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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