Genocea Biosciences Inc.
Harnessing human T cells to select antigens for vaccines
This article was originally published in Start Up
Executive Summary
Genocea Biosciences Inc. is one of a growing number of companies betting that it can stimulate the body’s T-cell response against particular antigens, and so create vaccines against pathogens never before bested by man, such as malaria, herpes and chlamydia. Like others working to develop new vaccines, Genocea suspects that the ability to conjure cellular immunity on demand could offer not only prophylaxis, but also therapeutic options to individuals already infected by pathogens. Many believe that T-cell-stimulating vaccines could eventually help people whose own cells have become cancerous.
161 1st Street
Suite 2C
Cambridge, MA 02139
Phone: (617) 876-8191
Web Site: www.genocea.com
Contact: Chip Clark, CEO
Industry Segment: Biotechnology
Business: Vaccine development
Founded: December 2006
Founders: Darren Higgins, PhD (Harvard University); Robert Paull (Lux Capital Management); Kevin Bitterman, PhD (Polaris Venture Partners)
Employees: 35
Financing To Date: $61 million
Investors: Polaris Venture Partners; Johnson & Johnson Development Corp.; Lux Capital Management; SR One; Skyline Ventures; Cycad Group; Auriga Partners; Morningside Ventures; Alexandria Real Estate Equities
Board of Directors: George Siber, MD, Chairman (formerly Wyeth Vaccines); Kevin Bitterman, PhD; Chip Clark; Dalton Einhorn (Johnson & Johnson Development Corp.); Simeon J. George, MD (SR One); Stephen J. Hoffman, MD, PhD (Skyline Ventures); Robert Paull
Scientific Advisory Board: George Siber; Darren Higgins; David Bernstein, MD (Cincinnati Children's Hospital); Robert Coffman, PhD (Dynavax Technologies); Patrice Dubois, PhD (ImmunoVac Consulting); Robert Finberg, MD (University of Massachusetts Medical School); Penny J. Hitchcock, DVM (Tauri Group); Peter Kiener, DPhil (Zyngenia); Adel Mahmoud, MD, PhD (Princeton University); Richard Malley, MD (Children's Hospital Boston and Harvard Medical School)
For more than 100 years, vaccines have been protecting individuals and societies from diseases caused by pathogens, including bacteria and viruses. In all this time, prophylactic vaccines have accomplished their noble goal primarily by stimulating the humoral arm of the immune system, which causes B cells to create antibodies that tag dangerous invaders for destruction. As yet, no one has managed to produce a vaccine that deliberately harnesses the other arm of the immune system: the cellular immune response that prompts specific types of T cells to identify and destroy diseased cells, and which also rallies cytokines to the cause.
Genocea Biosciences Inc. is one of a growing number of companies betting that it can stimulate the body’s T cell response against particular antigens, and so create vaccines against pathogens never before bested by man, such as malaria, herpes and chlamydia. This Cambridge, MA-based firm believes its approach could yield new vaccines that could complement some products long relied upon, like Pfizer Inc.’s blockbuster pneumococcal vaccine franchise Prevnar, and supercede others, like the current tuberculosis vaccine, widely acknowledged as weak. Like others working to develop new vaccines, Genocea suspects that the ability to conjure cellular immunity on demand could offer not only prophylaxis, but also therapeutic options to individuals already infected by pathogens. Many believe that T-cell-stimulating vaccines could eventually help people whose own cells have become cancerous.
Choosing antigens capable of rallying the body’s immune defenses in a robust, long-lasting way is the sine qua non of vaccine development – and precisely the reason why Genocea’s CEO Chip Clark is so bullish about his company’s prospects. “We think we are the only company with a platform for the T-cell antigen side,” he declares. Core technology developed by scientific founder Darren Higgins, a professor at Harvard University’s Harvard Medical School and previously at the University of California, Berkeley, allows Genocea to “recreate the human T-cell response in the laboratory” and then systematically evaluate antigens to find those best able to trigger a response. [See Deal]
Historically, vaccine developers have tried to figure out – first, empirically and in recent decades through molecular biology – which surface proteins antibodies (produced by B cells) latch onto in order to recognize and clear pathogens from the body. Those proteins then become the antigens around which vaccines are built, often with an adjuvant to further stimulate the immune response. It’s a good approach as far as it goes, which is plainly not far enough. Despite valiant efforts, scientists have been able to identify only a small number of surface proteins suitable for targeting pathogens.
Genocea’s method promises to dramatically expand the potential number of antigenic targets for nearly any pathogen, and then spotlight the best of these, because it deliberately mimics the way T cells are stimulated. Whereas B cells create antibodies against specific surface proteins, and once “programmed” produce the same antibodies against the same target over and over, the T cell response is both more diverse and more unique from human to human. T cells can form in response to nearly any protein that is taken up from a pathogen and presented on the surface of antigen-presenting cells by molecules known as the MHC or major histocompatibility complex.
“If you want to make a T-cell vaccine, you need to look at the entire proteome of a pathogen, not just a small number of surface proteins,” Clark asserts. The virus that causes influenza codes for approximately 11 proteins, he notes, “so you could probably guess or figure out which of those is the best with enough effort.” But the virus that causes genital herpes, HSV-2, codes for about 80 proteins, and chlamdyia for more than 1,000 and Streptococcus pneumoniae more than 2,200. “Trial and error won’t work,” Clark declares. “In order to figure out what proteins are triggering T-cell response, you need to look at it in a systematic way.” The challenge is further complicated, he explains, by the fact that genetic diversity in the MHC drives varied T-cell responses among human beings. There are now thought to be nine “supertypes” for one class of MHC, and “emerging” diversity in another class as well.
