Vaccine Research Center
Welcome to Response Team Members
Posted on by Lawrence Tabak, D.D.S., Ph.D.
NIH Welcomes HHS Leaders to Campus
Posted on by Dr. Francis Collins
Meet an Inspiring Researcher Who Helped Create COVID-19 mRNA Vaccines
Posted on by Dr. Francis Collins
More than 170 million Americans already have received COVID-19 vaccines. As this number continues to grow and expand to younger age groups, I’m filled with overwhelming gratitude for all of the researchers who worked so diligently, over the course of decades, to build the scientific foundation for these life-saving vaccines. One of them is Dr. Kizzmekia Corbett, who played a central role in the fact that, in the span of less than a year, we were able to develop safe and effective mRNA-based vaccines to protect against this devastating infectious disease.
As leader of the immunopathogenesis team at NIH’s Dale and Betty Bumpers Vaccine Research Center in Bethesda, MD, Dr. Corbett was ready, willing, and able when the COVID-19 pandemic emerged to take the critical first steps in developing what would become the Moderna and Pfizer/BioNTech mRNA vaccines. Recently, she accepted a position at Harvard University T.H. Chan School of Public Health, Boston, where she will soon open her own viral immunology lab to help inform future vaccine development for coronaviruses and other respiratory viruses.
While she was preparing for her move to Harvard, I had a chance to speak with Dr. Corbett about her COVID-19 research experience and what it was like to get immunized with the vaccine that she helped to create. Our conversation was part of an NIH Facebook Live event in which we connected virtually from our homes in Maryland. Here is a condensed version of our chat.
Collins: You’ve studied SARS, MERS, and other coronaviruses for many years. Then, in early January 2020, like all of us, you heard that something was going on that sounded worrisome in Wuhan, China. What did you think?
Corbett: Well, the story actually began for me on December 31, 2019. My boss Dr. Barney Graham sent me an email at 6 a.m. that said: “Get ready for 2020.” There had been some news of a respiratory virus outbreak in the Wuhan district of China. I honestly wrote it off as probably a strain of the flu. Then, we got back to NIH after the holidays, and it was determined around January 6 that the virus was for certain a coronavirus. That meant our team would be responding to it.
We sat down and planned to monitor the situation very closely. We knew exactly what to do, based on our past work. We would go into full force to make a vaccine—the one now known as “the Moderna vaccine” —as quickly as possible for testing in a clinical trial. The goal was to make the vaccine in 100 days. And so when the genetic sequence of this new virus came out on January 10, I sprung out of bed and so did everyone on the team. It’s been kind of a whirlwind ever since.
Collins: Tell us a little bit more about that. The sequence got posted on the internet by a Chinese scientist. So you have this sequence, and everyone gathers in NIH’s Vaccine Research Center. Then what happens?
Corbett: The cool thing about this type of technology is you don’t even need the lab to design the vaccine. All you need are the letters, or sequence, that encodes the virus’ genetic material displayed on your computer screen. We could actually do the work from our homes, obviously in close conversation with each other.
This sequence is the virus’s genetic code. Just like humans have families—brothers, sisters, cousins—viruses also have families. So, we could see when looking at the sequence of letters, how similar this particular virus was to viruses that we’ve worked with before in the coronavirus family. It was almost like “A-ha! This is the part of the sequence that represents the protein on the surface of the virus.”
We knew that we could take the sequence of that surface protein and use all of the knowledge that we had from previous years to design a vaccine. And that’s what we did. We took that sequence on our computer screen and said we said this is exactly how we want this vaccine to look. The process was as straightforward as that.
Collins: In other words, you already knew that these coronaviruses have spike proteins on their surface and that’s the thing that’s going to be really useful for making an antibody. You’d already taken this approach in developing a vaccine for MERS, right?
Corbett: Exactly, we’d done that for MERS. Vaccines are basically a way to teach your body how to see a pathogen. Over the years, as vaccinology and technology have progressed, different scientists have figured out that you don’t really need the whole virus as a part of the vaccine. You can just take a small portion of that virus to alert your body.
