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48 Immunogenicity of Canarypox (ALVAC)-HIV-1 Candidate Vaccines in Normal Volunteers
R. Dolin*1, R. El Habib2, and the NIAID HIV Vaccine Trials Network (HVTN)
1Harvard Med. Sch., Boston, MA, USA and 2Aventis Pasteur, Marcy l'Etoile, France
Background: Canarypox vectors are host-range restricted, safe, and accommodate large amounts of foreign DNA. The ALVAC canarypox constructs are being studied as candidate HIV-1 vaccines individually and in combination regimens.
Methods: NIAID-sponsored HIV vaccine trial networks have completed 11 phase I and 1 phase II studies of 5 ALVAC constructs that have been administered to 995 HIV-1 uninfected volunteers. The ALVAC constructs contain HIV-1 genes expressing the following proteins: MNgp160 (vCP 125); MNgp120, transmembrane LAIgp41, gagLAI, proLAI (vCP205); proteins expressed by vCP205 plus CTL epitopes of pol and nef products (vCP300 and vCP1433); and proteins expressed by vCP1433 plus vaccinia genes E3L and K3L (vCP1452). Some volunteers received boosts with SF-2 rgp 120, SF-2 p24, or rgp 160 MN/LAI-2. CD8 + CTL responses were assayed by bulk cytotoxicity in a 51Cr assay. Neutralization antibodies were measured using a vital dye neutralization or a multiple dose reduction infectivity assay.
Results: Cumulative CTL activity against env or gag antigens was detected in 38% (255/680) of subjects who received at least 4 immunizations with ALVAC vectors over 6 to 12 months. Relatively few anti-nef or anti-pol CTL responses were detected. Neutralization antibodies against MN were detected in 64% (181/283) of recipients of ALVAC alone, at relatively low titers (GMT: 8-35), and in 93% (316/338) who received ALVAC plus gp120 or gp160 boosts (GMT: 23-443). Recent studies (AVEG 034, 034A) have found lower than anticipated rates of CTL responses in recipients of vCP1433 (6/34 or 18%), vCP 1452 (18/71 or 25%), and vCP 205 (5/34 or 15%), which are currently unexplained. The immunogenicity of vCP1452 is being further investigated in a phase II study that is nearing completion (HVTN 203).
Conclusions: ALVAC HIV-1 vectors induce anti-env and anti-gag CTL activity after multiple dose administration to normal volunteers. Boosting with envelope proteins increases frequency and titer of neutralizing antibody responses against the homologous vaccine strain. Additional studies are underway or planned to further define the immunogenicity of the most complex vector, vCP 1452.
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