A graphic representation of the cytomegalovirus structure
Published:
5/27/2021

While a unique AIDS vaccine approach had previously shown an encouraging and unprecedented kind of protection against AIDS virus infection in nonhuman primate models, the underlying mechanism for this distinctive form of vaccine protection has remained unclear – until now. New research has provided important insights into understanding how the promising vaccine works. 

While the new vaccine did not completely prevent infection with the monkey AIDS virus Simian Immunodeficiency Virus (SIV), multiple studies found that between one-half and two-thirds of vaccinated monkeys stringently controlled and eventually cleared the infection, a never-before-seen result. 

The new results that help to explain how the novel vaccine is working were published in companion papers in Science and Science Immunology in March 2021 by three research groups lead by Louis Picker and Klaus Frueh at the Oregon Health and Science University and Jeff Lifson of the AIDS and Cancer Virus Program of the Frederick National Laboratory. 

Employing one virus to mount immune response against another 

The vaccine is based on splicing genetic information encoding proteins from SIV into another virus, cytomegalovirus (CMV). Cells infected with this “viral vector” express the SIV proteins to trigger immune responses. CMVs are large beta-herpes viruses that masterfully evade the immune system and persist in the body. At the same time, they elicit and indefinitely maintain robust cellular immune responses that restrain viral spread, including very high-frequency circulating and tissue-based effector-memory T cells. The investigators hoped these properties would also be true of the responses to the spliced-in SIV targets, potentially contributing to superior vaccine protection. While the vaccine-induced, anti-SIV responses did indeed show these properties, detailed mapping of the responses yielded surprises. 

A key component of antiviral responses, CD8 T lymphocytes, can recognize and kill virally infected cells by identifying pieces of viral proteins displayed on the surface of infected host cells by a certain class of host cell proteins. However, the responding CD8 T lymphocytes induced by the new vaccine were instead recognizing atypical viral targets, being presented by two other, unconventional classes of host cell proteins. It was not clear whether the unique form of protection mediated by the vaccine was linked to these unusual CD8 T lymphocyte responses.  

Unexpected genetic changes upend vaccine vector 

Close examination of the CMV used as the viral vector for the vaccine, which was not freshly isolated from an infected monkey but had been passaged in laboratory cell culture, revealed that over that period of passage, the virus had undergone multiple genetic changes, including both an inversion of the sequence of some genes, and some partial gene deletions. This resulted in functional changes, including influencing what kind of cells the virus was able to infect.  

The next step was to painstakingly reconstruct those genetic changes so they could be intentionally replicated. 

This process generated a whole panel of viruses in which the genetic changes from the “wild type” or typical virus were present individually, in various combinations, or had been repaired to the wild-type sequence. The researchers then assessed the immune responses to SIV inserts in these different CMV vaccine vectors to identify candidate vaccines that induced typical immune responses, typical immune responses along with the unconventional responses, or just the unconventional immune responses.  

These vaccines were then tested for their ability to protect monkeys. The results were clear: One of the two unconventional responses was both necessary and sufficient to provide this unique form of vaccine protection. 

Results have implications for future vaccine engineering 

While the researchers are still studying exactly how this subset of unconventional responses mediates vaccine protection, the current results will help guide the vaccine concept to clinical testing; initial clinical trials are expected to begin later in 2021. The results also have implications for AIDS virus vaccines, the understanding of basic T cell immunobiology, and prospects for engineering the properties of vaccines for other pathogens. 

“It’s been an exciting ride to start with an unconventional vaccine with promising activity, then to unravel the very unconventional basis for its activity,” said Lifson. “These results provide a big chunk of the explanation, while other ongoing studies are suggesting an explanation for why only half to two-thirds of vaccinated animals have been protected and providing clues about how to increase the proportion of protected vaccinees.” 

Replicating the genetic rearrangement and understanding the function of specific genes has bolstered the researchers’ knowledge of how CMV and other viruses evade the immune system, Lifson said.  

“It helps pave the way not only for clinical development, but also for improved and more expansive understanding and potential of T cell responses in cellular immunity, with the possibility of applying this in other settings to custom engineer different immune responses,” he said. 

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