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Meet the Researcher Leading NIH’s COVID-19 Vaccine Development Efforts

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A Conversation with John Mascola

A safe, effective vaccine is the ultimate tool needed to end the coronavirus disease 2019 (COVID-19) pandemic. Biomedical researchers are making progress every day towards such a vaccine, whether it’s devising innovative technologies or figuring out ways to speed human testing. In fact, just this week, NIH’s National Institute of Allergy and Infectious Diseases (NIAID) established a new clinical trials network that will enroll tens of thousands of volunteers in large-scale clinical trials testing a variety of investigational COVID-19 vaccines.

Among the vaccines moving rapidly through the development pipeline is one developed by NIAID’s Dale and Betty Bumpers Vaccine Research Center (VRC), in partnership with Moderna, Inc., Cambridge, MA. So, I couldn’t think of a better person to give us a quick overview of the COVID-19 vaccine research landscape than NIH’s Dr. John Mascola, who is Director of the VRC. Our recent conversation took place via videoconference, with John linking in from his home in Rockville, MD, and me from my place in nearby Chevy Chase. Here’s a condensed transcript of our chat:

Collins: Vaccines have been around since Edward Jenner and smallpox in the late 1700s. But how does a vaccine actually work to protect someone from infection?

Mascola: The immune system works by seeing something that’s foreign and then responding to it. Vaccines depend on the fact that if the immune system has seen a foreign protein or entity once, the second time the immune response will be much brisker. So, with these principles in mind, we vaccinate using part of a viral protein that the immune system will recognize as foreign. The response to this viral protein, or antigen, calls in specialized T and B cells, the so-called memory cells, and they remember the encounter. When you get exposed to the real thing, the immune system is already prepared. Its response is so rapid that you clear the virus before you get sick.

Collins: What are the steps involved in developing a vaccine?

Mascola: One can’t make a vaccine, generally speaking, without knowing something about the virus. We need to understand its surface proteins. We need to understand how the immune system sees the virus. Once that knowledge exists, we can make a candidate vaccine in the laboratory pretty quickly. We then transfer the vaccine to a manufacturing facility, called a pilot plant, that makes clinical grade material for testing. When enough testable material is available, we do a first-in-human study, often at our vaccine clinic at the NIH Clinical Center.

If those tests look promising, the next big step is finding a pharmaceutical partner to make the vaccine at large scale, seek regulatory approval, and distribute it commercially. That usually takes a while. So, from start to finish, the process often takes five or more years.

Collins: With this global crisis, we obviously don’t have five years to wait. Tell us about what the VRC started to do as soon as you learned about the outbreak in Wuhan, China.

Mascola: Sure. It’s a fascinating story. We had been talking with NIAID Director Dr. Anthony Fauci and our colleagues about how to prepare for the next pandemic. Pretty high on our list were coronaviruses, having already worked on past outbreaks of SARS and MERS [other respiratory diseases caused by coronaviruses]. So, we studied coronaviruses and focused on the unique spike protein crowning their surfaces. We designed a vaccine that presented the spike protein to the immune system.

Collins: Knowing that the spike protein was likely your antigen, what was your approach to designing the vaccine?

Mascola: Our approach was a nucleic acid-based vaccine. I’m referring to vaccines that are based on genetic material, either DNA or RNA. It’s this type of vaccine that can be moved most rapidly into the clinic for initial testing.

When we learned of the outbreak in Wuhan, we simply accessed the nucleic acid sequence of SARS-CoV-2, the novel coronavirus that causes COVID-19. Most of the sequence was on a server from Chinese investigators. We looked at the spike sequence and built that into an RNA vaccine. This is called in silico vaccine design. Because of our experience with the original SARS back in the 2000s, we knew its sequence and we knew this approach worked. We simply modified the vaccine design to the sequence of the spike protein of SARS-CoV-2. Literally within days, we started making the vaccine in the lab.

