One Year In: Vaccines

COVID-19 vaccine experts talk lessons learned, challenges ahead

By STEPHANIE DUTCHEN Research
Two women in white coats and surgical masks hold syringes labeled "COVID-19 vaccine"
Staff at Brigham and Women’s Hospital prepare to administer COVID-19 vaccine doses. Image: James Rathmell

This article is part of Harvard Medical School’s continuing coverage of medicine, biomedical research, medical education, and policy related to the SARS-CoV-2 pandemic and the disease COVID-19.

In the last 12 months, COVID-19 has overturned both individual lives and national economies.

Yet the pandemic has also sparked advances in scientific knowledge, treatments, and vaccines at a pace never before seen. Instead of the usual five to 10 years, the first clinical trial of a vaccine against SARS-CoV-2 began a mere six months after scientists sequenced the virus's genome.

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Two vaccines so far have been authorized for emergency use by the U.S. Food and Drug Administration. More than 31 million doses have been distributed and more than 12 million have been administered to people as of Jan. 15, according to the CDC. Doctors and researchers are studying 68 additional vaccine candidates in human clinical trials around the world.

Among those who have pushed the boundaries of vaccine science to address the global health crisis are the researchers at Harvard Medical School, in the greater Boston area, and at Guangzhou University in China who came together last March to form the Massachusetts Consortium on Pathogen Readiness, or MassCPR.

As the first anniversary of MassCPR approaches, Harvard Medicine News spoke with the co-leads of its vaccine working group about the striking accomplishments in COVID-19 vaccine development, what we’ve learned so far, and what lies ahead.

Head shot of a man in a white coatCo-lead Dan Barouch, the William Bosworth Castle Professor of Medicine at HMS and director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center, designed a vaccine platform that delivers the SARS-CoV-2 spike protein in deactivated adenovirus (common cold) shells and trains the immune system to recognize the invader. He conducted the lab dish and animal model studies that established the promise of the vaccine, called Ad26, and is now co-running an international clinical trial in conjunction with Johnson & Johnson.

Head shot of a manCo-lead Andrea Carfi is vice president and head of research for infectious disease at Moderna, a Cambridge-based biotechnology company that developed one of the FDA-approved COVID-19 vaccines. That vaccine stimulates immunity using messenger RNA (mRNA), which teaches cells to make and attack harmless pieces of the SARS-CoV-2 spike protein so the body is primed to fight future infection.

HM News: In a nutshell, what has the working group been doing over the past year?

Barouch: The working group is a discussion forum for outstanding scientists in academia, industry, and other areas with expertise in all aspects of COVID-19 vaccines. We meet online every two weeks to discuss the latest advances in immunology, virology, and vaccine science as well as vaccine development, regulatory approvals and distribution, ethics, and social-political-societal dimensions.

Andrea and I keep the group up to date with the Moderna and J&J vaccines; Luk Vandenberghe shares news about his AAV [adeno-associated virus] vaccine; and there are some protein-based vaccines people have been working on. There’s been a lot of vaccine science and immunology: Bruce Walker has his sample acquisition cohort, Steve Elledge has VirScan to look at viral epitopes, Galit Alter has systems serology. Many people are involved in vaccine immunology, which dovetails with vaccine development.

And there are many other topics. We have a philosopher and ethicist who’s been active in framing questions about human challenge models [clinical trials in which willing participants are deliberately exposed to COVID-19], equitable vaccine distribution, racial and ethnic issues, how to recruit participants into trials, and vaccine skepticism. We talk about some of the political issues and the international side of vaccination. Equity has been a major topic within our group and in the field as a whole in the past year and doubtless will be in the coming year as well.

HM News: How is this different from how science normally works?

Carfi: People are more willing to share research and resources without thinking about the priority of publication or being scooped. I’ve been impressed by people’s openness in sharing data and collaborating. This is reflected in publications with many different labs involved. Dan and I had never worked together before, and now we have a review paper coming out in March. People know more about what other groups are doing. We have greater insight into the field’s progress and challenges. It’s been very productive.

