Summary We report the primary analysis of the safety and efficacy of the MRKad5 gag/pol/nef HIV-1 sub-type B vaccine in South Africa (SA), where the major circulating clade is sub-type C. Methods This phase IIb double-blind, randomized test-of-concept study was conducted in sexually active HIV-1 sero-negative participants in SA. The co-primary endpoints were a vaccine-induced reduction in HIV-1 acquisition or viral-load setpoint. These were assessed independently in the modified intent-to-treat (MITT) cohort with two-tailed significance tests stratified by gender. Immunogenicity was assessed by interferon-gamma (IFNγ) ELISPOT in peripheral blood mononuclear cells. Following the lack of efficacy of the MRKAd5 HIV-1 vaccine in the Step study, enrollment and vaccination in this study was halted, treatment unblinding occurred and follow-up continued. This study is registered with the SA National Health Research Database (DOH-27-0207-1539) and ClinicalTrials.gov (NCT00413725). Results 801 of a scheduled 3000 participants were enrolled, of whom 360 (44.9%) were women, more than half (55.6%) had Ad5 titres > 200, and almost a third (29.3%) of men were circumcised. 62 MITT participants were diagnosed with HIV-1, 34 in the vaccine arm and 28 in the placebo arm, with infection rates of 4.54 and 3.70 per 100 person-years, respectively. There was no evidence of vaccine efficacy (VE); the hazard ratio adjusted for gender was 1.25 (95% CI: 0.76, 2.05). VE did not differ by Ad5 titre, gender, age, HSV-2 status, or circumcision. The geometric mean viral load setpoint was 20,483 copies/ml (N=33) in vaccinees and 34,032 copies/ml (N=28) in placebo recipients (p=0.39). The vaccine elicited IFNγ-secreting T cells recognizing both clade B (89.2%) and C (77.4%) antigens. Conclusion The MRKAd5 HIV-1 vaccine did not prevent HIV-1 infection or lower viral-load setpoint however early stopping likely compromised our ability to draw conclusions. The high incidence rates seen in SA highlight the critical need for intensified efforts to develop an efficacious vaccine.

Use of electroporation after PV administration provided superior immunogenicity than delivery without electroporation. This study illustrates the power of combined DNA approaches to generate impressive immune responses in humans.

In this presentation, issues that influenced the development of policies for inclusion of quality of life end points in cer-In this review, we address issues and methods associated with measurement of quality of life in clinical trials and recommend specific instruments appropriate for clinical trials research. Our review was initiated in November 1987 at the request of the Southwest Oncology Group Cancer Control Research Committee. One motivation for the assessment of quality of life was the increased attention to cancer control research, both at the National Cancer Institute and in the Southwest Oncology Group. We circulated a position paper among the leaders of the Southwest Oncology Group recommending how and to what extent quality of life end points should be included in the group's clinical trials. Our recommendations were adopted by the Cancer Control Research Committee in October 1988. The policies we developed for assessing quality of life in selected trials are potentially relevant, with appropriate modifications, to other multi-institution clinical trials.The Southwest Oncology Group was organized in 1956 with the objectives of reducing mortality from cancer and improving care of patients with malignant disease. Participating medical institutions work together to conduct cancer clinical trials that evaluate the efficacy of cancer therapies. In the last 12 months, approximately 4,000 cancer patients were registered in 130 studies; 69% were in randomized comparative phase HI trials.The benefits of a cancer treatment regimen should outweigh its cost in patient suffering (7,2). By adding quality of life end points to the traditional end points of overall survival, disease-free survival, and tumor response, medical researchers can make more informed decisions about risk-benefit trade-offs; for example, two types of survival-quality of life trade-offs can be described. In one case, two treatments are associated with similar survival rates, but one treatment produces more severe toxic effects; in another case, one of two treatments demonstrates a better survival rate but has more severe toxic effects (3). Quality of life data can add to medical knowledge obtained in the conduct of clinical trials; such data do not supplant existing traditional end points, nor do they replace data on toxic effects based on physician reports.Received October 24, 1988; revised January 3, 1989; accepted January 4, 1989. Supported by Public Health Service grant CA-37429 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. Based in part on work completed by Dr. C. M. Moinpour while she was a National Research Service Award postdoctoral fellow Barofsky (4) argued that many clinical trials have paid at least implicit attention to quality of life issues, e.g., the focus of the National Surgical Adjuvant Breast and Bowel Project on the survival time associated with different degrees of surgery. Other trials (5-70) with breast cancer patients address quality of life issues expl...