At the same time, we worked with a biotechnology company called Moderna that creates personalized cancer vaccines. From the time the sequence was made available in early January to the start of the first in-human study, it was about 65 days.

Collins: Wow! Has there ever been a vaccine developed in 65 days?

Mascola: I don’t think so. There are a lot of firsts with COVID, and vaccine development is one of them.

Collins: For the volunteers who enrolled in the phase 1 study, what was actually in the syringe?

Mascola: The syringe included messenger RNA (mRNA), the encoded instructions for making a specific protein, in this case the spike protein. The mRNA is formulated in a lipid nanoparticle shell. The reason is mRNA is less stable than DNA, and it doesn’t like to hang around in a test tube where enzymes can break it down. But if one formulates it just right into a nanoparticle, the mRNA is protected. Furthermore, that protective particle allows one to inject it into muscle and facilitates the uptake of the mRNA into the muscle cells. The cells translate the mRNA into spike proteins, and the immune system sees them and mounts a response.

Collins: Do muscle cells know how to take that protein and put it on their cell surfaces, where the immune system can see it?

Mascola: They do if the mRNA is engineered just the right way. We’ve been doing this with DNA for a long time. With mRNA, the advantage is that it just has to get into the cell [not into the nucleus of the cell as it does for DNA]. But it took about a decade of work to figure out how to do nucleotide silencing, which allows the cell to see the mRNA, not destroy it, and actually treat it as a normal piece of mRNA to translate into protein. Once that was figured out, it becomes pretty easy to make any specific vaccine.

Collins: That’s really an amazing part of the science. While it seems like this all happened in a blink of an eye, 65 days, it was built on years of basic science work to understand how cells treat mRNA. What’s the status of the vaccine right now?

Mascola: Early data from the phase 1 study are very encouraging. There’s a manuscript in preparation that should be out shortly showing that the vaccine was safe. It induced a very robust immune response to that spike protein. In particular, we looked for neutralizing antibodies, which are the ones that attach to the spike, blocking the virus from binding to a cell. There’s a general principle in vaccine development: if the immune system generates neutralizing antibodies, that’s a very good sign.

Collins: You’d be the first to say that you’re not done yet. Even though those are good signs, that doesn’t prove that this vaccine will work. What else do you need to know?

Mascola: The only real way to learn if a vaccine works is to test it in people. We break clinical studies into phases 1, 2, and 3. Phase 1 has already been done to evaluate safety. Phase 2 is a larger evaluation of safety and immune response. That’s ongoing and has enrolled 500 or 600 people, which is good. The plan for the phase 3 study will be to start in July. Again, that’s incredibly fast, considering that we didn’t even know this virus existed until January.

Collins: How many people do you need to study in a phase 3 trial?

Mascola: We’re thinking 20,000 or 30,000.

Collins: And half get the vaccine and half get a placebo?

Mascola: Sometimes it can be done differently, but the classic approach is half placebo, half vaccine.

Collins: We’ve been talking about the VRC-Moderna nucleic acid vaccine. But there are others that are coming along pretty quickly. What other strategies are being employed, and what are their timetables?

Mascola: There are many dozens of vaccines under development. The response has been extraordinary by academic groups, biotech companies, pharmaceutical companies, and NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) partnership. I don’t think I’ve ever seen so much activity in a vaccine space moving ahead at such a rapid clip.

As far as being ready for advanced clinical trials, there are a just handful and they involve different types of vaccines. At least three nucleic acid vaccines are in clinical trials. There are also two vaccines that use proteins, which is a more classic approach.

In addition, there are several vaccines based on a viral vector. To make these, one puts the genes for the spike protein inside an adenovirus, which is an innocuous cold virus, and injects it into muscle. In regard to phase 3 trials, there are maybe three or four vaccines that could be formally in such tests by the fall.

Collins: How is it possible to do this so much more rapidly than in the past, without imposing risks?

Mascola: It’s a really important question, Francis. A number of things are being done in parallel, and that wouldn’t usually be the case. We can get a vaccine into a first-in-human study much more quickly because of time-saving technologies.