If we can keep people this engaged, we will have an advantage in the future for other viruses, vaccines, and pandemics.

Barouch: Part of the community spirit has been based on the tremendous need for understanding a brand-new virus and the sheer global urgency to develop treatments and vaccines. That commonality of purpose brought people together in a way I’ve never seen. It’s the same on an international scale and in other COVID-related communities focused on therapeutics, pathogenesis, politics, implementation, and so forth. The enormity of the challenge and the sense of shared purpose has certainly facilitated sharing of unpublished data and plans.

HM News: Alongside this spirit of collaboration and sense of urgency, what do you think has contributed to vaccines against COVID-19 being developed in record time?

Carfi: There was large investment and commitment by government, regulatory agencies, and the academic community, including Harvard. We are talking both financial and intellectual resources. Being able to share infrastructure, labs, and animal models helped us move quickly.

All these vaccines couldn’t have moved to the clinic without having the basic science understanding behind them. Safety comes first, and a lot of experiments and preclinical data needed to be generated about how these new platforms—mRNA and adenovirus delivery—act at the molecular level. You need to know what you’re doing. Science provides the base to advance, and to advance quickly.

HM News: Does success in the COVID-19 realm mean we’ll see other vaccines reach fruition faster in the future?

Barouch: Going from gene sequencing to completion or near completion of phase 3 in a year is really unprecedented. It is possible to do again, but there has to be an enormous, urgent global need and a huge number of resources available. Under normal circumstances, there wouldn’t be those two factors. I also don’t think it’s humanly possible to sustain this level of intensity on a continuous basis.

That said, the mechanisms of collaboration where people see that talking to one another and sharing information leads to better outcomes for everyone will have long-lasting implications.

I think vaccine development won’t go as slowly as before. People won’t present to a company’s boardroom with a 10-year timeline. The COVID-19 vaccines will change how the vaccine world operates.

Carfi: I agree that it’s a special feature of the pandemic. The crisis brought everyone together to tackle the same question. The hope is that that collaboration will continue, both because I don’t think COVID is going away in a few months, and because we hope to expand [our new communal philosophy] to other research areas. We’ve created a team that hopefully can be applied in future.

Barouch: Our hope is certainly that elements of the MassCPR collaboration and infrastructure can be there for the next pathogen that comes through.

The COVID-19 vaccines will change how the vaccine world operates. 

Dan Barouch

William Bosworth Castle Professor of Medicine, HMS

HM News: Will vaccines be the end of the COVID-19 story?

Barouch: You need to have a whole lot of people get vaccinated for the story to be over. It has to be done quickly, and it has to be done before there are resistant variants of the virus that can escape vaccines, which, as we’ve seen recently, is a concern. More SARS-CoV-2 variants will emerge in the coming months. Some of those variants will arise because as we introduce more vaccines, there will be more selection pressure on the virus to escape them. We’re definitely not in a position to claim victory yet. We’re in the beginning of the next chapter.

HM News: Can you talk more about the problems posed by new SARS-CoV-2 variants and how they can be addressed?

Barouch: Once there are reports of new variants, they become part of the discussion at the next working group meeting. Some of the new variants look like they have the potential to circumvent dominant antibody responses, but the jury is still out. When a new variant appears, members of our group and others will do—and in fact are already doing—basic research to look at things like whether the variant evades the antibodies induced by infection or vaccination.

Then people will have to decide what the threshold is for remaking one or more vaccines. That’s a much more difficult question when hundreds of millions of doses have already been made. Whatever the criteria are, they should be based on data and should become standard across companies.

Basic research will continue, because when any new issue arises, whether it’s related to a variant or vaccine safety or immunology, we need to learn about it, and basic research is learning. The working group’s sweet spot is to do experiments and discuss and learn. We use the discovery process to generate knowledge and respond to changing conditions. The big companies then can take a product and run with it.

HM News: What other challenges concern you when it comes to COVID-19 vaccines and vaccinations?

Carfi: Right now, my main concern is vaccine access, distribution, and acceptance. The logistics of mass vaccination in a short amount of time are more complex than we expected.

