Browsing by Author "Gray, Glenda Elizabeth."

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Continued Follow-Up of Phambili Phase 2b Randomized HIV-1 Vaccine Trial Participants Supports Increased HIV-1 Acquisition among Vaccinated Men.
(Public Library of Science., 2015) Moodie, Zoe.; Metch, Barbara.; Bekker, Linda-Gail.; Churchyard, Gavin J.; Nchabeleng, Maphoshane.; Mlisana, Koleka Patience.; Laher, Faatima.; Roux, Surita.; Mngadi, Kathryn Therese.; Innes, Craig.; Mathebula, Matsontso.; Allen, Mary.; Bentley, Carter.; Gilbert, Peter B.; Robertson, Michael.; Kublin, James.; Corey, Lawrence.; Gray, Glenda Elizabeth.
Abstract available in pdf.
Does participation in an HIV vaccine efficacy trial affect risk behaviour in South Africa?
(Elsevier., 2012) Gray, Glenda Elizabeth.; Metch, Barbara.; Churchyard, Gavin J.; Mlisana, Koleka Patience.; Nchabeleng, Maphoshane.; Allen, Mary.; Moodie, Zoe.; Kublin, James.; Bekker, Linda-Gail.
Background: Increased sexual risk behaviour in participants enrolled in HIV prevention trials has been a concern. The HVTN 503/Phambili study, a phase 2B study of the Merck Ad-5 multiclade HIV vaccine in South Africa, suspended enrollment and vaccinations following the results of the Step study. Participants were notified of their treatment allocation and continue to be followed. We investigated changes in risk behaviour over time and assessed the impact of study unblinding. Methods: 801 participants were enrolled. Risk behaviours were assessed with an interviewer administered questionnaire at 6-month intervals. We assessed change from enrolment to the first 6-month assessment pre-unblinding and between enrolment and at least 6 months post-unblinding on all participants with comparable data. A one-time unblinding risk perception questionnaire was administered post-unblinding. Results: A decrease in participants reporting unprotected sex was observed in both measured time periods for men and women, with no differences by treatment arm. At 6 months (pre-unblinding), 29.6% of men and 35.8% of women reported changing from unprotected to protected sex (p < 0.0001 for each). Men (22%) were more likely than women (14%) to report behaviour change after unblinding (p = 0.009). Post-enrolment, 142 (45%) of 313 previously uncircumcised men underwent medical circumcision. 663 participants completed the unblinding questionnaire. More vaccine (24.6%) as compared to placebo recipients (12.0%) agreed that they were more likely to get HIV than most people (p < 0.0001), and attributed this to receiving the vaccine. Conclusion: We did not find evidence of risk compensation during this clinical trial. Some risk behaviour reductions including male circumcision were noted irrespective of treatment allocation.
Features of recently transmitted HIV-1 clade C viruses that impact antibody recognition : implications for active and passive immunization.
(Public Library of Science., 2016) Rademeyer, Cecilia.; Korber, Bette T. M.; Seaman, Michael S.; Giorgi, Elena E.; Thebus, Ruwayhida.; Robles, Alexander.; Sheward, Daniel J.; Wagh, Kshitij.; Garrity, Jetta.; Carey, Brittany R.; Gao, Hongmei.; Greene, Kelli M.; Tang, Haili.; Bandawe, Gama P.; Marais, Jinny C.; Diphoko, Thabo E.; Hraber, Peter.; Tumba, Nancy Lola.; Moore, Penelope L.; Gray, Glenda Elizabeth.; Kublin, James.; McElrath, Margaret Juliana.; Vermeulen, Marion.; Middelkoop, Keren.; Bekker, Linda-Gail.; Hoelscher, Michael.; Maboko, Leonard.; Makhema, Joseph.; Robb, Merlin L.; Abdool Karim, Salim Safurdeen.; Abdool Karim, Quarraisha.; Kim, Jerome H.; Hahn, Beatrice H.; Gao, Feng.; Swanstrom, Ronald.; Morris, Lynn.; Montefiori, David Charles.; Williamson, Carolyn.
