human immunodeficiency virus type 1 (HIV-1) uninfected, healthy volunteers who were enrolled into 51 National Institute of Allergy and Infectious Diseases (NIAID)-sponsored Phase I and II multicentred, randomized, double-blind trials of recombinant HIV-1 subunit vaccines (23 studies), synthetic peptide vaccines (7 studies), live vaccinia-vector recombinant envelope vaccines (7 studies), canarypox vector recombinant vaccines (13 studies), a DNA vaccine (1 study), and a Salmonella-vector vaccine (1 study). During the 12,340 person-years of follow-up, participants were monitored for adverse events including immune dysfunction/autoimmunity, anaphylaxis, cancer, death, and vaccine allergy. The analysis provides evidence that a preparation of a C4-V3 polypeptide vaccine emulsified in incomplete Freund’s caused serious toxicity, but otherwise no safety problems considered serious were identified for any of the vaccines and adjuvants studied. These data serve to solidify the growing safety base of current vaccine technologies utilized in candidate vaccines for HIV-1 infection.

Safety and Immunogenicity of a High-Titered Canarypox Vaccine in Combination With rgp120 in a Diverse Population of HIV-1–Uninfected Adults: AIDS Vaccine Evaluation Group Protocol 022A

To test the safety and immunogenicity of a high-titered preparation of ALVAC-HIV vCP205 in both high-risk and low-risk persons and to evaluate variations in dosing schedule, we conducted a multicenter, randomized, double-blind trial of this vector in combination with recombinant subunit gp120 in 150 HIV-1-seronegative volunteers. The high-titered ALVAC vaccine was well tolerated; adverse events were minimal and not influenced by dosing. At day 728, the cumulative probability of a cytotoxic T-lymphocyte (CTL) response was 76% (95% confidence interval [CI]: 64%-89%) among volunteers receiving vaccine, and the net amount attributable to vaccination was 50% (CI: 16%; 74%). The net probability of a repeated positive CTL response by day 728 was 50% (CI: 21%; 64%). There was a significant difference in CTL response at day 182 between volunteers who had received four doses versus three doses of vCP205 (42% vs. 24%, p =.052). The CTL response was similar in high-risk volunteers and vaccinia-naive volunteers compared with vaccinia-immune volunteers. Neutralizing antibody responses were detected in 95% of vaccinees at day 287, with higher geometric mean titers in recipients of sequential versus simultaneous dosing of the two vaccines and in vaccinia-naive volunteers. This high-titered preparation of ALVAC-HIV vCP205 in combination with gp120 was safe and immunogenic in a diverse group of HIV-1-seronegative volunteers.

Trial-related discrimination in HIV vaccine clinical trials.

Participants in preventive HIV vaccine trials may experience negative social consequences of trial participation, including problems related to a vaccine-induced positive HIV antibody test, yet few vaccine studies have reported on this issue. From October 1995 through November 1998, 1516 AIDS Vaccine Evaluation Group (AVEG) volunteers were assessed for reports of trial-related discrimination (TRD). Ninety TRD events were reported by 76 (5%) of 1516 volunteers. The most commonly reported incidents (n = 52, 57.8%) were negative reactions of friends, family, and co-workers to the volunteer. Few incidents (approximately 10%) were reported as linked to HIV testing. The majority of events (n = 47, 52%) were described by volunteers as "resolved" at the time of reporting, 36 (40%) as "not resolved," and for 7 (8%) events volunteers did not report resolution status. Reported incidents were analyzed by logistic regression to determine their association with the volunteer's age, sex, race, sexual orientation, and HIV risk category. There was no association between volunteer characteristics and TRD. Logistic regression and analysis of variance (ANOVA) were used to analyze association of trial sites with the number of TRD events reported. After controlling for site variation in data collection and reporting, no significant differences were found between the sites in terms of the number or type of TRD reported. Fears that TRD would be widespread and severe have not been borne out by this analysis. While the results of this study are reassuring, they should be interpreted with caution, as it is unclear whether these results may be extended to phase III trials enrolling large numbers of individuals at higher risk of HIV acquisition.

Therapeutic Immunization Against HIV During Pregnancy a Disappointment

Envelope vaccines against HIV have been evaluated in low- and high-risk seronegative adults. Given the risks for vertical transmission of HIV, the AIDS Vaccine Evaluation Group undertook a multicenter, clinical, phase 1 study of the safety and immunogenicity of MN rpg 120, an envelope-based alum adjuvant …

Preclinical AIDS vaccine development: formal survey of global HIV, SIV, and SHIV in vivo challenge studies in vaccinated nonhuman primates.

Journal of Medical PrimatologyVolume 26, Issue 1-2 p. 63-81 Preclinical AIDS vaccine development: Formal survey of global HIV, SIV, and SHIV in vivo challenge studies in vaccinated nonhuman primates Jonathan T. Warren Ph.D, Corresponding Author Jonathan T. Warren Ph.D The EMMES Corporation, Potomac, MarylandStaff Immunologist, AIDS Vaccine Evaluation Group (AVEG), The EMMES Corporation, 11325 Seven Locks Rd., Suite 214, Potomac, Maryland 20854, USASearch for more papers by this authorMark A. Levinson, Mark A. Levinson The EMMES Corporation, Potomac, MarylandSearch for more papers by this author Jonathan T. Warren Ph.D, Corresponding Author Jonathan T. Warren Ph.D The EMMES Corporation, Potomac, MarylandStaff Immunologist, AIDS Vaccine Evaluation Group (AVEG), The EMMES Corporation, 11325 Seven Locks Rd., Suite 214, Potomac, Maryland 20854, USASearch for more papers by this authorMark A. Levinson, Mark A. Levinson The EMMES Corporation, Potomac, MarylandSearch for more papers by this author First published: 06 September 2011 https://doi.org/10.1111/j.1600-0684.1997.tb00321.xCitations: 6AboutPDF 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 onFacebookTwitterLinked InRedditWechat Citing Literature Volume26, Issue1-2February‐April 1997Pages 63-81 RelatedInformation