Barouch: We need as many vaccines as possible deployed as fast as possible. The world will be a better place if we can get all 7 billion people vaccinated.

HM News: If you could go back one year, would you do anything differently?

Barouch: These vaccines were made faster than any in history, but is there a way we could have gone faster, done more? How good would it have been if we could have had vaccines come out in August or September instead of December or January? We’re experiencing 4,000 deaths a day [in the U.S.]. We could have saved countless lives. If we could have vaccinated people in the summer, before the winter surge, we might have prevented the emergence of variants that have the potential to undermine vaccines.

Still, I don’t think there’s any finger-pointing. For every person who said vaccine development wasn’t going fast enough, there was someone who said it was too fast.

Carfi: You do as much as you can. I wish we could have done more testing, for example including younger populations in our clinical trials, but at the same time we didn’t have infinite resources, and already what we pulled off was at the limit of what we could’ve done. We must focus on preparing for the next pandemic. A lot about COVID-19 exposed our weaknesses in terms of preparedness. We don’t have a system in place to monitor and quickly identify viral variants.

All these vaccines couldn’t have moved to the clinic without having the basic science understanding behind them.

Andrea Carfi

Vice president and head of research for infectious disease, Moderna

What has been done is very positive and we are happy. We should all be happy that we’re seeing vaccines being used. We’ve advanced vaccine technologies. We’ve made some progress in public education about how vaccines are developed and tested and why they’re important and safe, although there’s still a lot to do.

HM News: Rare allergic reactions to the vaccine have been covered heavily in the news. What would you say to people who are worried?

Carfi: These vaccines have been tested in large phase 3 clinical trials. Moderna’s included more than 30,000 participants. There is a very good record of safety with no serious adverse events. From all the data, the vaccine is safe and efficacious. There will be rare events for any vaccine. The good news is that so far, all have been treatable.

HM News: What about proposed policies in some countries to deviate from protocols established in vaccine trials, such as reducing doses to make the supply stretch further?

Barouch: We do clinical trials to establish knowledge of safety and efficacy. If there’s a deviation in the dose or interval or boosting reagent, then you’re in an area of no knowledge. For a clinical rollout, I don’t think you should deviate from what’s been proven to work. Mixing and matching vaccines may be safe, and it may be immunogenic, but that should be established in clinical trials. That’s what they’re for. It’s better to go with what we know is safe and what works.

Carfi: Any change introduces a level of risk. We have to be careful going into unproven territory.

HM News: What do we know about the vaccines’ effect on preventing SARS-CoV-2 infection versus preventing an infection from progressing to disease or severe disease?

Carfi: We know the vaccines prevent disease and prevent severe disease. We will learn in the next months if they also have impact on infection. If they do, that would have impact on transmission. The initial data suggest there is some impact.

We’re definitely not in a position to claim victory yet. We’re in the beginning of the next chapter. 

Dan Barouch

HM News: What has been the most exciting part of the process for you?

Carfi: Moving from gene sequence to clinical trial in 63 days was amazing. Then, seeing the first data suggesting that the mRNA was working in humans was not only exciting but also an important milestone. It’s been mind-blowing to see a technology that only a few people believed would become a reality have such an impact on the vaccine field and therapeutics. When we started this project, probably around 2,000 to 3,000 research participants had received mRNA. Now that number is in the millions. Soon it will be in the hundreds of millions. And of course, it was exciting to achieve an efficacy of 95 percent in our phase 3 trials when the goal had been 50 percent.

Barouch: Every step of the way has been important and exciting. Seeing different vaccine technologies go from largely experimental platforms to having the potential for major global health impact is tremendously exciting. The Moderna vaccine is going to make 500 million to 1 billion doses. If it’s successful, the Ad26 vaccine we’re trialing will have 1 billion doses. The Pfizer-BioNTech, AstraZeneca, and NovaVax vaccines are aiming for similar numbers. Together with vaccines from maybe China, Russia, and other nations, the goal is to get as close as possible to vaccinating the world.

This interview was edited for length and clarity.