Abstract available in PDF file.
Key issues in the clinical development and implementation of TB vaccines in South Africa.
(Elsevier., 2012) Rustomjee, R.; Mcleod, R.; Hanekom, W.; Steel, G.; Mahomed, H.; Hawkridge, Anthony.; Welte, A.; Sinanovic, E.; Loots, G.; Grobler, Anna Christina.; Mvusi, L.; Gray, Glenda Elizabeth.; Hesseling, Anneke C.; Ginsberg, A.; Lienhardt, C.; Shea, J.; Tong, X.; Lockhart, S.; Churchyard, Gavin J.
Significant progress has been made in advancing the development pipeline for a new and more effective TB vaccine with some candidate vaccines now in late stage clinical evaluation. However, progress has been hampered by an incomplete understanding of the components of a protective immune response and limited animal models, rendering the field unable to reliably predict vaccine efficacy earlier in preclinical development, including by evaluation in animal models, and limiting the predictive utility of comparing immunogenic effects across vaccine candidates in phase I/II studies. Consequently, new candidate vaccines have to be evaluated for efficacy in large-scale phase II/III trials using clinical endpoints. Apart from the technical challenges of characterising TB incidence in target populations at high risk of acquiring TB disease and standardising case definitions in order to improve both the sensitivity and more importantly the specificity of trial endpoints, there is an urgency in expanding and supporting the considerable trial infrastructure that will be required to evaluate and ultimately license a new TB vaccine. In the longer term, implementation strategies are dependent on what policy makers most value. Economic analyses will be essential to guide policy and implementation. This paper outlines the gaps and challenges and identifies solutions for effectively developing and efficiently introducing a new TB vaccine.
Pregnancy incidence and correlates during the HVTN 503 Phambili HIV vaccine trial conducted among South African women.
(Plos., 2011) Latka, Mary H.; Fielding, Katherine L.; Gray, Glenda Elizabeth.; Bekker, Linda-Gail.; Nchabeleng, Maphoshane.; Mlisana, Koleka Patience.; Nielson, Tanya.; Roux, Surita.; Mkhize, Baningi.; Mathebula, Matsontso.; Naicker, Nivashnee.; De Bruyn, Guy.; Kublin, James.; Churchyard, Gavin J.
Background: HIV prevention trials are increasingly being conducted in sub-Saharan Africa. Women at risk for HIV are also at risk of pregnancy. To maximize safety, women agree to avoid pregnancy during trials, yet pregnancies occur. Using data from the HVTN 503/‘‘Phambili’’ vaccine trial, we report pregnancy incidence during and after the vaccination period and identify factors, measured at screening, associated with incident pregnancy. Methods: To enrol in the trial, women agreed and were supported to avoid pregnancy until 1 month after their third and final vaccination (‘‘vaccination period’’), corresponding to the first 7 months of follow-up. Unsterilized women, pooled across study arms, were analyzed. Poisson regression compared pregnancy rates during and after the vaccination period. Cox proportional hazards regression identified associations with first pregnancy. Results: Among 352 women (median age 23 yrs; median follow-up 1.5 yrs), pregnancy incidence was 9.6/100 women-years overall and 6.8/100 w-yrs and 11.3/100 w-yrs during and after the vaccination period, respectively [Rate Ratio = 0.60 (0.32– 1.14), p = 0.10]. In multivariable analysis, pregnancy was reduced among women who: enrolled at sites providing contraception on-site [HR = 0.43, 95% CI (0.22–0.86)]; entered the trial as injectable contraceptive users [HR = 0.37 (0.21–0.67)] or as consistent condom users (trend) [HR = 0.54 (0.28–1.04)]. Compared with women with a single partner of HIV-unknown status, pregnancy rates were increased among women with: a single partner whose status was HIV-negative [HR = 2.34(1.16–4.73)] and; 2 partners both of HIV-unknown status [HR = 4.42(1.59–12.29)]. Women with 2 more of these risk factors: marijuana use, heavy drinking, or use of either during sex, had increased pregnancy incidence [HR = 2.66 (1.24–5.72)]. Conclusions: It is possible to screen South African women for pregnancy risk at trial entry. Providing injectable contraception for free on-site and supporting consistent condom use may reduce incident pregnancy. Screening should determine the substance use, partnering, and HIV status of both members of the couple for both pregnancy and HIV prevention.
