AIDSWEEKLY Plus; Monday, September 28, 1998
Daniel J. DeNoon, Senior Editor
The finding comes from the most extensive study to date of rhesus monkeys given a prototype live, attenuated AIDS vaccine (SIVmac239 delta nef) and then challenged with pathogenic virus (SIVmac251).
Aaron Diamond AIDS Research Center researchers Ruth I. Connor and colleagues collected data on not only on the animals' immune responses but also on both vaccine-virus and challenge-virus dynamics over time.
Among the study's provocative findings is the suggestion that host factors, already known to affect the permissiveness of an individual's cells to retroviral infection, profoundly affect how the vaccine virus acts.
"Our results imply that inherent host factors can also have a considerable impact on the ability of live, attenuated SIV vaccines to replicate in vivo," Connor et al. wrote. "It is possible that host factors which restrict replication of a live, attenuated vaccine in some individuals may prolong the period required for protective immunity to develop, while in others, replication of the same attenuated strain may be enhanced, leading to pathogenicity."
Connor et al. reported their findings in the Journal of Virology ("Temporal Analyses of Virus Replication, Immune Responses, and Efficacy in Rhesus Macaques Immunized with a Live, Attenuated Simian Immunodeficiency Virus Vaccine," J Virol, 1998;72(9):7501-9.)
The study called for 16 rhesus macaques to receive the SIVmac delta nef vaccine developed by Harvard researcher Ronald Desrosiers and colleagues. Four animals were intravenously challenged with pathogenic SIVmac251 at 5, 10, 15, or 25 weeks after immunization. Four nonimmunized animals served as controls and were challenged at each time point.
SIVmac251 infection was detected in all four animals challenged at 5 weeks, in two of four animals challenged at 10 weeks, in none of four animals challenged at 15 weeks, and in one of four animals challenged at 25 weeks.
Interestingly, even the animals challenged at 5 weeks showed some evidence of protection with a transient, 100-fold reduction in SIVmac251 viral load. Moreover, all animals had reduced viral load in their lymph nodes compared with control animals.
No correlation with anti-SIV antibodies occurred, and neutralization titers were not higher in protected monkeys.
"However, the lack of strong anti-Gag antibody responses in the nonimmunized control animals following SIVmac251 challenge suggests early immune dysfunction that was not evident in animals infected with SIVmac239 delta nef," Connor et al. observed.
The study's most sensational finding was that one of the animals challenged at 10 weeks had a high viral load and steady decline in CD4 counts despite lack of infection with the pathogenic challenge virus. Instead, this animal suffered burgeoning infection with the vaccine virus.
"Overall, our results suggest that protective responses can develop much more rapidly than was previously observed with more highly attenuated SIV strains and support the idea that the ability of live, attenuated vaccines to elicit protection is closely linked to their replicative capacity in vivo," Connor et al. wrote.
Thus a vaccine with sufficient replicative capacity to protect some animals likely will have enough replicative capacity to cause disease in some more susceptible animals. Conversely, a vaccine virus attenuated enough to be safe in all animals may not replicate well enough to protect.
"Our results support the idea that the duration of time between immunization and challenge is critical for protective immunity to develop and that this may be dependent on continuous replication of the attenuated strain," Connor et al. wrote.
"It is not yet known whether replication of the vaccine virus must be sustained in order to maintain protective immunity, or whether the initial antigenic stimulation achieved in the first 10 to 15 weeks following immunization is sufficient to impart long-lasting immunity."
This work was supported by National Institutes of Health grants AI42454, AI41373, and AI35166 and the Aaron Diamond Foundation.
The corresponding author for this study is Ruth I. Connor, Aaron Diamond AIDS Research Center, 455 First Ave., 7th Floor, New York, New York 10016. Phone: (212) 448-5040. Fax: (212) 725-1126. Email: <rconnor@adarc.org>.
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