In this case, taking the spike protein and teaching your immune system how to specifically spot and attack it, you can now protect yourself from COVID-19. So, we used the sequence of that spike protein, with some modifications to make it much better as a vaccine. We then deliver that to you as a message—messenger RNA (mRNA) —to get your muscle cells briefly to make the spike protein. Then, your body sees that spike protein hanging out on your cells and makes a really specific immune response to it. That way the next time your body sees the spike protein, if you ever come into contact with the virus, your immune system is armed and ready to attack.
Collins: Say more about this messenger RNA approach. It’s been so revolutionary and one of the reasons that we got vaccines into people’s arms in just 11 months. Had this approach ever been used before?
Corbett: Yes, messenger RNA technologies have been in development from a basic science perspective for over 15 years. A lot of that work was funded by NIH. Soon after I got to NIH, I attended a meeting in London called Transforming Vaccinology. At the time, Moderna was a smaller company that was working to make messenger RNA technologies, mostly centered around cancer therapies. But they had started to test some flu vaccines that used messenger RNA. My question to the presenter was: “Every single time I see you guys present, it looks like mRNA technology has always worked. Can you tell me a time that it hasn’t?” And he said, “I can’t.”
So, our understanding of how this technology works to make really good vaccines predates this pandemic. I think one of the worries that many people have is how fast and how new this technology is. But all science is compounded knowledge—everything builds on itself.
Collins: Right! We only learned about messenger RNA, because back in the 1950s and 1960s, some researchers decided to figure out how the information in our genetic instruction book, our DNA, can ultimately turn into proteins. It turned out that the message that carries that information is made of RNA.
So, you knew which kinds of letters to program into the messenger RNA vaccine. Would you explain how this vaccine, its messenger RNA, produces a spike protein. Where does that step happen?
Corbett: Your cells are machines built for this kind of thing. I like to remind people that, on a day-in, day-out basis, our cells make proteins—all of the hormones and other things our bodies needs to survive. So, we’re not teaching the cells to do anything different than they would normally do. That’s important to understand.
The way that cells do this is by reading the mRNA sequence. As they’re reading that sequence, they chew it up, like eating it, and say, “Okay, this sequence is for this very specific protein.” Then, they make that protein and push it to the surface of your cells. That’s how it happens.
Collins: And for mRNA vaccines, that’s the point when your immune system says “Wait a minute! I don’t recognize that as part of me, so I’ve got to make an antibody to it.” Then you’re off to the races and develop your immunity. Now that this mRNA vaccine strategy has succeeded for COVID-19, could it be applied to other infectious diseases or even non-infectious conditions?
Corbett: Yes, I heard that about 60 new companies have sprouted up in the last year around messenger RNA technology. They have ideas for different types of infectious disease vaccines and cancer therapies. I expect that this technology will be transformative to medicine in general.
Collins: Here’s a question from social media: “Why does it take two shots for the Pfizer and the Moderna mRNA vaccines? Why isn’t one good enough?”
Corbett: The way that these vaccines work is much like an alarm clock. Imagine your immune system is in bed and the first shot is the alarm clock going off to say, “Hey, wake up and get ready.” And just like I did this morning, the immune system pressed snooze and took a little nap. But when you hear the alarm clock the second time, it’s like someone rushing into your room and pouring a cold bucket of water on you. You have no choice but to get out of bed.
That’s what the second dose of the vaccine does. It pushes your immune response to the next level. That’s why you need two shots to get the type of efficacy that you want and be fully protected for the optimal immune response.
Collins: You were a co-leader of the team that created what became the Moderna vaccine—and you ended up getting immunized with the Moderna vaccine. What did that feel like?
Corbett: It was pretty surreal. I cried. At the end of it, I felt a lot of relief after getting my vaccine, particularly after getting the second dose. There was this breath of fresh air. It was also a birthday present. I got my second dose the day before my 35th birthday, as a birthday present to myself.
Collins: I have to admit, I cried a little bit too after my second dose. It’s just the sense of relief and incredible gratitude that we’ve reached this point. Here we are with vaccines that have 95 percent effectiveness and an incredibly good safety record, which is almost better than we could have hoped for. I’m a person of faith, so there were a lot of my prayers that went into this and it sure felt like they got answered.
