In a prior post, I briefly mentioned a new SIV challenge study conducted by Nancy Wilson and colleagues from the research lab of David Watkins at the University of Wisconsin. The full paper has now been published online in the Journal of Virology. The results show an impressive degree of control of an SIV challenge, obtained using a DNA prime/Ad5 boost vaccine approach including all SIV antigens except Env (which was specifically excluded to avoid induction of Env-specific antibodies).
Importantly, Wilson chose to use an SIV challenge virus (SIVsmE660) consisting of a viral “swarm” which is around 15% divergent from the cloned SIVmac239 used to make the vaccine antigens. The goal was to try and more closely recapitulate human exposure to genetically divergent viruses. In pursuit of the same goal, the researchers also collaborated with Beatrice Hahn’s group to carefully titrate their challenge dose such that only 1-4 viral variants caused systemic infection. Macaques with MHC alleles known to be associated with better immune control of SIV (Mamu-A*01, B*08 and B*17) were excluded from the study. The vaccine regimen induced very broad and high magnitude T cell responses to an average of around 20 epitopes (ranging from 11-34).
Eight vaccinated animals and eight naïve controls were given a series of low-dose rectal challenges (once every three weeks). Five macaques that remained uninfected after five such exposures subsequently received higher dose challenges, and all eventually became infected. Although there was no difference in the number of challenges required to infect vaccinees and controls, both peak and set point viral loads were dramatically lower in the vaccinated animals (in two cases peaking at only 300 copies/mL). The average reduction in viral load among vaccine recipients compared to controls was 1.9 log at peak and 3.3 log at set point.
Wilson and colleagues discuss the potential caveats to their data. Some reports have suggested that SIVsmE660 may be more easily controlled than other SIVs, and one control animal in the study did eventually reduce viral load to undetectable levels. However, this particular viral stock has been used to challenge other groups of naïve animals and the results have been very consistent, with the majority of animals showing high peak and set point viral loads. The stock has also been used to challenge animals immunized with the most successful SIV vaccine to date, the live-attenuated SIVdeltanef, and only a comparatively moderate degree of control was achieved, with the best results seen in macaques expressing the favorable Mamu-B*08 and B*17 alleles. In that study the challenge was high dose and intravenous, and the researchers stress that a similar study involving repeated low dose challenge of animals lacking favorable Mamu alleles is needed to gain a better understanding of the relative efficacy of the DNA/Ad5 and live-attenuated vaccines against a heterologous SIV challenge. Overall, the authors conclude that their data are encouraging and suggest “T cell based vaccines may have greater potential than previously appreciated.”
There is one lurking issue that may impact this interpretation. Recent findings from Steve Deeks group at UCSF show that even elite control of HIV infection – the degree of control being aimed for with T cell-based vaccines – is associated with elevated inflammation compared to uninfected controls. As covered on the blog previously, Peter Hunt has shown that this inflammation can eventually cause a decline in CD4 counts in many elite controllers and, more recently, data has been published indicating that it is also associated with an increase in risk of artheriosclerosis. While these data do not mean that T cell-based vaccines should be abandoned, they do reinforce that even an efficacious vaccine of this type would be a stop-gap, until a vaccine that fully prevents HIV infection can be developed.
JVI Accepts, published online ahead of print on 29 April 2009
J. Virol. doi:10.1128/JVI.00272-09
Vaccine-induced Cellular Responses Control SIV Replication After Heterologous Challenge
Nancy A. Wilson*, Brandon F. Keele, Jason S. Reed, Shari M. Piaskowski, Caitlin E. Mac Nair, Andrew J. Bett, Xiaoping Liang, Fubao Wang, Elizabeth Thoryk, Gwendolyn J. Heidecker, Michael R. Citron, Lingyi Huang, Jing Lin, Salvatore Vitelli, Chanook D. Ahn, Masahiko Kaizu, Nicholas J. Maness, Matthew R. Reynolds, Thomas C. Friedrich, John T. Loffredo, Eva G. Rakasz, Stephen Erickson, David B. Allison, Michael Piatak Jr., Jeffrey D. Lifson, John W. Shiver, Danilo R. Casimiro, George M. Shaw, Beatrice H. Hahn, and David I. Watkins
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin; Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI; Departments of Medicine and Microbiology, University of Alabama at Birmingham, Birmingham, Alabama; Section on Statistical Genetics, Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama; Merck Research Labs, West Point, Pennsylvania; SAIC Frederick, Inc., NCI-Frederick, Frederick, Maryland
All HIV vaccine efficacy trials to date have ended in failure. Structural features of the Env glycoprotein and its enormous variability have frustrated efforts to induce broadly-reactive neutralizing antibodies. To explore the extent to which vaccine-induced cellular immune responses, in the absence of neutralizing antibodies, can control replication of a heterologous, mucosal viral challenge, we vaccinated eight macaques with a DNA/Ad5 regimen expressing all of the proteins of SIVmac239 except Env. Vaccinees mounted high-frequency T cell responses against 11-34 epitopes. We challenged the vaccinees and eight naïve animals with the heterologous biological isolate SIVsmE660, using a regimen intended to mimic typical human HIV exposures resulting in infection. Viral loads in the vaccinees were significantly less at both peak (1.9 log reduction p<0.03) and at set point (3.3 log reduction p<0.003) than those of control naïve animals. Five of eight vaccinated macaques controlled acute peak viral replication to less than 80,000 vRNA copy Eq/ml and to less than 100 vRNA copy Eq/ml in the chronic phase. Our results demonstrate that broad vaccine-induced cellular immune responses can effectively control replication of a pathogenic, heterologous AIDS virus, suggesting that T cell based vaccines may have greater potential than previously appreciated.
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