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 its devising innovative technologies or figuring out ways to speed human testing. In fact, just this week, NIHs National Institute of Allergy and Infectious Diseases (NIAID) established anew clinical trials networkthat 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 NIAIDs Dale and Betty Bumpers Vaccine Research Center (VRC), in partnership with Moderna, Inc., Cambridge, MA. So, I couldnt think of a better person to give us a quick overview of the COVID-19 vaccine research landscape than NIHs 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. Heres 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 thats 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 cant 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 dont 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. Its 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 thespike proteinto 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. Im referring to vaccines that are based on genetic material, either DNA or RNA. Its 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 calledin silicovaccine 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 dont 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 doesnt 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. Weve 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: Thats 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. Whats the status of the vaccine right now?
Mascola: Early data from the phase 1 study are very encouraging. Theres 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. Theres a general principle in vaccine development: if the immune system generates neutralizing antibodies, thats a very good sign.
Collins: Youd be the first to say that youre not done yet. Even though those are good signs, that doesnt 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. Thats 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, thats incredibly fast, considering that we didnt even know this virus existed until January.
Collins: How many people do you need to study in a phase 3 trial?
Mascola: Were 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: Weve 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 NIHsAccelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) partnership. I dont think Ive 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: Its a really important question, Francis. A number of things are being done in parallel, and that wouldnt 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 whats called a Data Safety Monitoring Board for all the trials. Thats 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 its all done, and analyze the data. If it worked, youd 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, its 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 well manufacture a whole lot of doses that may have to be thrown out if the vaccine doesnt 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 its likely COVID-19 is not like the flu. Coronaviruses do have some mutation rate, but the data suggest its not as rapid as influenza. If were fortunate, the vaccine wont need to be changed. Still, theres the matter of whether the immunity lasts for a year, five years, or 10 years. That we dont know without more data.
Collins: Do we know for sure that somebody who has had COVID-19 cant get it again a few months later?
Mascola: We dont know yet. To get the answer, we must do natural history studies, where we follow people whove 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, its very likely you have some level of immunity.
Whats 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 didnt respond very robustly? Were not sure that everyone who gets an infection is equally protected. Thats going to require a natural history study, which will take about a year of follow-up to get the answers.
Collins: Lets 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 dont 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? Theyre 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? Couldnt 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 dont get sick, were 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 thats not too pathogenic. We dont 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 dont have curative treatments, so the current thinking is were 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: Im glad youre doing it the other way, John. Its going to take a lot of effort. Youre going to have to go somewhere where there is still ongoing spread, otherwise you wont know if the vaccine works or not. Thats 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, well 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. Whats your most optimistic view about when we might have a COVID-19 vaccine thats 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, its 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 youve 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, Ive never seen anything quite like this. Theres been a willingness among people to set aside all kinds of other concerns. Theyve 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. Were 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 weve 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. Theyre working really hard!