Corbett: Yes, same.
Collins: You are out there a lot talking to people about the vaccines. There are still about 100 million Americans that have not yet received their first dose. Many of them still unsure about getting vaccinated. What do you say to those who are on the fence?
Corbett: In this past year, I’ve spent a lot of time talking about the vaccine with people in the community. One thing that I realized, is that I don’t need to say anything unless I’m asked. I think it’s important that I listen first, instead of just speaking.
So I do that, and I try to answer people’s inquiries as specifically as possible. But people have some very broad questions. One thing that is happening is people are seeing vaccines being developed right before their eyes. That can be a little confusing. I try to explain the process, how we went from the preclinical stage all the way to the point of getting the vaccine to hundreds of millions of people. I explain how each step along the way is very highly vetted by regulatory agencies and data safety monitoring committees. I also tell them that the monitoring continues. People from the clinical trials are still being evaluated, and there’s monitoring in the real world as the vaccine is being rolled out. I think that all of those things are really important for people to know.
Collins: Another question from social media: “As a successful scientist, what advice would you give to people who are thinking about a career in science?”
Corbett: If you think you’re interested, you just have to start. There are internship programs, there are scholarship programs, there are shadowing programs all over this country and even globally that can help you get your feet wet. I think the first thing that you want to do with any career is to figure out whether or not you like it. The only way that you can do that is to just explore, explore, explore.
Collins: Didn’t you kind of roll up your sleeves and take the plunge at a young age?
Corbett: Yes, at age 16, I went off and did summer internships at the University of North Carolina. I was able to see first-hand the day-to-day life of science and what being a scientist would look like. That was really important for me. That’s what I mean by exploring.
Collins: And a follow-up question: “Is the biomedical research community welcoming to women of color?”
Corbett: Not always, frankly. I was very fortunate to have been under the wings of a lot of mentors and advocates, who have helped to advance my career to where it is now. I had great mentors at NIH. My graduate school mentor was amazing, and my main collaborator in the coronavirus field was on my dissertation committee. Even prior to this pandemic, when I was doing work that was very obscure, he checked on me very often and made sure that he had a sense of where I wanted to go and how he could help me get there, including collaborating with me.
That kind of thing is very important, particularly for women of color or anyone from a marginalized community. That’s because there will be a point where there might be a glass ceiling. Unfortunately, we don’t necessarily have the tools to break those just yet. So, someone else is going to have to break those down, and most often than not, that person is going to have to be a white man. Finding those people who are allies with you and joining in your fight for your career trajectory is very helpful.
I remember when I was choosing a college, it was a very difficult decision for me. I got accepted into Ivy League schools, and I’d gone to all of the scholarship weekends all over the country. When I was making the decision, my dad said, “Kizzy, just always go where there is love.”
That really sticks to me with every single choice that I make around my career. You want to be at a place that’s welcoming, a place that understands you, and a place that fosters the next version of who you are destined to be. You need to make sure to step back outside of the day-to-day stuff and say, “Okay, does this place love me and people like me?” It’s important to remember that’s how you thrive: when you are comfortable in and in love with your environment.
Collins: Yes, we have to move our scientific workforce into a place where it is not necessary for a white man to advocate for a talented Black woman. There’s something very wrong with that particular circumstance. As NIH Director, I want to assure you, we are motivated more than ever to change that, including through a new initiative called UNITE. We’re missing out on welcoming the talents of so many folks who currently don’t see our research agenda as theirs, and we need to change that.
Kizzmekia, this has been a lot of fun. Thank you for giving us a half-hour of your time when you’re in the midst of this crazy two-week period of moving from Bethesda to Boston. We wish you the very best for this next chapter, which I know is going to be just amazing.
Corbett: Thank you so much.
