One of the longtime bones of contention in the HIV vaccine field is: which animal model best reflects HIV infection in humans? A commonly used vaccine/challenge model involves rhesus macaques challenged with a highly virulent simian immunodeficiency virus called SIVmac239 (a clone of a virus isolate taken from its natural host, the sooty mangabey). It is widely appreciated that SIVmac239 replicates to higher levels and causes disease far more quickly in macaques than HIV does in humans; as a result, the approach has been legitimately criticized as perhaps being too stringent. An alternative that has also been used extensively over the last decade involves using HIV/SIV hybrid viruses called SHIVs. The most frequently used SHIV has been SHIV89.6P, which has been criticized for the opposite reason to SIVmac239; it seems it may be too easy to protect against, particularly as neutralizing antibody responses develop post-infection (unlike in HIV or SIVmac239 infection). SHIV89.6P also enters target cells via the X4 co-receptor rather than the R5 receptor used by essentially all infecting HIV strains. Newer SHIV's have been developed that utilize CCR5 but, thus far, they have not been widely used in vaccine challenge experiments and so where they fit into the picture is unclear.
Perhaps notably, in light of the news about Merck's V520 trial, most of the macaque experiments conducted during the vaccine's development used SHIV89.6P as the challenge virus. Robust, long-term control of post-infection viral load was seen in these studies, which were published to considerable fanfare in Nature in January of 2002. Merck did, however, subsequently perform similar experiments using SIVmac239 as a challenge virus. These results were published in the Journal of Virology in 2005 and received far less attention. The full text of the paper is now available free online.
The results of this study were not as encouraging as those seen with SHIV89.6P. A series of three shots of the adenovirus vaccine - the same schedule as used in the human trial, although in this case using a prototype construct encoding only the Gag protein (not Gag, Pol & Nef as in the final construct) - did not produce any post-challenge difference in SIVmac239 viral load compared to placebo immunizations. However, giving a DNA vaccine as a prime followed by the adenovirus vaccine as a boost led to a significantly lower (~7-fold) peak viral load in animals with the Mamu A*01 immune response gene (an equivalent to favorable HLA genes in humans) and a 3.2 fold lower peak viral load in animals lacking Mamu A*01 (a trend which did not reach significance). Viral load differences remained significant in the Mamu A*01 animals out to day 250 post-challenge but - in keeping with SIVmac239's virulence - differences between groups were no longer significant from that timepoint on.
Similarly, in the one other published study using Merck's constructs and a SIVmac239 challenge, significant restults were achieved with a DNA priming immunization and the inclusion of additional HIV genes (tat and rev). This study used a different low-dose challenge approach, but SIVmac239 viral loads in animals that became infected were just as high as seen in normal challenge experiments. Statistically significant differences were seen in both peak and post-peak viral loads in animals that were vaccinated, with reductions of approximately 1 log and 1.45 logs, respectively, compared to control animals that received a placebo immunization. Again, however, there is the caveat that all animals in this study possessed the Mamu A*01 allele.
It would be a huge overreach to suggest that these findings say anything certain about the human trial results, but they may offer a sliver of encouragement to researchers pursuing DNA prime/vector boost approaches. Merck had originally planned on including a DNA prime in their trial, but dropped the idea due to the lack of any obvious boosting effect compared to using adenovirus alone. At the meeting of the AIDS Vaccine Research Working Group (AVRWG - an advisory body to NIAID now called the AIDS Vaccine Research Subcommittee) in May 2004 where Merck's immunogenicity data were discussed, several AVRWG members suggested perhaps the DNA prime should be retained, but it was far from a clear-cut issue and, of course, as the cliché says: hindsight is 20/20.
Note: Thanks to Simon Noble, Editor of the IAVI Report, for the reminder about the 2005 J. Virology paper.
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