The rest is here:
Meet the Researcher Leading NIH's COVID-19 Vaccine Development Efforts - GovExec.com
- Technion team discovers important adaptive strategy of the microbiome, impacting immune system - The Jerusalem Post - April 16th, 2024
- Targeting aging and age-related diseases with vaccines - Nature.com - April 16th, 2024
- Single cell analysis unveils B cell-dominated immune subtypes in HNSCC for enhanced prognostic and therapeutic ... - Nature.com - April 16th, 2024
- After the Smoke Clears: Scars on the Immune System - The Scientist - April 16th, 2024
- Exercise and the Immune System: What's the Latest Research? - Technology Networks - April 16th, 2024
- Analysis of immune cell infiltration characteristics in severe acute pancreatitis through integrated bioinformatics ... - Nature.com - April 16th, 2024
- Vaccination impairs de novo immune response to omicron breakthrough infection, a precondition for the original ... - Nature.com - April 16th, 2024
- Harnessing the power of the body's own cells to defeat cancer - Press Publications Inc. - April 16th, 2024
- Best Life: Immunotherapy targets brain cancer - Action News 5 - April 16th, 2024
- Dietary factors and their influence on immunotherapy strategies in oncology: a comprehensive review | Cell Death ... - Nature.com - April 16th, 2024
- New insights on B cells: Researchers explore building better antibodies and curbing autoimmune diseases - Medical Xpress - April 16th, 2024
- Immune cells' intense reaction to the coronavirus may lead to pneumonia - Science News Magazine - April 16th, 2024
- The telltale traces long Covid leaves in the blood - healthcare-in-europe.com - April 16th, 2024
- Overview of the Immune System - The Merck Manuals - March 18th, 2024
- SUNDAY Unraveling The Gut-Brain Connection: How Infant Gut Bacteria Shape Immune Resilience | TheHealthSit - TheHealthSite - March 18th, 2024
- Making drugs from T cells: The quantitative pharmacology of engineered T cell therapeutics | npj Systems Biology and ... - Nature.com - March 18th, 2024
- Study unlocks the mystery of neonatal neutropenia in newborns - News-Medical.Net - March 18th, 2024
- Vertebral Subluxation and Systems Biology: An Integrative Review Exploring the Salutogenic Influence of Chiropractic ... - Cureus - March 18th, 2024
- A new strategy to attack aggressive brain cancer shrank tumors in two early tests - ABC News - March 18th, 2024
- Turning on the Bat Signal - The Scientist - March 18th, 2024
- Power Foods That Can Support Your Immune System - Videos from The Weather Channel - The Weather Channel - March 18th, 2024
- Report: Aggressive brain tumors respond to new, immune-focused therapy - UPI News - March 18th, 2024
- Designer immune-cell therapy could shrink deadly brain tumors, early trials show - Livescience.com - March 18th, 2024
- 20.2: Introduction to the Immune System - Biology LibreTexts - February 27th, 2024
- Can one shot of yoghurt really boost your immunity and gut health? - Daily Mail - February 27th, 2024
- New cancer therapy approved by FDA supercharges bodys immune system - The Washington Post - February 27th, 2024
- How bubonic plague rewired the human immune system - BBC.com - February 27th, 2024
- Innovative therapy targets and destroys leukemia stem cells - News-Medical.Net - February 27th, 2024
- Participate in Our Study for $100; Open Slots This Week - University of Arkansas Newswire - February 27th, 2024
- Sexual dimorphism during integrative endocrine and immune responses to ionizing radiation in mice | Scientific Reports - Nature.com - February 27th, 2024
- Comprehensive pan-cancer analysis identifies the RNA-binding protein LRPPRC as a novel prognostic and immune ... - ScienceDirect.com - February 27th, 2024
- YOUR HEALTH: The HAMR fights cancer - WAFB - February 27th, 2024
- Cycles of a diet that mimics fasting can reduce signs of immune system aging, as well as insulin resistance and liver fat - News-Medical.Net - February 27th, 2024
- How the powerhouse of the cell could be cancers Achilles heel - Freethink - February 27th, 2024
- Food is medicine: The science behind zinc and other supplements for immune health - Healio - February 27th, 2024
- Unleashing Our Immune Response to Quash Cancer - Medscape - February 27th, 2024
- Tumor histoculture captures the dynamic interactions between tumor and immune components in response to anti-PD1 ... - Nature.com - February 27th, 2024
- Converging and evolving immuno-genomic routes toward immune escape in breast cancer - Nature.com - February 27th, 2024
- Sanjula Jain Urges a Comprehensive Approach in Address Alarming Rise in Cancer Cases Among Younger Populations - Managed Healthcare Executive - February 27th, 2024
