Chances are you are infected with it. Cytomegalovirus (CMV) is a nearly ubiquitous, but rarely discussed, virus affecting a third of children by age five and half of adults by age 40. Except in the case of pregnancy, it typically causes no harm. Named after the first observation of abnormally swelling cells the virus causes, CMV has been evolving in humanity’s blood for millions of years. And, once infected, CMV stays in the body. 'Til death do human and CMV part.

As much as CMV may like us, our bodies don't like CMV. CMV causes a dramatic immune response. A flood of antibodies and T cells will quickly control the infection, pushing the virus into a dormant state. As CMV attempts to reactivate during our lifetime, we respond again and again with vigor. 

In 2011, scientists led by Louis Picker of Oregon Health and Science University published groundbreaking work on a CMV vaccine. It wasn’t a vaccine against CMV, but rather a new vaccine with CMV, but targeted against SIV (the non-human primate version of HIV). Since a successful vaccine hinges on a strong, robust reaction, they realized that the immunogenic effects of CMV could be used to design a new vaccine. By re-engineering the virus, the researchers turned CMV into a double-agent. 

In monkeys (rhesus macaques), a vaccine containing modified CMV with proteins from SIV – the HIV analog in monkeys – on its surface immunized about 50% of monkeys against SIV. For HIV vaccine research at the time, this was a tremendous result which still holds against other efforts today. By exploiting CMV’s ability to vigorously provoke an immune response, CD8+ T cells, which recognize infected cells and remove them, moved in after the initial infection to control SIV.

“People were very excited about it. That was the first iteration, you thought, 50%, well that’s fantastic. Maybe you’ll get better than that,” says Dr. Bruce Walker, Director of the Ragon Institute of Massachusetts General Hospital, MIT, and Harvard.

After the results were published, the field, including Picker’s own group, wanted more answers about how CMV provokes an immune response. Was there something fundamentally different about how CMV signaled our body’s SWAT team?

In the following years, contrary to typical behavior, it was discovered that these CD8+ T cells were recognizing a diversity of MHC class I and II proteins. MHC proteins signal "DANGER!" to the immune system by displaying small proteins on the surface of an infected cell. These signals are specific to each pathogen and provoke T cells developed to recognize that specific signal. In this case, CD8+ T cells were not following the rules. The T cells responding to CMV recognized different MHC proteins with a variety of signals, instead of just one particular signal. This breadth of recognition by T cells is thought to be behind the success of the CMV-based vaccine. Imagine Rafiki holding up Simba, if Rafiki was an infected cell, Simba a pathogen, and all the animals of the savanna your T cells. This is some trippy version of The Lion King where there are multiple Rafikis holding up multiple Simbas on Pride Rock. 

Interestingly, by changing the proteins within the CMV virus, different responses could be elicited, and in different tissues. This unconventional response to the CMV-based vaccine may have serious advantages in HIV, where subtypes have emerged, in the same way that there are many different types of influenza. This diversity has been a major challenge in the field.

“Pressure has been applied on HIV through certain immune responses that has resulted in diversification of the virus,” says Dr. Walker, who focuses on immune control in HIV. “[The] CMV vector induces responses to epitopes [immune response signals] that are not under selection pressure.” This may be advantageous for creating a broadly effective vaccine.

Nearly seven years later, new results continue to build upon new understanding of when, why, and how our T cells respond to a re-engineered vaccine vector-like CMV. Questions still remain though, as Dr. Walker points out. “In terms of mechanistically, we still don’t know what the effector mechanism responsible for control is.”

Dr. Walker raises another point. “Would a vaccine that gives 50% protection, but nothing in the other individuals, be a solution?” It has been over seven years since Louis Picker published his 50% effective CMV-based SIV vaccine. Considering the time it took to conduct and publish the study and the planning of the first human trials, we are looking at a decade with no human results yet. Dan Barouch, a Professor at Harvard Medical School and member of the Ragon Institute, has been working on an HIV vaccine for nearly 15 years now. “How do you iterate in making vaccines if it takes that long and it’s that expensive?” asks Dr. Walker.

Other targets have emerged as well. In January, Picker and an armada of scientists published more promising results on tuberculosis (TB)–the deadliest pathogen ever. Picker and the team prevented infection by the TB pathogen Mycobacterium tuberculosis with a CMV-based vaccine in over 40% of vaccinated monkeys. Michael Jarvis and his team, from the University of Plymouth, UK, added Ebola to the list of CMV targets.

Cancer could be a target too. The benefit of immunogenicity in cancer treatment has been a theme in research for some time – perhaps before we even truly understood it. Even now, our first-line treatment of bladder cancer is an injection of Mycobacterium bovis, a mostly harmless relative of Mycobacterium tuberculosis. The bacteria cause our immune system to invade the bladder and attack both bacteria and cancer alike. Vaccinating against cancer with CMV in mice caused a robust CD8+ T cell response, which both prevented the growth of newly implanted tumor cells and killed off established tumors.

Taken together, CMV may be both foe and friend. In that, CMV is not alone: adenovirus (Ad), an engineered vector commonly used for gene therapy, is another virus with potential utility in vaccine design. Whereas CMV-based vaccines controlled the viral infection, Ad-based vaccines are known to boost preventative protection against catching the infection in the first place.

Clinical trials are underway for adenovirus-based vaccines, like Dr. Barouch’s above-mentioned HIV vaccine. Over 2,600 women will be enrolled to test this vaccine. CMV-based vaccine trials, specifically for tuberculosis, are beginning soon, led by Vir Biotechnology, a company co-founded by Louis Picker.

Cytomegalovirus continues to ride in the sidecar during humans' evolutionary journey, infecting and persisting in an enormous fraction of the population. Now, its extraordinary ability to provoke and train our immune systems has redefined what we know about effective vaccination and, perhaps, holds promise in being part of an effective vaccine against human’s greatest foes.