Lessons from a multisite international trial in the Caribbean and South America of an HIV-1 Canarypox vaccine (ALVAC-HIV vCP1452) with or without boosting with MN rgp120

BACKGROUND: The first multicenter, international National Institutes of Allergy and Infectious Diseases (NIAID)-sponsored HIV vaccine trial took place in Brazil, Haiti, Peru and Trinidad. This randomized, double-blind, placebo-controlled, phase 2 trial evaluated the safety and immunogenicity of a clade B-derived, live canarypox HIV vaccine, vCP1452. vCP1452 was administered alone or with a heterologous boost of MN rgp120 glycoprotein. The trial was pivotal in deciding whether these vaccines advanced to phase 3 efficacy trials. METHODS: Forty seronegative volunteers per site were randomized to ALVAC alone, ALVAC plus MN rgp120, or placebo in a 0, 1, 3, and 6 month schedule. Immunogenicity was assayed by chromium-release cytotoxic T lymphocyte (CTL) responses; interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spot assays (ELISpot); lymphocyte proliferation assays (LPA); neutralization; and enzyme-linked immunosorbent assays (ELISA). RESULTS: Enrollment and follow-up were excellent. Both vaccines were well tolerated. Neutralizing antibody to the laboratory-adapted MN strain was detected. Cellular immune responses, as measured by CTL, ELISpot, and LPA, did not differ between vaccines and placebos. CONCLUSIONS: The observation of disappointing immunogenicity in this and a parallel domestic study has informed future vaccine development. Equally important, challenges to doing an integrated trial across countries, cultures, languages, and differing at-risk populations were overcome. The identification of specific safety, ethical, logistic, and immunological issues in this trial established the foundation for current larger international studies.     

HLA class I serotypes and cytotoxic T-lymphocyte responses among human immunodeficiency virus-1-uninfected Thai volunteers immunized with ALVAC-HIV in combination with monomeric gp120 or oligomeric gp160 protein boosting

Antigen-induced cellular immunogenicity may vary between populations due to differences in human leukocyte antigen (HLA) diversity and, hence, may play a critical role in the protection afforded by vaccines. In the setting of two, phase I/II human immunodeficiency virus-1 vaccine trials of a recombinant canarypox prime, and boosting with either recombinant monomeric gp120 or oligomeric gp160, we assessed the association between specific human leukocyte antigen (HLA) class I serotypes and the presence of cytotoxic T-lymphocyte response measured by 51Cr-release assay. HLA class I serotypes A11, A24, A33, B46, and B75 were the most common, present in 10% or more of 245 individuals studied. Forty of 187 (21.4%) Thai adults who received either ALVAC-HIV with gp120 or oligomeric gp160 or ALVAC alone had a precursor cytolytic CD8 T-cell response (pCTL). HLA-B44 was positively and significantly associated with a pCTL response (odds ratio 7.6, 95% CI: 2.7-21.2), whereas B46 was negatively associated but not robust when adjusted for multiple comparisons. Responses to Env proteins accounted for the majority (nine of 11) of pCTL activity among those persons with B44. This HLA class I serotype occurred in 9.4% of participants overall (including the placebo group), less commonly than what is reported from populations of European ancestry. These results strengthen the importance of assessing HLA class I distributions in conjunction with studies of vaccines designed to elicit cellular immunity in different populations.     

A phase 1/2 comparative vaccine trial of the safety and immunogenicity of a CRF01_AE (subtype E) candidate vaccine: ALVAC-HIV (vCP1521) prime with oligomeric gp160 (92TH023/LAI-DID) or bivalent gp120 (CM235/SF2) boost

BACKGROUND: The development of an effective HIV-1 vaccine is critical to control the pandemic. A prime-boost HIV-1 vaccine trial assessing safety and immunogenicity was conducted in Thailand as part of an evaluation of candidate regimens for a phase 3 efficacy trial. METHODS: ALVAC-HIV (vCP1521), expressing circulating recombinant form 01_AE (CRF01_AE) gp120/subtype B LAI and subtype B Gag/Protease boosted with recombinant envelope oligomeric CRF01_AE gp160 (ogp160) or bivalent CRF01_AE/subtype B gp120 CM235/SF2, was evaluated in a phase 1/II trial of 130 HIV-negative Thai adults. RESULTS: One hundred forty volunteers were enrolled, and 130 completed all safety and immunogenicity visits. Reactogenicity was common but generally mild, and there was no significant difference in the adverse event rate between vaccine and placebo recipients (P = 0.26). There were 7 serious adverse events during the follow-up period, none of which were vaccine related. Cumulative HIV-specific, CD8-mediated, cytotoxic T-lymphocyte responses were observed in 11 (25%) of 44 subjects who received ALVAC boosted by bivalent gp120 and in 5 (11%) of 45 subjects who received ALVAC boosted by ogp160, but these differences were not statistically significant compared with those in placebo recipients (P = 0.62 and P = 0.37, respectively). HIV-specific lymphoproliferative responses were detected in 84% of subunit-boosted vaccine recipients and in 10% of placebo recipients. Neutralizing antibody responses to CRF01_AE and subtype B laboratory strains were seen in 95% of ogp160-boosted and 100% of gp120 B/E-boosted vaccinees, respectively. CONCLUSIONS: These 2 different prime-boost regimens seem to be safe and displayed cell-mediated immune responses consistent with those in other trials of canarypox vectors.