BackgroundDNA vaccines are a promising approach to vaccination since they circumvent the problem of vector-induced immunity. DNA plasmid cytokine adjuvants have been shown to augment immune responses in small animals and in macaques.Methodology/Principal FindingsWe performed two first in human HIV vaccine trials in the US, Brazil and Thailand of an RNA-optimized truncated HIV-1 gag gene (p37) DNA derived from strain HXB2 administered either alone or in combination with dose-escalation of IL-12 or IL-15 plasmid cytokine adjuvants. Vaccinations with both the HIV immunogen and cytokine adjuvant were generally well-tolerated and no significant vaccine-related adverse events were identified. A small number of subjects developed asymptomatic low titer antibodies to IL-12 or IL-15. Cellular immunogenicity following 3 and 4 vaccinations was poor, with response rates to gag of 4.9%/8.7% among vaccinees receiving gag DNA alone, 0%/11.5% among those receiving gag DNA+IL-15, and no responders among those receiving DNA+high dose (1500 ug) IL-12 DNA. However, after three doses, 44.4% (4/9) of vaccinees receiving gag DNA and intermediate dose (500 ug) of IL-12 DNA demonstrated a detectable cellular immune response.Conclusions/SignificanceThis combination of HIV gag DNA with plasmid cytokine adjuvants was well tolerated. There were minimal responses to HIV gag DNA alone, and no apparent augmentation with either IL-12 or IL-15 plasmid cytokine adjuvants. Despite the promise of DNA vaccines, newer formulations or methods of delivery will be required to increase their immunogenicity.Trial RegistrationClinicaltrials.gov NCT00115960 NCT00111605

Background The Phambili study, conducted in South Africa amongst a predominantly heterosexual population, evaluated the efficacy of the MRK Ad5 gag/pol/nef subtype B HIV-1 preventive vaccine. Enrollment and vaccinations were stopped, participants unblinded, and follow-up extended when the Step study evaluating the same vaccine in the Americas, Caribbean and Australia was unblinded for non-efficacy with more HIV infections amongst vaccinee than placebo recipients [ZM1]. Extensive analyses over the complete follow-up period, most of which was unblinded, are reported. Methods Phambili participants were HIV-1 uninfected, sexually active men and women aged 18–35 years, followed for 3.5 years. HIV testing and risk reduction counseling occurred at weeks 0, 12, 30 and were switched to a 3 monthly schedule after unblinding. Cox proportional hazards models were used to estimate HIV-1 infection hazard ratios (HR) comparing vaccine to placebo recipients, overall and within subgroups. Long-term vaccine efficacy was evaluated in participants who were unblinded early in follow-up. Results Of the 801 participants enrolled (400 vaccine, 401 placebo), 112 (28%) received 1 vaccination, 259 (65%) 2 vaccinations and 29(7%) 3 vaccinations. More infections occurred in vaccinees (n=63) as compared to placebo (n=37) (adjusted HR (vaccine:placebo) 1.70, 95% CI 1.13–2.55, p = 0.01). We found no increase in infections with the number of vaccinations received and that the HRs did not differ by gender, circumcision, or Ad5 serostatus. Differences in risk behavior at baseline or during the study, or differential drop-out (p=0.40) are unlikely explanations for the increased rate of HIV-1 infections seen in vaccinees. Conclusion The increased HR of HIV-1 acquisition, irrespective of number of doses received, warrants further investigation to understand the biological mechanism. Further use of the Ad5 vector for HIV vaccines is not warranted