But the real important point is that for the phase 3 trial, there are no timesavers. One must enroll 30,000 people and watch them over months in a very rigorous, placebo-controlled environment. The NIH has stood up what’s called a Data Safety Monitoring Board for all the trials. That’s an independent group of investigators that will review all vaccine trial data periodically. They can see what the data are showing: Should the trial be stopped early because the vaccine is working? Is there a safety signal that raises concern?

While the phase 3 trial is going on, the U.S. government also will be funding large-scale manufacture of the vaccine. Traditionally, you would do the vaccine trial, wait until it’s all done, and analyze the data. If it worked, you’d build a vaccine plant to make enough material, which takes two or three years, and then go to the Food and Drug Administration (FDA) for regulatory approval.

Everything here is being done in parallel. So, if the vaccine works, it’s already in supply. And we have been engaging the FDA to get real-time feedback. That does save a lot of time.

Collins: Is it possible that we’ll manufacture a whole lot of doses that may have to be thrown out if the vaccine doesn’t work?

Mascola: It certainly is possible. One would like to think that for coronaviruses, vaccines are likely to work, in part because the natural immune response clears them. People get quite sick, but eventually the immune system clears the virus. So, if we can prime it with a vaccine, there is reason to believe vaccines should work.

Collins: If the vaccine does work, will this be for lifelong prevention of COVID-19? Or will this be like the flu, where the virus keeps changing and new versions of the vaccine are needed every year?

Mascola: From what we know about coronaviruses, we think it’s likely COVID-19 is not like the flu. Coronaviruses do have some mutation rate, but the data suggest it’s not as rapid as influenza. If we’re fortunate, the vaccine won’t need to be changed. Still, there’s the matter of whether the immunity lasts for a year, five years, or 10 years. That we don’t know without more data.

Collins: Do we know for sure that somebody who has had COVID-19 can’t get it again a few months later?

Mascola: We don’t know yet. To get the answer, we must do natural history studies, where we follow people who’ve been infected and see if their risk of getting the infection is much lower. Although classically in virology, if your immune system shows neutralizing antibodies to a virus, it’s very likely you have some level of immunity.

What’s a bit tricky is there are people who get very mild symptoms of COVID-19. Does that mean their immune system only saw a little bit of the viral antigen and didn’t respond very robustly? We’re not sure that everyone who gets an infection is equally protected. That’s going to require a natural history study, which will take about a year of follow-up to get the answers.

Collins: Let’s go back to trials that need to happen this summer. You talked about 20,000 to 30,000 people needing to volunteer just for one vaccine. Whom do you want to volunteer?

Mascola: The idea with a phase 3 trial is to have a broad spectrum of participation. To conduct a trial of 30,000 people is an enormous logistical operation, but it has been done for the rotavirus and HPV vaccines. When you get to phase 3, you don’t want to enroll just healthy adults. You want to enroll people who are representative of the diverse population that you want to protect.

Collins: Do you want to enrich for high-risk populations? They’re the ones for whom we hope the vaccine will provide greatest benefit: for example, older people with chronic illnesses, African Americans, and Hispanics.

Mascola: Absolutely. We want to make sure that we can feel comfortable to recommend the vaccine to at-risk populations.

Collins: Some people have floated another possibility. They ask why do we need expensive, long-term clinical trials with tens of thousands of people? Couldn’t we do a human challenge trial in which we give the vaccine to some healthy, young volunteers, wait a couple of weeks, and then intentionally expose them to SARS-CoV-2. If they don’t get sick, we’re done. Are challenge studies a good idea for COVID-19?

Mascola: Not right now. First, one has to make a challenge stock of the SARS-CoV-2 that’s not too pathogenic. We don’t want to make something in the lab that causes people to get severe pneumonia. Also, for challenge studies, it would be preferable to have a very effective small drug or antibody treatment on hand. If someone were to get sick, you could take care of the infection pretty readily with the treatments. We don’t have curative treatments, so the current thinking is we’re not there yet for COVID-19 challenge studies [1]. If you look at our accelerated timeline, formal vaccine trials still may be the fastest and safest way to get the answers.