Clark believes Genocea is positioned to create vaccines that will work broadly with any pathogen, because it can assess the human immune response to antigens even before animal testing that FDA requires. Here’s how the approach works in early discovery: “For a given pathogen, we collect blood from hundreds of people who may have been exposed to it,” Clark explains. For HSV-2, for instance, the company collected blood from 200 human subjects exposed to it. Some of these individuals reported having a high number of annual outbreaks, others just a few. Still others had a documented infection but no apparent outbreaks subsequent to the initial one that earned the diagnosis. Genocea also took blood from individuals who generated a natural protective response to HSV-2. “We ran each protein from the HSV-2 proteome through each person’s antigen-presenting cells, to determine a per-person, per T-cell immune response,” Clark says. These individual arrays allow the company to make comparisons within clinical cohorts and across cohorts, and thereby identify T-cell antigens correlated in humans with protection. “We’ve now done this with several pathogens,” he says, and taken the best antigens on into animal testing.
“To the extent that one can rely on animal data, our HSV-2 vaccine candidate looks terrific in guinea pigs,” Clark claims. He says Genocea expects to present and publish data in the latter half of 2012, showing that the frequency and severity of symptoms, as well as asymptomatic viral shedding, were reduced in guinea pigs that had been infected with HSV-2, and then exposed to antigens selected by Genocea.
The company aims to begin a Phase I/IIa trial of a therapeutic HSV-2 vaccine candidate in the second half of 2012. If the FDA approves, Genocea will give its vaccine candidate to people who have HSV-2 infections but are otherwise healthy. Clark notes, “We’ll enroll people with relatively severe disease, so we can quickly measure effects on clinical symptoms,” as well as immune response by B and T cells, and of course overall safety. In theory, the goal is for the vaccine to stimulate T cells to intercept the herpes virus as it migrates to the skin during outbreaks. The company has designed its dosing regimen in hopes of providing lasting protection with just a few shots, but Clark acknowledges there is no way to tell until people are inoculated whether protection will last for a year or 10 years.
While many would-be vaccine developers emphasize the importance of delivery vehicles for antigens, Clark says Genocea is “agnostic to approach,” because the company believes its antigens will work with any of them. Currently, the company plans to use full proteins, because they are immunogenic and in some cases, people with different MHC types may respond to the same basic protein but different epitopes in it. The two antigens in the HSV-2 vaccine candidate are paired with a novel adjuvant created by Sweden’s Isconova AB.
Next in the pipeline is a vaccine candidate against pneumococcus, which causes dangerous invasive infections such as pneumonia and meningitis. The market for pneumococcal vaccine is already huge, and dominated by Prevnar-7 and Prevnar-13, which combined to earn about $4 billion for Pfizer last year alone. The vaccine does not prevent infection, but prevents it from causing disease. It was developed by Wyeth Vaccines, where George Siber, the chairman of Genocea’s board of directors, long served as chief scientific officer. Prevnar-13 elicits B-cell response to 13 strains of the bacteria most prevalent in the Western world, but Clark points out that there are in fact more than 90 strains.
“There is some fear that strains not covered by Prevnar will become more prevalent, and some evidence that has already started to happen,” says Clark, who suggests that Pfizer will have a hard time expanding its blockbuster vaccine to cover more strains. “Their vaccine is enormously complicated to make,” he points out, because it comprises synthetic versions of the polysaccharide shells of 13 bacterial strains, each conjugated separately to carrier molecules, and then combined.
Prevnar would be hard to usurp, given how successful and widely adopted it is, but Genocea is clearly contemplating doing just that. Clark says the company has assessed about 2,200 proteins expressed by pneumococcus, and has found some that are well-conserved across strains and that stimulate the T-cell response. “If these antigens work in humans, they could at least complement those that elicit the B-cell response in Prevnar and perhaps by working upstream lead to a vaccine to replace them,” Clark muses, noting that Genocea’s collaborator, Richard Malley of Boston Children’s Hospital, has produced “great” data in animals. [See Deal]
Genocea expects to get its pneumococcal vaccine into the clinic in late 2013, and Clark says the company, which presently has just 35 employees, may be able to take a regulatory path that could spare it direct competition with Prevnar and other competing products of Big Pharma. He explains that adults typically clear pathogens like pneumococci from their nasopharynxes with a particular kind of T cell, the Th27 CD4 T cell. Young children and elderly people have more difficulty clearing the bacteria, and marketed vaccines such as Prevnar have only modest impact on bacterial colonization in the nasal pharynx. Genocea’s animal data show that its vaccine candidate, based on conserved proteins, stimulates Th27 cells to reduce colonization. Human data supportive of that could be enough to win marketing approval for a vaccine candidate, Clark suggests. Prevnar was approved on the basis of an assays showing that it stimulates B cells to make antibodies, he says, “so it’s possible a vaccine with our antigens could also be approved with that kind of surrogate marker.”
For now, Clark recognizes that Genocea may need to generate human data to establish the credibility of its intriguing technology platform and attract commercial partners that can maximize the value of it. The company is deliberately hunting T-cell stimulating antigens from a range of pathogens, he says, to demonstrate the breadth of the platform. Ultimately, Genocea expects partners and investors will be won over by the power of a discovery platform that allows molecular details to be correlated with human clinical realities in previously unaddressed pathogens from the very start.
To date, Genocea has raised $61 million from investors including Polaris Venture Partners, Johnson & Johnson Development Corp., Lux Capital Management, SR One, Skyline Ventures, Cycad Group, Auriga Partners, Morningside Ventures and Alexandria Real Estate Equities. [See Deal][See Deal]