Induction of simian immunodeficiency virus (SIV)-specific CTL in rhesus macaques by vaccination with modified vaccinia virus Ankara expressing SIV transgenes: influence of pre-existing anti-vector immunity

A major aim in AIDS vaccine development is the definition of strategies to stimulate strong and durable cytotoxic T lymphocyte (CTL) responses. Here w e report that simian immunodeficiency virus (SIV)-specific CTL developed in 4/4 macaques following a single intramuscular injection of modified vaccin ia virus Ankara (MVA) constructs expressing both structural and regulatory/ accessory genes of SIV. In two animals Nef-specific responses persisted, b ut other responses diminished and new responses were not revealed, followin g further vaccination. Vaccination of another two macaques, expressing Mamu A*O1 MHC class I, with MVA constructs containing nef and gag-pol under the control of the moderate strength natural vaccinia virus early/late promote r P7.5, again induced an early Nef-specific response, whereas responses to Gag remained undetectable. Anti-vector immunity induced by this immunizatio n was shown to prevent the efficient stimulation of CTL directed to the cog nate Gag epitope, p1 1C C-M, following vaccination with another MVA constru ct expressing SIV Gag-Pol under a strong synthetic vaccinia virus-specific promoter. In contrast, vaccination of a previously unexposed animal resulte d in a SIV-specific CTL response widely disseminated in lymphoid tissues in cluding lymph nodes associated with the rectal and genital routes of SIV en try. Thus, despite the highly attenuated nature of MVA, repeated immunizati on may elicit sufficient anti-vector immunity to limit the effectiveness of later vaccination.