John Mascola, M.D., didn't expect to be here this long. But now it's been 22 years—spanning the full length of the National Institutes of Health's (NIH's) Vaccine Research Center's (VRC's) existence—and he's preparing to hand over the keys to the “NASA-type incubator."
Mascola, who to date has worked his entire career in public medicine and vaccinology, is leaving his post as director of the VRC at the end of the week. Since joining the center first as a founding investigator when it launched in 2000, he’s progressed research on an HIV vaccine and helped develop an Ebola treatment. But his crowning achievement may be his most recent: overseeing the center’s collaboration with Moderna on a COVID-19 vaccine.
“There are so many highlights,” he said in an interview with Fierce Biotech, ultimately deciding that the main one was seeing the center “grow to fulfill its original mission,” which was to be a translational R&D hub.
“And to see that come to fruition and to see products actually be developed that have an impact is probably the most gratifying.”
To understand Mascola’s professional mission is to understand the founding principles of the center itself. After graduating from Georgetown University School of Medicine, he completed a fellowship in infectious disease with the U.S. Navy followed by another in retroviral diseases at the Walter Reed Army Institute of Research (WRAIR). He continued his work at WRAIR for seven years as a research physician focused on HIV immunology and vaccine development before landing at the VRC.
Concurrent with Mascola’s early career, President Bill Clinton was looking to redouble the government’s efforts to develop an HIV vaccine. The president called on a new national goal for the U.S. to develop the shot in a decade, which included plans to launch a new dedicated vaccine research center, in an April 1997 speech. Thus, the center was born.
Fast-forward more than two decades, and the pitfalls of scientific development are clear as day: We still don't have an HIV vaccine. Mascola acknowledges that a shot to protect against the HIV pathogen has proven to be “one of the most difficult vaccines to develop.” The latest effort designed by VRC failed to sufficiently protect women from infection, according to a primary assessment released last fall.
The field is no where near dormant, however. A new crop of vaccine candidates have come forward from Moderna, Johnson & Johnson and others in recent years.
“But certainly the research and development, the technologies, the insights for HIV had a huge impact on other diseases,” he said. “So I have viewed the overall impact of HIV research and development … to almost be a NASA-type incubator for the field of vaccinology.”
The result of this shift—from being unilaterally focused on HIV to incorporating other diseases—has made the VRC part-academic research center, part-medium-sized biotech, according to Mascola. As evidence of that, he emphasized the VRC’s work partnering with other biotechs, a staple of the industry but something that’s more foreign to federal health institutions, which usually revolve around grants and research funding. In 2018, the VRC licensed out its monoclonal antibody treatment for Ebola to Ridgeback Biotherapeutics, which was subsequently approved by the FDA two years later.
But the backbone of the center has always been vaccines, and one of the most consequential recent developments in virology came from the VRC and former Deputy Director Barney Graham M.D., Ph.D. Graham, alongside Peter Kwong, Ph.D., and then-postdoc Jason McLellan, Ph.D., figured out how to design a version of a critical respiratory syncytial virus protein before it fused with cells. They hypothesized that if you could attach the prefused version to a vaccine molecule, the body may respond better. The result of that new structure, published in a 2013 Science article, was a significantly more robust immune response. The findings have since become the basis for recent vaccine developments, including shots developed by GlaxoSmithKline and Pfizer.
Graham and McClellan continued to tinker with this method, using it to design a vaccine for Middle East respiratory syndrome. And in 2020, Graham, in partnership with Kizzmekia Corbett, Ph.D., partnered with Moderna to design their COVID vaccine, which eventually came to be called Spikevax. Mascola says the fact that this success came just before the pandemic is a sprinkle of luck that was dusted upon the record-fast development of the COVID shots.
“So you have the RNA on one side, you have years of structure-based design—a lot of which was really empowered by HIV—that were coming together and were available really not much earlier than 2019, 2020 to be tapped for COVID,” he said.
Who invented the shot?
Since first being authorized more than 15 months ago, the Moderna shot has proven to be one of the most effective, currently boasting the lowest COVID death rate among the three FDA-authorized and approved vaccines. Due in part to its efficacy, the global demand for the jab is eclipsing supply, an expected outcome that global health equity experts warned about as the shots were being developed.
It’s a dilemma that’s caused a schism to form between the VRC and Moderna over who invented the vaccine, thus informing who can make decisions regarding the vaccine’s intellectual property. The implications are wide-ranging, with less-developed nations asking for international IP rights to be waived so that generic versions can be quickly manufactured. In theory, if the VRC researchers were considered “co-inventors," they’d have more influence in IP decisions. But in an August 2021 filing to the U.S. Patent and Trademark Office, Moderna claimed Mascola, Graham and Corbett did not “co-invent” the shot.
The Cambridge-based biotech has since backed off that statement, saying in December 2021 that it was no longer pursuing issuance of the patent to continue working out a resolution with the NIH.
Mascola did not comment when asked where discussions with Moderna stood but said the relationship between the two organizations remains “very productive." He added that even amid the dispute, the success of the shot proved that public-private partnerships can be fruitful.
“There were ups and downs and not everything was perfect, but in the end, I think the system worked, both on the public side and the private side,” he said.
But the exact virus that was circulating when the vaccine was first developed is not the same one that’s now widely circulating. It’s mutated and evolved, updating itself and the formidable spike protein to be more transmissible and evade immune protection. The omicron subvariant BA.2, now the globe’s most dominant version of the virus, is roughly 30% more transmissible than BA.1, which wreaked havoc worldwide over the winter. The rapid evolution of the virus has prompted calls for the vaccines themselves to be specifically tailored to the omicron variant, which the major manufacturers have been preparing. Mascola cautions we might not quite be there yet.
“It would be ideal if you had a vaccine that was good enough with one shot or two, but that's not where we are right now,” he said, noting that much of the world (and almost all of the U.S.) has some level of pre-existing immunity either through infection or vaccination. Mascola also said that we take for granted that additional doses with the current vaccines not only boosts immunity but broadens it.
“The current data suggests that if we were to boost with omicron, it wouldn’t necessarily be better overall,” he said. The debate comes as the FDA authorized an additional booster dose for Americans 65 and older and those 50 and older with compromised immune systems just yesterday.
Irrespective of present and future debates, Mascola is looking forward to new endeavors. He acknowledged finalizing an opportunity to join the industry following a break, although he wasn’t ready to disclose a specific company yet, hinting: “I certainly look forward to staying in vaccines and related work.” He added that now felt like the right time to leave after being able to see the VRC live out its promise.
“I certainly wanted to make sure that the vaccine center had grown and fulfilled some of its potential and, along with my many colleagues, I think we’ve done that.”