Links:
Video: COVID-19 mRNA Vaccine Q & A – Kizzmekia Corbett and Francis Collins (NIH)
Video: Lead COVID-19 scientist Kizzmekia Corbett to join Harvard Chan School faculty (Harvard University, Boston)
COVID-19 Research (NIH)
Dale and Betty Bumpers Vaccine Research Center (National Institute of Allergy and Infectious Diseases/NIH)
UNITE Initiative (NIH)
Senators Visit NIH
Posted on by Dr. Francis Collins
President Biden Gets a First-Hand Look at NIH Research
Posted on by Dr. Francis Collins
On February 11, 2021, I had the great honor of welcoming President Joe Biden to the National Institutes of Health, where he toured the Dale and Betty Bumpers Vaccine Research Center. Joining me in briefing the President about our recent progress against COVID-19 were Dr. Kizzmekia Corbett (right), an NIH researcher who helped to develop COVID-19 vaccines in record time, and Dr. Anthony Fauci (far left), Director of NIH’s National Institute of Allergy and Infectious Diseases and a key leader of the President’s coronavirus response team. As we move forward in our tireless efforts to advance treatments, tests, and vaccines for COVID-19, I’m heartened by the President’s acknowledgement of NIH and the amazing science that we support.
COVID-19 Vaccine Appears Well-Tolerated and Effective in Developing Antibodies in Small Study of Older Adults
Posted on by Dr. Francis Collins
It’s been truly breathtaking to watch the progress being made on a daily basis to develop safe and effective vaccines for SARS-CoV-2, the novel coronavirus that causes COVID-19. Indeed, months sooner than has ever been possible for a newly emerging infection, several promising vaccines are already working their way through Phase 3 studies, the final stage of clinical evaluation. I remain optimistic that we will have one or more vaccines that prove to be safe and effective by January 2021.
But, as encouraging as the early data have been, uncertainty has remained over whether vaccines that appear safe and effective in developing antibodies in younger adults will work as well in older people, too. It’s a critical issue given that older individuals also are at greater risk for severe or life-threatening illness if they do get sick from COVID-19.
So, I’m pleased to highlight some recent findings, published in the New England Journal of Medicine [1], from an early Phase 1 clinical trial that was expanded to include 40 adults over age 55. While we eagerly await the results of ongoing and larger studies, these early data suggest that an innovative COVID-19 vaccine co-developed by NIH’s Vaccine Research Center (VRC), in partnership with Moderna Inc., Cambridge, MA, is both well tolerated and effective in generating a strong immune response when given to adults of any age.
The centerpiece of the vaccine in question, known as mRNA-1273, is a small, non-infectious snippet of messenger RNA (mRNA). When this mRNA is injected into muscle, a person’s own body will begin to make the key viral spike protein. As the immune system detects this spike protein, it spurs the production of antibodies that may help to fend off the novel SARS-CoV-2.
Earlier findings from the NIH-supported phase 1 human clinical trial found mRNA-1273 was safe and effective in generating a vigorous immune response in people ages 18 to 55, when delivered in two injections about a month apart. Based on those findings, a large Phase 3 clinical trial is currently enrolling 30,000 volunteers, with results expected in the next few weeks [2]. But, given that immune response to many other vaccines tends to grow weaker with age, how well would this new COVID-19 vaccine work for older individuals?
To find out, a team at Kaiser Permanente Washington Health Research Institute, Seattle, and Emory University School of Medicine, Atlanta, expanded the initial Phase 1 trial to include 20 healthy volunteers ages 56 to 70 and another 20 healthy volunteers ages 71 and older. Ten volunteers in each of the two older age groups received a lower dose of the vaccine (25 micrograms) in two injections given about a month apart. The other 10 in each age group received a higher dose (100 micrograms), given on the same schedule.
Here’s what they found:
• No volunteers suffered serious adverse events. The most common adverse events were mild-to-moderate in severity and included headache, fatigue, muscle aches, chills and pain at the injection site. Those symptoms occurred most often after the second dose and in individuals receiving the higher dose of 100 micrograms.
• Volunteers showed a rapid production of protective antibodies against the spike protein following immunization. After the second injection, all participants showed a strong immune response, with production of robust binding and neutralizing antibodies against SARS-CoV-2.
• The higher dose of 100 micrograms safely produced a stronger immune response compared to the lower dose, supporting its use in larger clinical studies.
• Most importantly, the immune response observed in these older individuals was comparable to that seen previously in younger adults.
