Last week’s surprising news that a combination of two old HIV vaccine candidates – ALVAC vCP1521 and AIDSVAX B/E - showed marginal but significant protective efficacy in the RV144 trial in Thailand continues to reverberate around the world. The media coverage has not always been accurate, however, and one erroneous statement that has been made by the BBC and many other outlets is that ALVAC has previously failed to protect against HIV infection In fact, the ALVAC vector has never been evaluated for efficacy, either in terms of protecting against acquisition of HIV or reducing post-infection viral load. It is only AIDSVAX that has failed, in two large previous efficacy trials (links to the published results are included in the prior post).
The history is that there was another large phase III efficacy trial of ALVAC planned by the HIV Vaccine Trials Network (HVTN). The trial would have compared ALVAC alone to ALVAC + AIDSVAX (albeit slightly different constructs using components from just HIV subtype B rather than B & E). But one of the aims of the trial was to try and assess whether HIV-specific CD8 T cells induced by ALVAC would be a correlate of immune protection, and the study design required that at least 30% of recipients developed these responses. When immunogenicity data from a phase II study, HVTN 203, showed that the proportion of ALVAC recipients who developed HIV-specific CD8 T cell responses was far lower than this threshold, plans for the efficacy trial were dropped. The upshot is that it cannot be assumed that AIDSVAX B/E contributed to the results of the RV144 trial, because the protective efficacy of ALVAC is unknown.
The detailed story of how events unfolded is described in this excellent article from the IAVI Report by Patricia Kahn:
NIH Drops Plans for Phase III Trial - IAVI Report - January/February 2002
Additional useful sources of historical information include these background documents on the RV144 trial from the FDA website; their Vaccines and Related Biological Products Advisory Committee discussed the trial on September 23, 2004.
Also appended below are the published results of HVTN 203, and links to two papers reporting immunogenicity data from RV135, the phase I/II immunogenicity study in Thailand that preceded RV144.
J Acquir Immune Defic Syndr. 2007 Feb 1;44(2):203-12.
Russell ND, Graham BS, Keefer MC, McElrath MJ, Self SG, Weinhold KJ, Montefiori DC, Ferrari G, Horton H, Tomaras GD, Gurunathan S, Baglyos L, Frey SE, Mulligan MJ, Harro CD, Buchbinder SP, Baden LR, Blattner WA, Koblin BA, Corey L; National Institute of Allergy and Infectious Diseases HIV Vaccine Trials Network.
Program in Infectious Diseases, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
BACKGROUND: A goal of T-cell HIV vaccines is to define the correlation between a vaccine-induced immune response and protection from HIV infection. We conducted a phase 2 trial to determine if a canarypox vaccine candidate (vCP1452) administered with rgp120 subunit protein would "qualify" for a trial to define a correlate of efficacy. METHODS: A total of 330 healthy volunteers were enrolled into 4 groups: 120 received vCP1452 alone (0, 1, 3, and 6 months), 120 received vCP1452 with 2 different regimens of rgp120 coadministration, and 90 received placebo. HIV-specific antibody responses were measured by enzyme-linked immunoassay (ELISA) and neutralizing activity. T-cell responses were measured by chromium release and interferon-gamma (IFNgamma) enzyme-linked immunospot (ELISpot) assay. RESULTS: Significant neutralizing antibody responses to the HIV MN strain were detected in all vaccine groups, with net responses ranging from 57% (95% confidence interval [CI]: 40% to 71%) to 94% (95% CI: 85% to 99%). Net cumulative HIV-specific CD8 IFNgamma ELISpot assay responses were 13% (95% CI: -1% to 26%) for recipients of vCP1452 alone and 16% (95% CI: 2% to 29%) for recipients of vCP1452 plus rgp120. CONCLUSIONS: Overall, the HIV-specific CD8 cytotoxic T lymphocyte (CTL) response was not sufficient to qualify the regimen for a subsequent trial designed to detect an immune correlate of protection requiring a minimum CD8 CTL frequency of 30%.
The Journal of Infectious Diseases 2004;190:702–706
DOI: 10.1086/422258
BRIEF REPORT
Sorachai Nitayaphan,1 Punnee Pitisuttithum,3 Chitraporn Karnasuta,2 Chirapa Eamsila,1 Mark de Souza,2 Patricia Morgan,2 Victoria Polonis,2,a Michael Benenson,2 Tom VanCott,5 Silvia Ratto‐Kim,2,a Jerome Kim,5,a Darawan Thapinta,4 Robin Garner,5 Valai Bussaratid,3 Pricha Singharaj,2 Raphaelle el Habib,6 Sanjay Gurunathan,6 William Heyward,7 Deborah Birx,5 John McNeil,5,a and Arthur E. Brown,2 for the Thai AIDS Vaccine Evaluation Groupb
1Royal Thai and 2US Army Components, Armed Forces Research Institute of Medical Sciences, and 3Vaccine Trial Centre, Faculty of Tropical Medicine, Mahidol University, Bangkok, and 4Faculty of Nursing, Chiang Mai University, Chiang Mai, Thailand; 5Walter Reed Army Institute of Research, Rockville, Maryland; 6Aventis Pasteur, Swiftwater, Pennsylvania; 7VaxGen, Brisbane, California
ALVAC‐HIV (vCP1521) and AIDSVAX B/E were evaluated in a phase 1/2 trial of human immunodeficiency virus (HIV)–negative Thai adults. Of 133 volunteers enrolled, 122 completed the trial. There were no serious vaccine‐related adverse events, nor were there intercurrent HIV infections. Lymphoproliferative responses to glycoprotein 120 E were induced in 63% of the volunteers, and HIV‐specific CD8 cytotoxic T lymphocyte responses were induced in 24%. Antibody responses increased in frequency and magnitude in association with the dose level of AIDSVAX B/E. Binding and neutralizing antibodies to the MN strain were induced in 100% and 98%, respectively, of the volunteers receiving 600 μg of AIDSVAX B/E, and such antibodies to E strains were induced in 96% and 71%, respectively, of these volunteers. This vaccine combination was well tolerated and was immunogenic, meeting milestones for advancement to phase 3 evaluation.
Vaccine. 2005 Mar 31;23(19):2522-9.
Karnasuta C, Paris RM, Cox JH, Nitayaphan S, Pitisuttithum P, Thongcharoen P, Brown AE, Gurunathan S, Tartaglia J, Heyward WL, McNeil JG, Birx DL, de Souza MS; Thai AIDS Vaccine Evaluation Group, Thailand.
Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
Antibody-dependent cell-mediated cytotoxicity (ADCC) was assessed in volunteers participating in an ALVAC-HIV (vCP1521)/AIDSVAX B/E gp120 prime-boost vaccine trial in Thailand. ADCC activity was measured using chromium release from gp120 subtype B- and CRF01_AE-coated targets in 95 vaccinees and 28 placebo recipients. There was a significant difference in the magnitude of the ADCC response to both targets between vaccinees and placebo recipients. The frequency of responders to subtype B and to CRF01_AE was 96% and 84% in the vaccine group versus 11% and 7% in the placebo group. The results demonstrate that this HIV vaccine is a potent inducer of ADCC activity and may be an additional protection of this prime-boost vaccine in preventing HIV disease.
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