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Rapid development of vaccine protection in macaques by live-attenuated simian immunodeficiency virus
C Stahl-Hennig1, U Dittmer, T Nisslein
1German Primate Centre, Goettingen, Germany. stahlh@w.w.w.dpz.gwdg.de
Abstract:
Convincing data on experimental vaccines against AIDS have been obtained in the simian immunodeficiency virus (SIV) macaque model by preinfection with a virus attenuated by a nef deletion. To investigate the efficacy of a nef deletion mutant of SIVmac32H called pC8 as a live-attenuated vaccine after shorter preinfection periods and to learn more about the nature of the immune protection induced, eight rhesus monkeys were infected intravenously with the pC8 virus. All monkeys became persistently infected, exhibiting low cell-associated viral loads, but strong cellular and, in terms of binding antibodies, strong humoral antiviral responses. Two of eight pC8-infected monkeys developed an immunodeficiency and were not challenged. Sequence analysis of their nef revealed complete replenishment of the deletion. The other six monkeys, two preinfected for 42 weeks and four for 22 weeks, were challenged with pathogenic spleen-derived SIV. Complete protection was achieved in four vaccinees. Virus was consistently detected in two vaccinees from the 22-week-group challenge, however, they remained clinically healthy over a prolonged period. Protection from challenge virus infection or a delayed disease development seemed to be associated with a sustained SIV-specific T helper cell response after challenge. Thus, a sterilizing immunity against superinfection with pathogenic SIV can be induced even after a relatively short waiting period of 22 weeks. Nevertheless, such a vaccine raises severe safety concerns because of its potential to revert to virulence.
Insights
Experimental vaccines using a nef-deleted SIV (simian immunodeficiency virus) showed promise in macaques. Even with shorter preinfection periods, this live-attenuated vaccine induced protection against pathogenic SIV, though safety concerns remain.
Area of Science:
- Virology
- Immunology
- Vaccinology
Background:
- Live-attenuated vaccines, particularly those with nef deletion mutants of simian immunodeficiency virus (SIV), have shown potential in AIDS vaccine development using the macaque model.
- Understanding the efficacy of these vaccines after shorter preinfection periods is crucial for practical application.
Purpose of the Study:
- To evaluate the efficacy of the SIVmac32H nef deletion mutant (pC8) as a live-attenuated vaccine in rhesus monkeys after shorter preinfection durations.
- To elucidate the mechanisms of immune protection induced by the pC8 vaccine.
Main Methods:
- Eight rhesus monkeys were intravenously infected with the live-attenuated SIV pC8 vaccine.
- Persistent infection, viral loads, and immune responses (cellular and humoral) were monitored.
- Six monkeys were subsequently challenged with pathogenic SIV after preinfection periods of 22 or 42 weeks.
Main Results:
- All pC8-infected monkeys showed persistent infection with low viral loads but strong antiviral immune responses.
- Two monkeys developed immunodeficiency due to nef reversion and were excluded from challenge.
- Four out of six challenged monkeys achieved complete protection against pathogenic SIV.
- Two monkeys from the 22-week preinfection group showed delayed disease progression while remaining clinically healthy.
Conclusions:
- A nef-deleted SIV vaccine can induce sterilizing immunity or delayed disease development against pathogenic SIV challenge, even after a 22-week preinfection period.
- Sustained SIV-specific T helper cell responses post-challenge appear associated with protection.
- The potential for the vaccine to revert to virulence raises significant safety concerns.