Collins: I’m glad you’re doing it the other way, John. It’s going to take a lot of effort. You’re going to have to go somewhere where there is still ongoing spread, otherwise you won’t know if the vaccine works or not. That’s going to be tricky.

Mascola: Yes. How do we know where to test the vaccine? We are using predictive analytics, which is just a fancy way of saying that we are trying to predict where in the country there will be ongoing transmission. If we can get really good at it, we’ll have real-time data to say transmission is ongoing in a certain area. We can vaccinate in that community, while also possibly protecting people most at risk.

Collins: John, this conversation has been really informative. What’s your most optimistic view about when we might have a COVID-19 vaccine that’s safe and effective enough to distribute to the public?

Mascola: An optimistic scenario would be that we get an answer in the phase 3 trial towards the end of this year. We have scaled up the production in parallel, so the vaccine should be available in great supply. We still must allow for the FDA to review the data and be comfortable with licensing the vaccine. Then we must factor in a little time for distributing and recommending that people get the vaccine.

Collins: Well, it’s wonderful to have someone with your skills, experience, and vision taking such a leading role, along with your many colleagues at the Vaccine Research Center. People like Kizzmekia Corbett, Barney Graham, and all the others who are a part of this amazing team that you’ve put together, overseen by Dr. Fauci.

While there is still a ways to go, we can take pride in how far we have come since this virus emerged just about six months ago. In my 27 years at NIH, I’ve never seen anything quite like this. There’s been a willingness among people to set aside all kinds of other concerns. They’ve gathered around the same table, worked on vaccine design and implementation, and gotten out there in the real world to launch clinical trials.

John, thank you for what you are doing 24/7 to make this kind of progress possible. We’re all watching, hoping, and praying that this will turn out to be the answer that people desperately need after such a terribly difficult time so far in 2020. I believe 2021 will be a very different kind of experience, largely because of the vaccine science that we’ve been talking about today.

Mascola: Thank you so much, Francis. And thanks for recognizing all the people behind the scenes who are making this happen. They’re working really hard!

Reference:

[1] Accelerating Development of SARS-CoV-2 Vaccines—The Role for Controlled Human Infection Models. Deming ME, Michael, NL, Robb M, Cohen MS, Neuzil KM. N Engl J Med. 2020 July 1. [Epub ahead of print].

Links:

Coronavirus (COVID-19) (NIH)

John R. Mascola (National Institute of Allergy and Infectious Diseases/NIH)

Novel Vaccine Technologies for the 21st Century. Mascola JR, Fauci AS. Nat Rev Immunol. 2020 Feb;20(2):87-88.

Vaccine Research Center (NIAID/NIH)

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)


A Conversation on COVID-19

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A Conversation on COVID-19
I had an excellent conversation about coronavirus disease 2019 (COVID-19) with my NIH colleague Tony Fauci, director of the National Institute of Allergy and Infectious Diseases and a true expert on the subject. While the conversation streamed over Twitter and Facebook Live, I posed questions to Dr. Fauci that were sent into NIH recently over social media. The topics addressed included the current status of the COVID outbreak, social responsibility, vaccine development, and so much more. We video-conferenced on July 6, 2020.


Seeing Coronavirus Replicate in Kidney Cells

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Bernbaum Imaging Post
Credit: NIAID Integrated Research Facility, Fort Detrick, MD

You’ve probably seen pictures of SARS-CoV-2—the novel coronavirus that causes COVID-19—that look alarming. But the high-resolution micrograph above paints a rather different picture, using rich pseudo-colors to show how newly assembled viral particles cause infected cells to bulge, or bleb, and then self-destruct.