- Cystic fibrosis breakthrough points to zinc as infection buster - New Atlas - February 27th, 2024
- Exploring synergies between B- and T-cell vaccine approaches to optimize immune responses against HIVworkshop ... - Nature.com - February 27th, 2024
- Is the 100-year old TB vaccine a new weapon against Alzheimers? - The Guardian - February 27th, 2024
- Immune system in the blood of Alzheimer's patients found to be epigenetically altered - News-Medical.Net - February 10th, 2024
- What impact does exercise have on your immune system? And how to stay well while cycling - BikeRadar - February 10th, 2024
- Had COVID recently? Here's what to know about how long immunity lasts, long COVID, and more - AAMC - February 10th, 2024
- Noor Momin harnesses the immune system to treat heart disease | Penn Today - Penn Today - February 10th, 2024
- Research reveals a process tumors use to induce immune suppressor cells and evade immunotherapy - Medical Xpress - February 10th, 2024
- Immune targeting of HIV-1 reservoir cells: a path to elimination strategies and cure - Nature.com - February 10th, 2024
- Preventing severe allergic reactions with nanoparticles - National Institutes of Health (NIH) (.gov) - February 10th, 2024
- Sugary handshakes are how cells talk to each other understanding these name tags can clarify how the immune ... - The Conversation Indonesia - February 10th, 2024
- Scientists have identified an immune cell that can cause allergies - EL PAS USA - February 10th, 2024
- Sickle cell and the importance of the immune system - Punch Newspapers - February 10th, 2024
- Which cancers can be treated with immune checkpoint inhibitors? - MD Anderson Cancer Center - February 10th, 2024
- How does waste leave the brain? Washington University School of Medicine in St. Louis - Washington University School of Medicine in St. Louis - February 10th, 2024
- Healthy Kids: Give your immune system a boost to stay healthy this winter - nbc16.com - February 10th, 2024
- The impact of prior exposure to hypoglycaemia on the inflammatory response to a subsequent hypoglycaemic episode ... - Cardiovascular Diabetology - February 10th, 2024
- Impact of Chronic Stress on Immune System and Depression | Health News - Medriva - February 10th, 2024
- I tried 'swamp soup,' the viral recipe that promises to boost your immune system - Yahoo News - February 10th, 2024
- Understanding Immune Checkpoint Inhibition Therapy: Challenges and Strategies - Medriva - February 10th, 2024
- One Simple Change May Dramatically Boost The Effect of COVID-19 Vaccines - ScienceAlert - February 10th, 2024
- The gut virome is associated with stress-induced changes in behaviour and immune responses in mice - Nature.com - February 10th, 2024
- Cancer vaccines are in the works to fight BRCA-linked gene mutations - The Philadelphia Inquirer - February 10th, 2024
- What are the organs of the immune system? - InformedHealth.org - NCBI ... - January 17th, 2024
- Novel insights into the immune response to bacterial T cell superantigens - Nature.com - January 17th, 2024
- FDA signs off on Takeda's HyQvia as maintenance therapy for CIDP - FiercePharma - January 17th, 2024
- CBDs Pobezinsky and Pobezinskaya Use Flow Cytometry to Determine How Tumor Cells Outwit the Bodys Immune ... - UMass News and Media Relations - January 17th, 2024
- Boosting. What To Do. - Science Based Medicine - January 17th, 2024
- Axelia Oncology takes its TLR2/6 agonist into the clinic to harness the innate immune system - BioWorld Online - January 17th, 2024
- Long COVID manifests with T cell dysregulation, inflammation and an uncoordinated adaptive immune response to ... - Nature.com - January 17th, 2024
- Opinion | Thanks to mRNA, Future Drugs Will Be Easier and Faster to Make - Mississippi Free Press - January 17th, 2024
- Elon research team models the COVID immune response, one equation at a time - Today at Elon - January 17th, 2024
- Are plant-based meals good for your immune system? 4 things to know about improving your health this week. - Yahoo Life - January 17th, 2024
- Scientists Find Key To Potential Breast Cancer Prevention, Treatment | Newsroom - UNC Health and UNC School of Medicine - January 17th, 2024
- What if every germ hit you at the exact same time? An immunologist explains - The Conversation - January 17th, 2024
- Why Don't We Have a Staph Vaccine? - Healthnews.com - January 17th, 2024
- Best ways to improve your immune system - The Business Standard - January 17th, 2024
- Stanford University researchers think future pandemics could be prevented with universal vaccines - KGO-TV - January 17th, 2024
- Why you may feel depressed and anxious when you're ill and how to cope with it - The Conversation - January 17th, 2024
- New mechanism with potential to boost checkpoint-blocking cancer immunotherapies identified - Medical Xpress - January 17th, 2024
- Battling Bugs and Blues: The Interplay of Infection and Emotion - News-Medical.Net - January 17th, 2024