Abstract
A major safety concern of using live-attenuated vaccine strategies against AIDS is the potential exposure of neonates or fetuses to vaccine virus from the mother. Here we report that high viral loads and disease were observed in only 2 of 18 neonatal monkeys infected with gene-deleted vaccine strains of simian immunodeficiency virus. Pathogenicity was restricted to neonates born to unvaccinated mothers, that is, lacking maternal immunity, and that received extremely high doses of vaccine virus orally. No in utero transmission of vaccine virus was observed in four neonates born to mothers vaccinated during the second trimester. Our results suggest that the live attenuated vaccine approach should remain a viable option for preventing HIV infection and disease in high-risk human populations.
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Giavedoni, L.D. et al. Immune response of rhesus macaques to recombinant simian immunodeficiency virus gp 130 does not protect from challenge infection. J. Virol. 67, 577–583 ( 1993).
Cranage, M. et al. Immune responses to both cellular and viral proteins can mediate protection against infection with SIVmac. in Vaccines 94: Modern Approaches to New Vaccines Including Prevention of AIDS. (eds. Norrby, E., Brown, F., Chanock, R. & Ginsberg, H.S.) 203–209 (Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 1994).
Cranage, M.P. et al. Intrarectal challenge of macaques vaccinated with formalin-inactivated simian immunodeficiency virus. Lancet 339, 273–274 ( 1992).
Putkonen, P. et al. Whole inactivated SIV vaccine grown on human cells fails to protect against homologous SIV grown on simian cells. J. Med. Primatol. 22, 100–103 ( 1993).
Stahl-Hennig, C. et al. Protection of monkeys by a split vaccine against SIVmac depends upon biological properties of the challenge virus. AIDS 7, 787–795 ( 1993).
Mills, K.H.G. et al. Immunization of macaques with SIV env recombinants: Specificity of T cell and antibody responses and evaluation of protective efficacy. J. Med. Primatol. 22, 104–109 ( 1993).
Daniel, M.D. et al. High titer immune responses elicited by recombinant vaccinia virus priming and particle boosting are ineffective in preventing virulent SIV infection. AIDS Res. Hum. Retroviruses 10, 839–851 ( 1994).
Daniel, M.D., Kirchhoff, F., Czajak, S.C., Sehgal, P.K. & Desrosiers, R.C. Protective effects of a live-attenuated SIV vaccine with a deletion in the nef gene. Science 258, 1938–1941 ( 1992).
Almond, N. et al. Protection by attenuated simian immunodeficiency virus in macaques against challenge with virus-infected cells. Lancet 345, 1342–1344 ( 1995).
Wyand, M.S., Manson, K.H., Garcia-Moll, M., Montefiori, D. & Desrosiers, R.C. Vaccine protection by a triple deletion mutant of simian immunodeficiency virus. J. Virol. 70, 3724 ( 1996).
Kestler, H.W., III et al. Importance of the nef gene for maintenance of high virus loads and for the development of AIDS. Cell 65, 651–662 ( 1991).
Baba, T.W. et al. Pathogenicity of live, attenuated SIV after mucosal infection of neonatal macaques. Science 267, 1820–1825 ( 1995).
Gibbs, J.S. et al. Progression to AIDS in the absence of genes for vpr or vpx . J. Virol. 69, 2378–2383 ( 1995).
Horvath, C.J., Hunt, R.D., Simon, M.A., Sehgal, P.K. & Ringler, D.J. An immunohistologic study of granulomatous inflammation in SIV-infected rhesus monkeys. J. Leukocyte Biol. 53, 532–540 ( 1993).
Ilyinskii, P.O., Daniel, M.D., Simon, M.A., Lackner, A.A. & Desrosiers, R.C. The role of upstream U3 sequences in the pathogenesis of simian immunodeficiency virus-induced AIDS in rhesus monkeys. J. Virol. 68, 5933–5944 ( 1994).
Daniel, M.D. et al. Long-term persistent infection of macaque monkeys with the simian immunodeficiency virus. J. Gen. Virol. 68, 3183–3189 ( 1987).
Lewis, M.G. et al. Titration and characterization of two rhesus derived SIVmac challenge stocks. AIDS Res. Hum. Retroviruses 10, 213–220 ( 1994).
Ridge, J.P., Fuchs, E.J. & Matzinger, P. Neonatal tolerance revisited: Turning on newborn T cells with dendritic cells. Science 271, 1723–1726 ( 1996).
Sarzotti, M., Robbins, D.S. & Hoffman, P.M. Induction of protective CTL responses in newborn mice by a murine retrovirus. Science 261, 1726–1728 ( 1996).
Forsthuber, T., Yip, H.C. & Lehmann, P.V. Induction of TH1 and TH2 immunity in neonatal mice. Science 271, 1728–1730 ( 1996).
Desrosiers, R.C., Daniel, M., Lifson, J. & Arthur, L.O. Infection of chimpanzees with attenuated HIV-1 deletion mutants. in Dixième Colloque des Cent Gardes: Retroviruses of Human AIDS and Related Animal Diseases, 23–25 October 1995, Marnes-la-Coquette, Paris, France (eds. Girard, M. St Dodet, B.) 197– (Elsevier, Amsterdam, 1995).
Dickover, R.E. et al. Identification of levels of maternal HIV-1 RNA associated with risk of perinatal transmission: effect of maternal zidovudine treatment on viral load. JAMA 275, 599–605 ( 1996).
Weiser, B. et al. Quantitation of human immunodeficiency virus type 1 during pregnancy: relationship of viral titer to mother-to-child transmission and stability of viral load. Proc. Natl. Acad. Sci. USA 91, 8037–8041 ( 1994).
Deacon, N.J., McPhee, D.A., Crowe, S., Learmont, J. & Mills, J. Attenuated HIV vaccine: caveats: Response. Science 271, 1790–1792 ( 1996).
Gibbs, J.S., Regier, D.A. & Desrosiers, R.C. Construction and in vitro properties of SIVmac mutants with deletions in the “nonessential” genes. AIDS Res. Hum. Retroviruses 10, 607–616 ( 1994).
Kirchhoff, F., Kestler, H.W. III & Desrosiers, R.C. Upstream U3 sequences in simian immunodeficiency virus are selectively deleted in vivo in the absence of an intact nef gene. J. Virol. 68, 2031–2037 ( 1994).
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Wyand, M., Manson, K., Lackner, A. et al. Resistance of neonatal monkeys to live attenuated vaccine strains of simian immunodeficiency virus. Nat Med 3, 32–36 (1997). https://doi.org/10.1038/nm0197-32
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DOI: https://doi.org/10.1038/nm0197-32
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