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.
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