IMAGE: CDC/ C, GOLDSMITH P. FEORINO, E. L. PALMER, W. R. MCMANUSA new vaccine for simian immunodeficiency virus (SIV), a model for HIV, controlled SIV in half of tested rhesus monkeys, research published today (May 11) in Nature reports. The vaccine, which employs a viral vector that remains latent throughout the body for a lifetime, appears to keep T-cells active and ready to fight the invading virus.
"This is an absolutely momentous development," said pathologist Peter Barry of University of California Davis who was not involved in the research. "There is still room for optimization, but it's really quite remarkable that they're getting essentially 50 percent control."
Scientists have struggled to develop an effective vaccine against SIV and HIV, in part due to how quickly the viruses spread through the body and evolve to evade immune defenses. Previous vaccines, such as the one tested in the failed STEP trial in 2007, encoded HIV antigens into an adenovirus, but because the vector is short-lived, the memory T-cells generated by the vaccine retreat to the lymph nodes to await another attack. In this position, the T-cells are too slow to respond to an incoming HIV infection, said immunologist Louis Picker of Oregon Health and Science University. By the time they leave the lymph nodes to proliferate and differentiate into effector T-cells, which do the actual fighting, HIV has already spread beyond control. To be effective, he hypothesized, an HIV vaccine should constantly stimulate the body's defenses to attack the virus as soon as it enters the body, when it is the most vulnerable.
To do this, Picker and his colleagues engineered SIV antigens into a cytomegalovirus (CMV), a latent virus that can persist throughout the body asymptomatically for long periods. The researchers gave the vaccine to 24 rhesus macaques, then infected them with SIV more than a year later. Thirteen of the monkeys controlled the virus at initial infection, quickly reducing the virus in blood to undetectable levels. Over the following months, the virus reemerged in those animals, but 12 of the 13 monkeys were once again able to fight it back down.
"This pattern of this protection -- when the virus went up and came down instead of remaining at baseline -- supports their claim that the immunity needs to persist" to effectively control the virus, said Ira Berkower, chief of the laboratory of immunoregulation at the US Food and Drug Administration, who was not involved in the research.
The vaccine does not prevent infection, however, but rather limits viral levels to nearly undetectable levels, added Berkower. As a result, "if [the] immune system should ever be immunosuppressed or attenuated in some fashion, you could get full blown virus."
Furthermore, while CMV's ability to persist in the body may boost the effectiveness of the vaccine, the viral vector could also become a safety concern should a patient's immune system be compromised, said Genoveffa Franchini, a retrovirologist at the Center for Cancer Research at the United States National Institutes of Health who was not involved in the research. It will be "very difficult" to satisfy all the safety requirements of a vaccine that requires giving "a chronic virus for the rest of [one's] life."
Since 50 percent of the US population over 55 has latent CMV already, you "could make a case for testing it in [already infected individuals] to find out if it's immunogenic in people," said Berkower. "But at the end of the day, you'd like to have something safe enough for everybody."
Picker and his team are currently working to engineer a safety-enhanced CMV vector with lower pathogenicity. "To me, it's promising that we can make a safe vector that works and could have benefits to humans," Picker said.
S.G. Hansen et al., "Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine," Nature, DOI: 10.1038/nature10003, 2011.