This image depicts a common primate kidney cell line (green) infected with SARS-CoV-2. Notice the bulging, spherical cellular blebs, seen best in the upper right and bottom left corners. These badly damaged cells, which are filled to the point of bursting with viral particles, are beginning to self-destruct. Some cells have apparently already burst open, allowing hundreds of viral particles (purple) to spill out and potentially infect other cells.

This stunning picture was taken by John Bernbaum, an electron microscopist with NIH’s National Institute of Allergy and Infectious Diseases (NIAID). Bernbaum works at NIAID’s Integrated Research Facility (IRF), Fort Detrick, MD, a specialized, high-level biocontainment facility equipped with unique medical imaging capabilities. In this special environment, Bernbaum and his colleagues can safely visualize SARS-CoV-2, as well as other viruses and microbes that pose serious risks to human health.

To get this shot of SARS-CoV-2, Bernbaum relied on a conventional scanning electron microscope (SEM). First, a sample of kidney cells that had been exposed to SARS-CoV-2 was dehydrated, chemically preserved, and coated with a thin layer of metal. Once everything was ready, the SEM was used to focus a high-energy beam of electrons onto the sample. As electrons bounced off the metal surface, they revealed spatial variations and properties in the sample that were used to generate this 3D image.

Originally, this image was in gray scale. To better highlight the destructive powers of SARS-CoV-2, Jiro Wada, a skilled graphic illustrator at the IRF, used a computer program to colorize key features in exquisite detail. By studying these 3D images, researchers can learn about things such as the rate of infection and the prodigious number of particles each infected cell produces. They can also learn about how the infection affects the conditions inside cells.

Interestingly, what Bernbaum finds most striking about SARS-CoV-2 is what you don’t see in his images. Uninfected kidney cells look like a flat, delicately interwoven quilt (not pictured). When Bernbaum used SEM to study this sample of kidney cells, about 80 to 90 percent of the cells appeared flat and unremarkable. Yet, as the scan progressed, he came across a small subset of cells that appeared to be deformed by SARS-CoV-2 infection. Those abnormalities include the spherical bulges that I pointed out earlier, along with some worm-like protrusions that you can see in the top left.

Bernbaum has been producing amazing images like this one for 32 years—the last 11 of them at the IRF. If you’d like to see even more of his impressive work and that of the IRF team, check out the NIAID’s image gallery.

Links:

Coronavirus (NIH)

Integrated Research Facility (National Institute of Allergy and Infectious Diseases/NIH)

NIH Support: National Institute of Allergy and Infectious Diseases


Testifying on COVID-19 Vaccine Development

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Testifying on Vaccine Development for COVID-19
It was an honor to testify before the U.S. Senate Appropriations Subcommittee on Labor, Health and Human Services, Education, and Related Agencies on July 2. The topic of the hearing was the President’s plan to develop and distribute a COVID-19 vaccine. Also testifying were Robert Redfield, director of the Centers for Disease Control and Prevention, and Gary Disbrow, acting director of Biomedical Advanced Research and Development Authority (BARDA). The nearly three-hour hearing allowed a productive exchange of information on this critical topic and many of NIH’s high-priority efforts to develop vaccines and therapeutics for COVID-19. Credit: C-Span.


Finding Antibodies that Neutralize SARS-CoV-2

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Neutralizing Antibodies
Caption: Model of three neutralizing antibodies (blue, purple and orange) bound to the spike protein, which allows SARS-CoV-2 attach to our cells. Credit: Christopher Barnes and Pamela Bjorkman, California Institute of Technology, Pasadena.

It’s now clear that nearly everyone who recovers from coronavirus disease 2019 (COVID-19) produces antibodies that specifically target SARS-CoV-2, the novel coronavirus that causes the infection. Yet many critical questions remain. A major one is: just how well do those particular antibodies neutralize the virus to fight off the infection and help someone recover from COVID-19? Fortunately, most people get better—but should the typical antibody response take the credit?

