The race to develop a vaccine for the SARS-CoV-2 virus is progressing at an unprecedented speed and scale, with approximately 135 vaccines now in development worldwide.

Unlike most races, however, the goal here is not to produce one winner, but to identify and accelerate all of the most promising candidates into production.

This was one of the key messages from vaccine experts at a recent Grand Rounds session co-hosted by the Departments of Medicine at Massachusetts General Hospital and Beth Israel Deaconess Medical Center (BIDMC).

"There are seven billion people in the world, so we need multiple vaccines to be successful. This is not a race of one developer against another developer—this is a global collaborative effort," said Daniel Barouch, MD, PhD, director of the Center for Virology and Vaccine Research at BIDMC. "I probably speak for all the vaccine developers in saying we want all these programs to succeed."

At Mass General, there are at least three different vaccine development projects underway—each employing a different scientific strategy.

A team from the Vaccine and Immunotherapy Center (VIC) led by Mark Poznansky, MD, PhD, is developing a vaccine using their VaxCelerate platform, which was developed with funding from the Defense Advances Resources Projects Agency (DARPA).

Bruce Walker, MD, director of the Ragon Institute of MGH, MIT, and Harvard, received funding from the Massachusetts Consortium for Pathogen Readiness to develop a "highly networked, exosome-based SARS-CoV-2 vaccine."

Mason Freeman, MD, director of the Translational Research Center at Massachusetts General Hospital, is collaborating with investigators at Mass Eye and Ear on a gene therapy-based vaccine.

Dr. Freeman was one of three investigators featured at the recent Grand Rounds session along with Barouch and Lindsey Baden, MD, director of Clinical Research at Brigham and Women's Hospital.

Laying the Groundwork

Barouch, who is also an investigator at the Ragon Institute of MGH, MIT and Harvard, kicked off the session by discussing preclinical research he has done to investigate two questions crucial to successful vaccine development:

  1. Is there evidence of natural protective immunity to SARS-CoV-2 after an individual has been infected and recovered?
  2. Is there evidence that a vaccine can induce immunity in subjects who have not been exposed to the virus, and if so, what does that look like in terms of types and numbers of antibodies?

Barouch recently published a proof-of-concept study showing that rhesus macaque monkeys who were exposed to the SARS-CoV-2 virus and subsequently recovered fared much better during a second exposure compared to monkeys who were exposed for the first time. The monkeys with past exposure to the virus had little or no detectable levels of virus in their lungs when compared to those being exposed for the first time.

In a second study, Barouch demonstrated that prototype DNA vaccines expressing six different spike proteins from the SARS-CoV-2 virus were able to induce an immune response in rhesus monkeys without previous exposure to the virus, and that the vaccine expressing the full-length spike protein on the SARS-CoV-2 virus provided optimum protection.

“In both cases, it is likely that protection is not sterilizing—which is true for most respiratory vaccines that we know of—but is likely mediated by rapid immunologic control following the challenge," he said.

While these results are encouraging, the results need to be replicated in humans, Barouch said. Monkeys do not develop a severe form of COVID-19 disease like humans do, so their immune response is not necessarily parallel.

A Wide Range of Approaches

Freeman then discussed the size and scale of the worldwide vaccine effort.

About a third of the vaccines in development are using a protein subunit approach in which proteins that are unique to the virus are introduced to the body via RNA or DNA constructs.

About 10% of the vaccines in development are using a more traditional approach, which employs a weakened or inactive form of the virus.

Nearly half of all the vaccines under development are using gene-editing technology that is designed to prompt the body's own cells to start making viral proteins, so the immune system can learn to recognize and neutralize them.

“This is certainly a big change from the vaccines that many of us would have grown up with where this kind of gene transfer technology didn’t exist,” Freeman said.

Freeman is collaborating with Luk Vandenberghe, PhD, from the Grousbeck Gene Therapy Center at Mass Eye and Ear on AAVCOVID, a gene-therapy vaccine that uses the adeno-associated virus (AAV) as a vector to deliver genetic sequences of the SARS-CoV-2 spike antigen.

AAV technology has been used extensively in the field of gene therapy and two AAV-based drugs have been approved by FDA in recent years.

One key advantage of the AAV platform is its scalability—one run of this vaccine produces a million doses of the vaccine, which is very attractive given the need to develop the vaccine on a large scale, Freeman said. The AAVCOVID team is hoping to start first-in-human trials at Mass General by the end of the summer.

Key Questions Remain

Baden highlighted some of the key questions that researchers are trying to answer as they continue to work towards a vaccine.

The SARS-CoV-2 virus has only been infecting humans for less than a year, so we still don't know how long immunity lasts after an infection, or what immune protection looks like in terms of the types and numbers of antibodies, he said.

Another question is what endpoint vaccine developers should be working towards—is it to prevent SARS-CoV-2 infections entirely, or to limit the effects of COVID-19, the disease caused by the virus?

In the preclinical studies conducted by Barouch, COVID-19 disease was prevented but it appeared that SARS-CoV-2 infection was not, Baden noted.

"Ultimately, we'd like our patients not to get sick and not to have significant morbidity and the consequences of hospitalization, intubation and ICU care, so [protecting against] disease is critically important."

There are also questions related to the risks/benefits of accelerating vaccine development, Baden said. Vaccine developers do not want to compromise safety for the sake of speed, but it may be possible to save time by ramping up manufacturing while efficacy trials are still being completed if sponsors are willing to take a financial risk.

"I think that the rate at which we're doing the development is quite remarkable," Baden said. "We all wish we could do it faster, but speed does not diminish the importance of safety."

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Image info: 3D print of a spike protein of SARS-CoV-2—also known as 2019-nCoV, the virus that causes COVID-19—in front of a 3D print of a SARS-CoV-2 virus particle. The spike protein (foreground) enables the virus to enter and infect human cells. On the virus model, the virus surface (blue) is covered with spike proteins (red) that enable the virus to enter and infect human cells. For more information, visit the NIH 3D Print Exchange at Credit: NIH