The researchers will continue to follow the volunteer trial participants of all ages for about a year to monitor the vaccine’s longer-term effects. But these findings provided support for continued testing of this promising vaccine in older adults in the ongoing Phase 3 clinical trial.
There are currently four SARS-CoV-2 vaccines in phase 3 clinical trials in the United States (though two are currently on hold). Trials of two more vaccines are expected start in the next month or two.
It is not known whether all of these vaccines will have the same vigorous immune response in older individuals that has been demonstrated for this one. But if more than one of these vaccines turns out to be safe and effective, it will be important to know about the response in various populations, so that distribution to high-risk groups can be planned accordingly.
References:
[1] Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults. Anderson EJ, Rouphael NG, Widge AT, Jackson LA, Roberts PC, Makhene M, Chappell JD, Denison MR, Stevens LJ, Pruijssers AJ, McDermott AB, Flach B, Lin BC, Doria-Rose NA, O’Dell S, Schmidt SD, Corbett KS, Swanson PA 2nd, Padilla M, Neuzil KM, Bennett H, Leav B, Makowski M, Albert J, Cross K, Edara VV, Floyd K, Suthar MS, Martinez DR, Baric R, Buchanan W, Luke CJ, Phadke VK, Rostad CA, Ledgerwood JE, Graham BS, Beigel JH; mRNA-1273 Study Group. N Engl J Med. 2020 Sep 29.
[2] “Phase 3 clinical trial of investigational vaccine for COVID-19 begins.” National Institutes of Heath. July 27, 2020
Links:
Coronavirus (COVID-19) (NIH)
COVID-19 Prevention Network (National Institute of Allergy and Infectious Diseases/NIH)
Dale and Betty Bumpers Vaccine Research Center (National Institute of Allergy and Infectious Diseases/NIH)
Moderna, Inc. (Cambridge, MA)
Safety and Immunogenicity Study of 2019-nCoV Vaccine (mRNA-1273) for Prophylaxis of SARS-CoV-2 Infection (COVID-19) (ClinicalTrials.gov)
NIH Support: National Institute of Allergy and Infectious Diseases
Meet the Researcher Leading NIH’s COVID-19 Vaccine Development Efforts
Posted on by Dr. Francis Collins
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)
White House Coronavirus Task Force Briefing at NIH
Posted on by Dr. Francis Collins
President Trump Visits NIH Vaccine Research Center
Posted on by Dr. Francis Collins
Structural Biology Points Way to Coronavirus Vaccine
Posted on by Dr. Francis Collins
Credit: McLellan Lab, University of Texas at Austin
The recent COVID-19 outbreak of a novel type of coronavirus that began in China has prompted a massive global effort to contain and slow its spread. Despite those efforts, over the last month the virus has begun circulating outside of China in multiple countries and territories.
Cases have now appeared in the United States involving some affected individuals who haven’t traveled recently outside the country. They also have had no known contact with others who have recently arrived from China or other countries where the virus is spreading. The NIH and other U.S. public health agencies stand on high alert and have mobilized needed resources to help not only in its containment, but in the development of life-saving interventions.
On the treatment and prevention front, some encouraging news was recently reported. In record time, an NIH-funded team of researchers has created the first atomic-scale map of a promising protein target for vaccine development [1]. This is the so-called spike protein on the new coronavirus that causes COVID-19. As shown above, a portion of this spiky surface appendage (green) allows the virus to bind a receptor on human cells, causing other portions of the spike to fuse the viral and human cell membranes. This process is needed for the virus to gain entry into cells and infect them.
Preclinical studies in mice of a candidate vaccine based on this spike protein are already underway at NIH’s Vaccine Research Center (VRC), part of the National Institute of Allergy and Infectious Diseases (NIAID). An early-stage phase I clinical trial of this vaccine in people is expected to begin within weeks. But there will be many more steps after that to test safety and efficacy, and then to scale up to produce millions of doses. Even though this timetable will potentially break all previous speed records, a safe and effective vaccine will take at least another year to be ready for widespread deployment.
