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299 Immunogenicity in Neonatal Mice of a Hyperattenuated Listeria Vaccine Directed against HIV
M. Rayevskaya, N. Kushnir, and F. R. Frankel*
Univ. of Pennsylvania Sch. of Med., Philadelphia, USA
Background: CD8+ T cells are a major component of the adaptive response of a host to infections by viruses and other intracellular pathogenic agents. However, because of the intrinsic immaturity of their immune systems, neonatal animals are sensitive to a variety of pathogens and may be unable to respond in a protective manner. For example, nef-deleted mutants of SIV are attenuated in adult macaques and protect these animals against subsequent pathogenic virus infection, whereas immunization of neonatal macaques with these viruses can result in viremia and death. Whether this results from the reduced numbers of T cells and immature B and dendritic cells of neonates or from the tendency of neonates to become tolerized by early antigen exposure is not known. Thus, although vaccination of neonates is desirable, early postnatal immunization may not be effective and is not entirely without risk. We have developed a hyperattenuated strain of Listeria monocytogenes that induces strong CTL responses and long-lasting systemic and mucosal protection against challenge with an HIV-surrogate virus, recombinant vaccinia-gag. We wanted to determine whether this vector is safe and immunogenic in neonatal animals.
Results: We found that as many as 1 million gag-recombinant attenuated Listeria were completely avirulent in 3- to 5-day-old neonatal mice, whereas as few as 10 wild-type Listeria resulted in the death of half of the infected animals. When we examined adult animals 1 to 2 months after neonatal immunization, splenic lymphocytes showed moderate gag-specific CTL activities. Animals that had been boosted 2 weeks after neonatal priming had very high CTL activities and showed no evidence of tolerization by the vaccine. These CTL activities appeared to provide functional immunity since the neonatally primed animals showed partial protection against vaccinia-gag challenge and the boosted neonates were fully protected against the virus. Examination of the gag-specific T-cell subset in these animals by FACS showed a persistent memory level many-fold higher than seen in naïve mice in spleen and lamina propria. This memory level increased dramatically following virus challenge.
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