Abstract
The influence of preexisting immunity to viral vectors is a major issue for the development of viral-vectored vaccines. In this study, we investigate the effect of preexisting vaccinia virus immunity on the immunogenicity and efficacy of a DNA/modified vaccinia Ankara (MVA) SIV vaccine in rhesus macaques using a pathogenic intrarectal SIV251 challenge. Preexisting immunity decreased SIV-specific CD8 and CD4 T cell responses but preserved the SIV-specific humoral immunity. In addition, preexisting immunity did not diminish the control of an SIV challenge mediated by the DNA/MVA vaccine. The peak and set point viremia was 150- and 17-fold lower, respectively, in preimmune animals compared with those of control animals. The peak and set point viremia correlated directly with colorectal virus at 2 wk postchallenge suggesting that early control of virus replication at the site of viral challenge was critical for viral control. Factors that correlated with early colorectal viral control included 1) the presence of anti-SIV IgA in rectal secretions, 2) high-avidity binding Ab for the native form of Env, and 3) low magnitude of vaccine-elicited SIV-specific CD4 T cells displaying the CCR5 viral coreceptor. The frequency of SIV-specific CD8 T cells in blood and colorectal tissue at 2 wk postchallenge did not correlate with early colorectal viral control. These results suggest that preexisting vaccinia virus immunity may not limit the potential of recombinant MVA vaccines to elicit humoral immunity and highlight the importance of immunodeficiency virus vaccines achieving early control at the mucosal sites of challenge.
Footnotes
This work was supported by National Institute of Allergy and Infectious Diseases/National Institutes of HealthGrants R01 AI057029 and R01 AI071852 (to R.R.A.), Yerkes National Primate Research Center Base Grant P51 RR00165, Emory Centers for AIDS Research Grant P30 AI050409, and National Institutes of Health Grant R24 RR16038 (to David I. Watkins).
The online version of this article contains supplemental material.
Abbreviations used in this paper:
- Ad5
- adenovirus type 5
- C
- control
- DI
- Dryvax-immune
- DN
- Dryvax-naive
- GM
- geometric mean
- MVA
- modified vaccinia Ankara
- rs
- Spearman’s rank correlation
- SHIV
- simian HIV
- TCLA
- T cell line adapted
- VV
- vaccinia virus.
- Received March 11, 2010.
- Accepted October 13, 2010.