'The Ultimate Quest'

Need for speed

Whereas vaccine development typically takes five to 10 years, the first phase 1 clinical trial of a vaccine against SARS-CoV-2 began only six months after the virus's genome was sequenced in mid-January. (Phase 1 of a clinical trial aims to establish safe dosages.)

"It's fast, but we need to be as fast as this virus is," said infectious disease and vaccine specialist Lindsey Baden, HMS associate professor of medicine at Brigham and Women’s Hospital.

Baden is co-principal investigator of the first phase 3 clinical trial of a COVID-19 vaccine candidate, which launched nationwide July 27 in partnership with the National Institutes of Health. (Phase 3 trials compare the safety and efficacy of experimental therapies to standard-of-care treatments.)

Baden and other speakers stressed that safety remains the top priority, despite accelerated timelines based on the urgent need for a vaccine. They also noted that the best strategy for eradicating the virus as quickly as possible is to explore many different types of vaccine candidates at once—and even to take the financial risk of ramping up manufacturing ahead of trial results, so that any vaccines that receive FDA approval will be poised for broad distribution.

As for when the first vaccine—or vaccines—may become available, the researchers echoed other experts in proposing that early 2021 would be an optimistic but not impossible timeline.

In the absolute best case, a vaccine could be approved for limited, emergency use in late fall 2020, said Dan Barouch, the William Bosworth Castle Professor of Medicine at HMS, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center and co-leader of the MassCPR vaccine development arm. But "a tremendous number of things would have to go perfectly" for that to happen, he said.

Given that it takes one to two months for vaccines to reach full effect in the body and that it's not always possible to predict where and when COVID-19 cases will arise, "The end of the year would be quite a surprise to have had enough infections [among trial participants] to show efficacy," agreed Kenneth Mayer, professor of medicine at HMS and medical research director and co-chair of the Fenway Institute.

Mayer added that it might be possible to safely shorten future vaccine trials based on findings from the first round of trials, such as administering single doses rather than current strategies of two doses spaced days or weeks apart.

Angles of attack

Arlene Sharpe, faculty co-leader of MassCPR and chair of the Department of Immunology in the Blavatnik Institute at HMS, gave an overview of natural and vaccine-induced immunity. She described how four major types of vaccines work:

• Genetic vaccines, such as DNA and messenger RNA vaccines, use one or more viral genes to stimulate an immune response.
• Viral vector vaccines use a harmless form of another virus, such as a common-cold adenovirus, to deliver viral genes into cells and stimulate the immune system.
• Protein-based vaccines use whole proteins or protein fragments from the virus to stimulate an immune response.
• Whole-virus vaccines use a weakened or inactivated form of the virus that doesn’t cause disease but still stimulates an immune response.

Speakers then provided updates on several trials currently or imminently taking place in the HMS and MassCPR communities and beyond.

Baden spoke about the Phase 3 trial that had begun just the day before at sites including Brigham and Women's. That team is studying a messenger RNA vaccine: a lipid nanoparticle that is injected into muscle and taken up by cells in the body, which then produce antigens on their surfaces that alert B and T cells in the immune system to mount defenses. The vaccine candidate is made by the pharmaceutical company Moderna.

Barouch spoke about promising work from his lab and collaborators indicating that both natural infection with SARS-CoV-2 and inoculation with a DNA vaccine that incorporates material from the virus's spike protein reduced virus levels in the lungs of rhesus macaques and protected against reinfection.

Two days after the briefing, Barouch's group announced in Nature that a single dose of the latest version of the experimental vaccine, which uses an adenovirus called Ad26 to deliver the coronavirus spike protein, stimulated the macaques' immune systems to produce antibodies that neutralize SARS-CoV-2. He said his group hopes to enter human trials this fall. The vaccine candidate is made by Johnson & Johnson, which has committed to producing 1 billion doses without profit.

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Nicole Frahm from the Bill and Melinda Gates Medical Research Institute described efforts to produce protein-based vaccines that include adjuvants: substances that can boost, diversify and prolong immune responses. Protein-based vaccines and adjuvants are the best strategies for supplying vaccines in low-resource settings around the world, Frahm said. The key is to find the Goldilocks amount of adjuvant that doesn't under- or overstimulate the immune response, she said.

Along with a trial being run by Oxford University and AstraZeneca, the studies Baden and Barouch are involved in are part of Operation Warp Speed, a COVID-19 diagnostic, treatment and vaccine acceleration program administered by the U.S. Department of Health and Human Services. The program aims to enroll up to 150,000 people in COVID-19 vaccine efficacy trials by the end of 2020, Mayer said.

The program represents only a few of the more than 170 vaccine candidates that researchers around the world are currently exploring, ranging from preclinical studies to clinical trials.

But vaccines won't help if they aren't effective in and available for all populations—or if people choose not to get vaccinated.

All or none

"We can only know how a vaccine works in the people who are studied," said Baden.