Coronaviruses are a large family of viruses, including some that cause “the common cold” in healthy humans. In fact, these viruses are found throughout the world and account for up to 30 percent of upper respiratory tract infections in adults.
This outbreak of COVID-19 marks the third time in recent years that a coronavirus has emerged to cause severe disease and death in some people. Earlier coronavirus outbreaks included SARS (severe acute respiratory syndrome), which emerged in late 2002 and disappeared two years later, and MERS (Middle East respiratory syndrome), which emerged in 2012 and continues to affect people in small numbers.
Soon after COVID-19 emerged, the new coronavirus, which is closely related to SARS, was recognized as its cause. NIH-funded researchers including Jason McLellan, an alumnus of the VRC and now at The University of Texas at Austin, were ready. They’d been studying coronaviruses in collaboration with NIAID investigators for years, with special attention to the spike proteins.
Just two weeks after Chinese scientists reported the first genome sequence of the virus [2], McLellan and his colleagues designed and produced samples of its spike protein. Importantly, his team had earlier developed a method to lock coronavirus spike proteins into a shape that makes them both easier to analyze structurally via the high-resolution imaging tool cryo-electron microscopy and to use in vaccine development efforts.
After locking the spike protein in the shape it takes before fusing with a human cell to infect it, the researchers reconstructed its atomic-scale 3D structural map in just 12 days. Their results, published in Science, confirm that the spike protein on the virus that causes COVID-19 is quite similar to that of its close relative, the SARS virus. It also appears to bind human cells more tightly than the SARS virus, which may help to explain why the new coronavirus appears to spread more easily from person to person, mainly by respiratory transmission.
McLellan’s team and his NIAID VRC counterparts also plan to use the stabilized spike protein as a probe to isolate naturally produced antibodies from people who’ve recovered from COVID-19. Such antibodies might form the basis of a treatment for people who’ve been exposed to the virus, such as health care workers.
The NIAID is now working with the biotechnology company Moderna, Cambridge, MA, to use the latest findings to develop a vaccine candidate using messenger RNA (mRNA), molecules that serve as templates for making proteins. The goal is to direct the body to produce a spike protein in such a way to elicit an immune response and the production of antibodies. An early clinical trial of the vaccine in people is expected to begin in the coming weeks. Other vaccine candidates are also in preclinical development.
Meanwhile, the first clinical trial in the U.S. to evaluate an experimental treatment for COVID-19 is already underway at the University of Nebraska Medical Center’s biocontainment unit [3]. The NIH-sponsored trial will evaluate the safety and efficacy of the experimental antiviral drug remdesivir in hospitalized adults diagnosed with COVID-19. The first participant is an American who was repatriated after being quarantined on the Diamond Princess cruise ship in Japan.
As noted, the risk of contracting COVID-19 in the United States is currently low, but the situation is changing rapidly. One of the features that makes the virus so challenging to stay in front of is its long latency period before the characteristic flu-like fever, cough, and shortness of breath manifest. In fact, people infected with the virus may not show any symptoms for up to two weeks, allowing them to pass it on to others in the meantime. You can track the reported cases in the United States on the Centers for Disease Control and Prevention’s website.
As the outbreak continues over the coming weeks and months, you can be certain that NIH and other U.S. public health organizations are working at full speed to understand this virus and to develop better diagnostics, treatments, and vaccines.
References:
[1] Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, Graham BS, McLellan JS. Science. 2020 Feb 19.
[2] A new coronavirus associated with human respiratory disease in China. Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG, Hu Y, Tao ZW, Tian JH, Pei YY, Yuan ML, Zhang YL, Dai FH, Liu Y, Wang QM, Zheng JJ, Xu L, Holmes EC, Zhang YZ. Nature. 2020 Feb 3.
[3] NIH clinical trial of remdesivir to treat COVID-19 begins. NIH News Release. Feb 25, 2020.
Links:
Coronaviruses (National Institute of Allergy and Infectious Diseases/NIH)
Coronavirus (COVID-19) (NIAID)
Coronavirus Disease 2019 (Centers for Disease Control and Prevention, Atlanta)
NIH Support: National Institute of Allergy and Infectious Diseases
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