Safety and efficacy of the HVTN 503/Phambili Study of a clade-B-based HIV-1 vaccine in South Africa: a double-blind, randomised, placebo-controlled test-of-concept phase 2b study.
(Elsevier., 2011) Gray, Glenda Elizabeth.; Allen, Mary.; Moodie, Zoe.; Churchyard, Gavin J.; Bekker, Linda-Gail.; Nchabeleng, Maphoshane.; Mlisana, Koleka Patience.; Metch, Barbara.; De Bruyn, Guy.; Latka, Mary H.; Roux, Surita.; Mathebula, Matsontso.; Naicker, Nivashnee.; Ducar, Constance.; Carter, Donald K.; Puren, Adrian.; Eaton, Niles.; McElrath, Margaret Juliana.; Robertson, Michael.; Corey, Lawrence.; Kublin, James.
Background. The MRKAd5 HIV-1 gag/pol/nef subtype B vaccine was designed to elicit T-cell-mediated immune responses capable of providing complete or partial protection from HIV-1 infection or a decrease in viral load after acquisition. We aim to assess the safety and efficacy of the vaccine in South Africa, where the major circulating clade is subtype C. Methods. We did a phase 2b double-blind, randomised test-of-concept study in sexually active HIV-1 seronegative participants at five sites in South Africa. Randomisation was by a computer-generated random number sequence. The vaccine and placebo were given by intramuscular injection on a 0, 1, 6 month schedule. Our coprimary endpoints were a vaccine-induced reduction in HIV-1 acquisition and viral-load setpoint. These endpoints were assessed independently in the modified intention-to-treat (MITT) cohort with two-tailed significance tests stratified by sex. We assessed immunogenicity by interferon-γ ELISPOT in peripheral-blood mononuclear cells. After the lack of efficacy of the MRKAd5 HIV-1 vaccine in the Step study, enrolment and vaccination in our study was halted, treatment allocations were unmasked, and follow-up continued. This study is registered with the South Africa National Health Research Database, number DOH-27-0207-1539, and ClinicalTrials.gov, number NCT00413725. Findings. 801 of a scheduled 3000 participants, of whom 360 (45%) were women, were randomly assigned to receive either vaccine or placebo. 445 participants (56%) had adenovirus serotype 5 (Ad5) titres greater than 200, and 129 men (29%) were circumcised. 34 MITT participants in the vaccine group were diagnosed with HIV-1 (incidence rate 4·54 per 100 person-years) and 28 in the placebo group (3·70 per 100 person-years). There was no evidence of vaccine efficacy; the hazard ratio adjusted for sex was 1·25 (95% CI 0·76–2·05). Vaccine efficacy did not differ by Ad5 titre, sex, age, herpes simplex virus type 2 status, or circumcision. The geometric mean viral-load setpoint was 20 483 copies per mL (n=33) in the vaccine group and 34 032 copies per mL (n=28) in the placebo group (p=0·39). The vaccine elicited interferon-γ-secreting T cells that recognised both clade B (89%) and C (77%) antigens. Interpretation. The MRKAd5 HIV-1 vaccine did not prevent HIV-1 infection or lower viral-load setpoint; however, stopping our trial early probably compromised our ability to draw conclusions. The high incidence rates noted in South Africa highlight the crucial need for intensified efforts to develop an efficacious vaccine.
Which new health technologies do we need to achieve an end to HIV/AIDS?
(Public Library of Science., 2016) Gray, Glenda Elizabeth.; Laher, Faatima.; Doherty, Tanya.; Abdool Karim, Salim Safurdeen.; Hammer, Scott.; Mascola, John R.; Beyrer, Chris.; Corey, Larry.
Abstract available in PDF file.