A new NIH-funded study of nearly 150 people who recovered from COVID-19 offers some essential insight. The study, published in the journal Nature, shows that most people, in fact, do produce antibodies that can effectively neutralize SARS-CoV-2. But there is a catch: 99 percent of the study’s participants didn’t make enough neutralizing antibodies to mount an ideal immune response.

The good news is that when researchers looked at individuals who mounted a strong immune response, they were able to identify three antibodies (depicted above) that were extremely effective at neutralizing SARS-CoV-2. By mass-producing copies of these antibodies as so-called monoclonal antibodies, the researchers can now better evaluate their potential as treatments to help people who don’t make strongly neutralizing antibodies, or not enough of them.

These findings come from a team led by Michel Nussenzweig, Paul Bieniasz, and Charles Rice at The Rockefeller University, New York, and Pamela Bjorkman at the California Institute of Technology, Pasadena. In the Nussenzweig lab, the team has spent years searching for broadly neutralizing antibodies against the human immunodeficiency virus (HIV). In response to the COVID-19 pandemic and its great urgency, Nussenzweig and team shifted their focus recently to look for promising antibodies against SARS-CoV-2.

Antibodies are blood proteins that the immune system makes to neutralize viruses or other foreign invaders. The immune system doesn’t make just one antibody to thwart an invader; it makes a whole family of antibodies. But not all antibodies in that family are created equal. They can vary widely in where they latch onto a virus like SARS-CoV-2, and that determines how effective each will be at blocking it from infecting human cells. That’s one reason why people respond differently to infections such as COVID-19.

In early April, Nussenzweig’s team began analyzing samples from volunteer survivors who visited The Rockefeller Hospital to donate plasma, which contains the antibodies. The volunteers had all recovered from mild-to-severe cases of COVID-19, showing their first signs of illness about 40 days prior to their first plasma collection.

Not surprisingly, all volunteers had produced antibodies in response to the virus. To test the strength of the antibodies, the researchers used a special assay that shows how effective each one is at blocking the virus from infecting human cells in lab dishes.

Overall, most of the plasma samples—118 of 149—showed at best poor to modest neutralizing activity. In about one-third of individuals, their plasma samples had below detectable levels of neutralizing activity. It’s possible those individuals just resolved the infection quickly, before more potent antibodies were produced.

More intriguing to the researchers were the results from two individuals that showed an unusually strong ability to neutralize SARS-CoV-2. Among these two “elite responders” and four other individuals, the researchers identified 40 different antibodies that could neutralize SARS-CoV-2. But again, not all antibodies are created equal. Three neutralized the virus even when present at extremely low levels, and they now will be studied further as possible monoclonal antibodies.

The team determined that those strongly neutralizing antibodies bind three distinct sites on the receptor-binding domain (RBD) of the coronavirus spike protein. This portion of the virus is important because it allows SARS-CoV-2 to bind and infect human cells. Importantly, when the researchers looked more closely at plasma samples with poor neutralizing ability, they found that they also contained those RBD-binding antibodies, just not in very large numbers.

These findings help not only to understand the immune response to COVID-19, they are also critical for vaccine design, revealing what a strong neutralizing antibody for SARS-CoV-2 should look like to help the immune system win. If a candidate vaccine can generate such strongly neutralizing antibodies, researchers will know that they are on the right track.

While this research showed that there’s a lot of variability in immune responses to SARS-CoV-2, it appears that most of us are inherently capable of producing antibodies to neutralize this devastating virus. That brings more reason for hope that the many vaccines now under study to elicit such neutralizing antibodies in sufficient numbers may afford us with much-needed immune protection.

Reference:

[1] Convergent antibody responses to SARS-CoV-2 in convalescent individuals. Robbiani DF, Gaebler C, Muecksch F, et al. Nature. 2020 Jun 18. [Published online ahead of print].

Links:

Coronavirus (COVID-19) (NIH)

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)

Nussenzweig Lab (The Rockefeller University, New York)

Bjorkman Lab (California Institute of Technology, Pasadena)

NIH Support: National Institute of Allergy and Infectious Diseases


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