Important note: Information in this article was accurate in May 1999. The state of the art may have changed since the publication date.AIDSWEEKLY Plus; Monday, May 31 & June 7, 1999
Daniel J. DeNoon, Senior Editor
CW HENDERSON PUBLISHER -- Mucosal administration of a vaccinia-vectored vaccine can overcome preexisting vaccinia immunity in mice, a National Institutes of Health study demonstrates.
The finding breathes new life into vaccines based on recombinant vaccinia virus. It suggests that such vaccines can be effective in people already immunized against smallpox. More importantly, it indicates that these vaccines can be used many times - for boosting or even for completely different vaccinations.
One reason vaccinia makes such an excellent vaccine vector is its extraordinary immunogenicity. Fowlpox vectors, developed as alternatives to vaccinia vectors, appear to be less potent. While the avian poxvirus vectors cannot replicate in mammalian cells and are completely safe, highly attenuated vaccinia viruses have been proven safe in humans and retain their powerful immunogenicity.
The drawback to vaccinia-based vaccines springs from this potency: once systemically vaccinated via subcutaneous inoculation, a person becomes immune to further vaccinations. The new findings - if they prove applicable to humans - suggest that this barrier can be overcome.
"This study establishes that mucosal routes of immunization can be used to induce systemic recombinant protein-specific cytotoxic lymphocyte (CTL) and antibody responses with vaccinia vectors in the face of preexisting systemic immunity to vaccinia," concluded NIH researchers Igor M. Belyakov and colleagues.
"The ability to circumvent preexisting vaccinia immunity should greatly improve the utility of this otherwise very promising viral vector for vaccines against a variety of pathogens, including HIV."
Belyakov et al. reported their findings in the Proceedings of the National Academy of Sciences ("Mucosal Vaccination Overcomes the Barrier to Recombinant Vaccinia Immunization Caused by Preexisting Poxvirus Immunity," Proc Natl Acad Sci U S A 1999 Apr 13;96(8):4512-7.
The NIH team has developed an experimental HIV vaccine in which recombinant vaccinia virus expresses a peptide (dubbed P18) from the V3 region of the HIV-1 gp160 envelope precursor protein (amino-acid residues 311-320). In previous studies, they found that systemic, subcutaneous inoculation of mice with this recombinant vaccinia induced CTL responses to the HIV protein in systemic lymphoid tissue but not in mucosal sites (Belyakov, I. et al., J Virol 1998 Oct;72(10):8264-72.
This finding led them to hypothesize that even after systemic inoculation against vaccinia, mucosal sites may remain naive to vaccinia antigens. To test this system they employed the BALB/c mouse model, which mimics human vaccinia immunity.
Mice immune to vaccinia vaccine showed HIV specific serum antibody and strong HIV specific CTL responses after mucosal immunization with the HIV gp160-expressing vaccinia. Both mucosal and systemic lymphoid tissues exhibited these responses. Systemic immunization of control mice was, as expected, not effective.
Greater immune responses occurred after intrarectal than after intranasal vaccine administration; boosting also was most effective by the intrarectal route.
In addition, coadministration of recombinant interleukin 12 (rIL- 12) significantly increased systemic HIV specific CTL responses.
"The conclusion that trafficking of CTL from mucosal sites to the systemic immune system is efficient in contrast to migration in the reverse direction may have implications beyond the application described here," Belyakov et al. wrote.
Co-author Bernard Moss acknowledged that he is the inventor of a U.S. government-owned patent on recombinant vaccinia viruses that express the HIV envelope protein.
The corresponding author for this study is Jay A. Berzofsky, National Cancer Institute, National Institutes of Health, Building 10, Room 6B-12, Bethesda, Maryland 20892-1578. Email: <berzofsk@helix.nih.gov>.
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