Mercurial mercenary: A colored scanning electron micrograph of a T cell.
For some infectious diseases, traditional vaccines just don’t cut it. Microbes that hide inside human cells and cause chronic illness aren’t stymied by the antibody response generated by the kind of vaccine available at the doctor’s office. T-cell vaccines, which activate a different type of immune response, could, in theory, better prevent or control such chronic infections, but so far nobody has been successful at transitioning T-cell vaccines from the lab bench to the clinic.
A Cambridge, Massachusetts, biotech company called Genocea thinks its high-throughput method could change that. The company will begin its first clinical trial later this year, when its experimental herpes vaccine will be the first test of its claims.
All existing vaccines rouse the body into creating antibodies that attach to the surface of infecting microbes and flag them for destruction. But pathogens that live inside our cells, such as the viruses, bacteria, and other microbes that cause AIDS, malaria, herpes, and chlamydia, can evade this surveillance. “In order to deal with those types of pathogens, oftentimes we have to stimulate what we call cellular immunity. Unlike antibody immunity, which recognizes pathogens directly, cellular immunity has to recognize the infected cell and get rid of your own infected cells,” says Darren Higgins, a biologist at Harvard Medical School who studies the interaction between hosts and pathogens and is a cofounder of Genocea.
But activating cellular immunity—and the family of infection-fighting cells known as T cells that drive it—is challenging. The trial-and-error method used to develop antibody-based vaccines has not worked for T-cell vaccines. Despite years of academic and industry work, and even clinical trials, there are no T-cell vaccines for infectious disease on the market. “We don’t know all of the rules yet if it’s possible to make a T-cell vaccine, [nor] how effective it would be,” says Robert Brunham, a physician-scientist at the University of British Columbia in Vancouver who is working on developing a chlamydia T-cell vaccine.
Indeed, our understanding of how T cells control infection is still developing. The challenge is to identify the right protein—or antigen—from a pathogen that will grab a T cell’s attention and signal that a human cell harbors an infectious agent. “If you can figure out what those protein pieces are, then you can use those proteins as a vaccine to sort of educate your immune system on what to respond to,” says Higgins, who is now a consultant and scientific advisor for Genocea.
The size of the challenge depends on the number of proteins encoded by a pathogen’s genome. Each of the 80 or so proteins in the herpes simplex 2 genome is a possibility, as are the thousand or so proteins in chlamydia and the 5,000 or so in malaria. Testing each protein one by one is a slow and expensive process. Genocea’s approach involves collecting as many of the pathogen’s proteins as can reasonably be produced in a lab, and then monitoring how human immune cells respond to each.
Generally, this involves isolating two kinds of immune cells from people—T cells and antigen-presenting cells, which carry bits of bacteria or other pathogens on their outer surface to display them to T cells. If a T cell produces immune-signaling molecules in response to a particular antigen, researchers at Genocea consider that antigen to be a potential vaccine candidate. By screening through nearly all of a pathogen’s proteins in its initial hunt for good vaccine candidates, the company thinks it can reduce the amount of time and money needed to develop a T-cell vaccine.
But there’s another layer of complication to the T-cell response that requires further refining to the vaccine candidate pool: human genetics. A protein that elicits a response in one person may not work in another, because there is genetic variety in the structures that antigen-presenting cells use to hold up antigens. “Whether that’s a barrier to having a universal vaccine or not is something the field is working through,” says Brunham. Genocea hopes to approach this problem by testing T-cell responses in immune cells from a variety of genetic backgrounds.
Genocea plans to enter clinical trials with its genital herpes vaccine later this year. If successful, Genocea’s herpes simplex 2 vaccine would be the first to combat the disease, which affects one out of every six people aged 15 to 49. Currently, patients can take antiviral drugs as a treatment, but there is no cure. Genocea’s candidate vaccine would be used as a therapeutic treatment for patients who already have the disease.
Genocea’s herpes vaccine program is moving faster than typical vaccine research, which can take 10 years to go from discovery to proof-of-concept and 20 years to reach the market, says Higgins. “Now you can screen very rapidly what is going to be the optimal vaccine component that allows you to get into clinical trials at a rapid rate.”