While the spotlight is on the ALVAC vCP1521 and AIDSVAX B/E vaccine constructs, I thought it might be worthwhile to review the ingredients and some additional immunogenicity information. The ALVAC vCP1521 vector is a modified version of a bird virus called canarypox. While the natural form of the virus can be harmful to birds, it can only enter human cells and not replicate in them. A number of different versions of the ALVAC vector have been developed, each with a unique vCP code. ALVAC vCP1521 contains the gene encoding the gp120 protein from a virus codenamed 92TH023 that was isolated from a Thai individual in Bangkok by the WHO Network for HIV Isolation and Characterization. The virus was originally designated as belonging to subtype E, but it has since been recognized that this subtype is largely a circulating recombinant form now known by the name CRF01_AE. The 92TH023 virus isolate uses the CCR5 co-receptor to enter cells, like almost all primary HIV isolates.
In the ALVAC vCP1521 construct, the 92TH023 gp120 protein is linked to a portion of the gp41 protein from the first HIV ever isolated, LAI (originally misnamed LAV). Part of the gp41 protein is deleted to make it easier to distinguish vaccine-induced antibodies from those induced by HIV infection. LAI belongs to subtype B and was isolated by Françoise Barré-Sinoussi and Luc Montagnier in Paris in 1983. LAI uses the CXCR4 co-receptor to enter cells. The other two HIV-1 proteins encoded by the ALVAC vector are Gag and Protease, also derived from LAI.
The AIDSVAX B/E vaccine contains two gp120 proteins. One is from the subtype B HIV-1 isolate MN, a CXCR4-using virus originally isolated from a child with AIDS-related complex (as it was then known) by George Shaw and colleagues in 1984. The other gp120 is from a CRF01_AE virus isolate name A244 or CM244 that was obtained in Northern Thailand (CM=Chang Mai) in 1990 by Francine McCutchan and colleagues. The source of the isolate was a young Thai man who tested HIV positive after being randomly selected for military service. Like 92TH023, CM244 is an R5-using isolate.
Although it may seem notable that two of the gp120 proteins in the vaccines come from viruses isolated from the population involved in the RV144 trial, the antibody responses induced by the vaccine combination have been shown to have no neutralizing activity against primary isolates from subtype CRF01_AE (including the 92TH023 virus from which one of the gp120s is derived). A non-neutralizing antibody activity called antibody-dependent cellular cytotoxicity (ADCC) has been described in the recipients of the prime-boost combination, but only against targets pulsed with vaccine antigens; based on prior studies of ADCC breadth it is unlikely that this activity extends to circulating viruses. The only antibody activity induced by the vaccines that has been shown to have any reactivity with primary isolates is binding of antibody to cell surface gp120 of two CRF01_AE primary isolates, CM244 and 92TH009; this activity was described in recipients of AIDSVAX B/E alone (I can’t find any reference to testing of antibody binding to primary isolates in trials of the ALVAC/AIDSVAX prime-boost regimen).
Gag-specific CD8 T cell responses have been detected in around 8-20% of recipients of the ALVAC vector, although statistically this level of response was not different from placebo recipients. Very little information appears to be available on Gag-specific CD4 T cell responses, the one piece of data I could find was from a trial involving vCP205, which reported proliferative responses to p24 in only 7.8% of recipients. As mentioned in prior posts, the most consistent CD4 T cell response is to the Env protein, as measured by lymphoproliferation, which has been observed in around 60-80% of recipients. The Thai trial investigators have previously looked at the epitope specificity of the Env-specific CD4 T cell response in studies of a similar prototype prime-boost regimen (ALVAC vcp205 plus/minus rgp160MN/LAI-2), finding that multiple epitopes in gp120 were targeted. The extent to which these Env-specific CD4 T cell responses recognize circulating primary isolates has not been reported, to my knowledge. It should also be noted that AIDSVAX alone induces Env-specific proliferative responses.
In terms of the viruses circulating in the provinces where RV144 was conducted, the study appended below describes efforts to establish baseline information on the genotypes of strains isolated in the period 1998 to 2001.
AIDS Res Hum Retroviruses. 2006 Aug;22(8):801-7.
Watanaveeradej V, Benenson MW, Souza MD, Sirisopana N, Nitayaphan S, Tontichaivanich C, Amphaipit R, Renzullo PO, Brown AE, McNeil JG, Robb ML, Birx DL, Tovanabutra S, Carr JK, McCutchan FE.
Department of Pediatrics, Phramongkutklao Hospital School of Medicine, Bangkok, Thailand.
To characterize HIV-1 genotypes in candidate populations for a prime-boost phase III vaccine trial in Thailand, specimens from prevalent and incident HIV-1 infections from a family planning clinic population in Rayong Province and a community cohort in Chon Buri Province, collected from 1998 to 2001, were genotyped. A new multiregion hybridization assay, MHAbce, capable of distinguishing HIV-1 CRF01_AE, subtype B, and subtype C and their recombinants, was developed and applied to prevalent infections. Most incident and selected prevalent infections were studied by complete genome sequencing. By MHAbce, 168 of 194 prevalent infections were genotyped. Of these, 90.5% were CRF01_AE, 2.4% were subtype B, and 7.2% showed discordant or dual probe reactivity, indicative of recombination or dual infection, respectively. Among 23 incident infections, 20 were sequenced. Eighteen CRF01_AE, one subtype B, and one CRF01/B recombinant strains were seen. Two CRF01/B and one CRF01/C recombinant were identified among selected prevalent infections. These results indicate that incident and prevalent HIV-1 infections in Rayong and Chon Buri during 1998-2001 were 90% CRF01_AE, 3% subtype B, and 7% either recombinant or dual. This study frames the genetic diversity of HIV-1 in these cohorts in their preparatory phase for the ongoing ALVACHIV (vCP1521) prime, AIDSVAX B/E boost, phase III vaccine trial and will provide a benchmark for interpretation and analysis.