Clinical trials must include diverse participants to ensure that vaccines are safe and effective across populations, whether Black or white, old or young, said Bisola Ojikutu, assistant professor of global health and social medicine at HMS and assistant professor of medicine at Brigham and Women's.

Diversifying trials is especially important given that SARS-CoV-2 has caused disproportionate infection rates, more severe disease and more deaths among groups historically underrepresented in medical research in the U.S., specifically Black, Latinx and Native Americans, Ojikutu pointed out.

"Diversity in clinical trials is both scientific common sense and it promotes social justice," she said.

Ojikutu and others also worry that even if trials include a sufficient variety of participants and vaccines are ultimately approved, vaccination rates will still be low among marginalized populations. Recent surveys and past experiences with vaccines for other diseases suggest that Black and Latinx people will be less likely to get vaccinated against SARS-CoV-2 than white people, she said.

Ojikutu outlined barriers that patients and clinicians face, both individual and systemic, from cost and lack of access to longstanding mistrust in the medical establishment stemming from infamous ethical breaches as well as more subtle forms of discrimination.

She cited an op-ed she co-authored in June outlining concrete steps that clinicians and researchers can take to increase trial diversity and vaccine uptake among Black and Latinx groups.

The first step, she said, is to acknowledge the problem.

There are also broader concerns about global equity, the speakers said. For instance, asked Baden, will the first U.S. manufacturer of a COVID-19 vaccine be expected to produce 320 million doses to cover the nation—or 7.8 billion to cover the world?

"Do we serve ourselves if we don't protect everybody?" Baden asked.

Frahm noted that SARS-CoV-2 infections are rising in so-called low- and middle-income countries, making low-cost approaches critical for ensuring global vaccine access. Her group is working to overcome hurdles such as cost and the need to store many vaccines in refrigerators and freezers en route to communities.

"Our goal is sustainability rather than speed" to ensure that people in low-resource areas can get vaccinated, she said.

The final challenge then becomes balancing vaccine uptake—the number of people who can and choose to get vaccinated—with the effectiveness of the vaccines themselves, the speakers said.

Although an ideal vaccine would be 99 percent effective against the virus, one with less potency could still make a huge advance in the fight, said Barouch.

"Even 60 to 70 percent effectiveness could achieve herd immunity and stop the pandemic," he said.

Public health officials could supplement a lower-efficacy vaccine with other prevention methods to maximize community protection, added Baden.

But the math only works if enough people get the vaccine, speakers said.

"Uptake matters," said Baden. "Even if we have a 90 percent effective vaccine but only 30 or 40 or 50 percent of people use it, we still have a problem."

Although some people cannot get vaccinated or decide not to, there are opportunities to address the concerns of those still on the fence, said Ojikutu.

"There's room [to intervene] where people are unsure," she said.

The road ahead

As vaccine development races onward, researchers are addressing the uncertainties that arise.

At the top of people's minds is the question of what defines a "successful" vaccine strategy.

"Is our goal to prevent COVID illness?" asked Baden. Is it to reduce illness severity? To reduce death? To prevent infection? All of the above? More? "There are different ways to determine success," he said.

Other questions abound:

• Does natural immunity, acquired after SARS-CoV-2 infection, protect against reinfection?
• Will vaccines also induce immunity? If so, what biological mechanisms will they invoke? Will different vaccine platforms work in the same way?
• How long will a vaccine dose be effective? Will SARS-CoV-2 develop different strains, requiring a strategy akin to the seasonal flu vaccine?
• Does a particular vaccine work differently in different populations? Will different age groups require different doses?
• Since antibodies against SARS-CoV-2 appear to diminish after infection or illness, does that mean they continue to dwindle? Does it mean a vaccine would also quickly wear off?

That last question, at least, has a hopeful answer: A decline in antibodies is normal in the first few months after many types of infections, said Barouch.

The issue is whether SARS-CoV-2 antibodies stabilize after the initial drop and whether those remaining antibodies last a long time, he said.

"That is critical information we don't yet have," he said.

As these and other uncertainties swirl, it's important to remember that "we are only months into knowing this virus," said Baden. "Our understanding of the biology and the durability of the biology will take time."

"There is cause for optimism, yet it must be tempered with caution," said Daley. "Long-term, a vaccine is our best chance for ending the pandemic, but it’s unlikely to be a silver bullet for the disease itself."

Those engaged in the fight against SARS-CoV-2 can learn from the successes and failures of past vaccines as well as from vaccine uptake campaigns, the speakers said.

In closing, Bruce Walker, faculty co-leader of MassCPR and the Phillip T. and Susan M. Ragon Professor of Medicine at HMS, reminded attendees that although treatments and vaccines offer the greatest hope for conquering COVID-19, people do not need to wait for study completion to protect themselves and others from the disease.

"There is a way to prevent infection now, today," he said, "and that is to wear masks."