One tendentious issue in vaccine research highlighted by the recent failure of Merck’s HIV vaccine candidate is the use of animal models. Merck’s vaccine had shown good control of an SIV/HIV hybrid challenge virus called SHIV89.6P in macaque studies, but failed to show efficacy against a more aggressive SIV isolate called SIVmac239. Before the STEP trial results became known, it was uncertain which challenge virus would be most predictive of the outcome in humans. Now, opinion has shifted toward using prevention and/or control of SIV challenges as a yardstick for measuring the potential of new HIV vaccine candidates. Historically, obtaining any attenuation of SIV infection with vaccines has proven very difficult, but recent reports suggest that progress is being made.
Dan Barouch and colleagues offer one example in a paper published online by the journal Nature. The study immunized macaques with a variety of prime-boost regimens using different serotypes of adenovirus vectors (Ad5, Ad26 and Ad35) encoding the SIV Gag protein. None of the macaques possessed the Mamu A*01 or B*17 genes, which are associated with enhanced control of SIV replication in the absence of vaccination (similar to known favorable HLA genes in humans). After a challenge with SIVmac251, peak viral loads in macaques that received an Ad26 prime/Ad5 boost regimen were 1.43 logs lower than unvaccinated control animals. Set point viral loads (defined as the mean level from day 112 to day 420 after challenge) were 2.44 logs lower than controls. Immune responses to SIV Gag were notably broader than has been seen with in human vaccine trials to date; macaques vaccinated with the Ad26/Ad5 regimen developed T cell responses to a mean of 16 Gag epitopes (in the Merck trial, participants responded to a mean of 1 epitope from Gag). Both the magnitude and breadth of the T cell responses elicited by vaccination correlated with control of the SIVmac251 challenge. While the safety issues raised by the STEP trial results likely preclude the further development of Ad5 vectors as HIV vaccines, Barouch’s results at least suggest that the development of more effective T cell-based vaccines is possible.
Additional evidence that the SIV challenge may not be insurmountable comes from two late-breaker presentations at the recent AIDS Vaccine 2008 conference in Cape Town. As covered in an excellent article in the IAVI Report by Kristen Jill Kresge, Nancy Wilson from David Watkins laboratory at the University of Wisconsin presented a study in which a virulent virus "swarm" called SIVE660 was used for the challenge. Macaques were immunized with a DNA/Ad5 regimen encoding all of the SIVmac239 genes except env. After a series of low-dose mucosal challenges, five of eight vaccinated macaques became infected but showed massively reduced peak viral loads compared to controls (12,600 copies/ml versus four million copies/ml). Eight weeks post-infection, the average viral load in the vaccine recipients was undetectable compared to 200,000 copies/ml among controls.
Louis Picker from the Vaccine and Gene Therapy Institute at the Oregon Health and Science University also presented data from study that employed a novel CMV-based vaccine vector to deliver SIV gag, rev, nef, tat, and env genes. Picker reported that immunized animals required significantly more low-dose SIVmac239 challenges to become infected compare to controls (a median of eight versus two) and four of 12 vaccine recipients resisted persistent SIV infection. Further details on both these studies should be forthcoming in the near future.
Nature advance online publication 9 November 2008 | doi:10.1038/nature07469; Received 18 August 2008; Accepted 29 September 2008; Published online 9 November 2008
Letter
Immune control of an SIV challenge by a T-cell-based vaccine in rhesus monkeys
Jinyan Liu1, Kara L. O'Brien1, Diana M. Lynch1, Nathaniel L. Simmons1, Annalena La Porte1, Ambryice M. Riggs1, Peter Abbink1, Rory T. Coffey1, Lauren E. Grandpre1, Michael S. Seaman1, Gary Landucci2, Donald N. Forthal2, David C. Montefiori3, Angela Carville4, Keith G. Mansfield4, Menzo J. Havenga5, Maria G. Pau6, Jaap Goudsmit6 & Dan H. Barouch1
Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA
University of California, Irvine School of Medicine, Irvine, California 92697, USA
Duke University Medical Center, Durham, North Carolina 27710, USA
New England Primate Research Center, Southborough, Massachusetts 01772, USA
TNO Biosciences, 2301 CE, Leiden, The Netherlands
Crucell Holland BV, 2301 CA, Leiden, The Netherlands
A recombinant adenovirus serotype 5 (rAd5) vector-based vaccine for HIV-1 has recently failed in a phase 2b efficacy study in humans1, 2. Consistent with these results, preclinical studies have demonstrated that rAd5 vectors expressing simian immunodeficiency virus (SIV) Gag failed to reduce peak or setpoint viral loads after SIV challenge of rhesus monkeys (Macaca mulatta) that lacked the protective MHC class I allele Mamu-A*01 (ref. 3). Here we show that an improved T-cell-based vaccine regimen using two serologically distinct adenovirus vectors afforded substantially improved protective efficacy in this challenge model. In particular, a heterologous rAd26 prime/rAd5 boost vaccine regimen expressing SIV Gag elicited cellular immune responses with augmented magnitude, breadth and polyfunctionality as compared with the homologous rAd5 regimen. After SIVMAC251 challenge, monkeys vaccinated with the rAd26/rAd5 regimen showed a 1.4 log reduction of peak and a 2.4 log reduction of setpoint viral loads as well as decreased AIDS-related mortality as compared with control animals. These data demonstrate that durable partial immune control of a pathogenic SIV challenge for more than 500 days can be achieved by a T-cell-based vaccine in Mamu-A*01-negative rhesus monkeys in the absence of a homologous Env antigen. These findings have important implications for the development of next-generation T-cell-based vaccine candidates for HIV-1.
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