Skip to main content

ACTIV

Charting a Rapid Course Toward Better COVID-19 Tests and Treatments

Posted on by

Point of care anti
Credit: Quidel; iStock/xavierarnau

It is becoming apparent that our country is entering a new and troubling phase of the pandemic as SARS-CoV-2, the novel coronavirus that causes COVID-19, continues to spread across many states and reaches into both urban and rural communities. This growing community spread is hard to track because up to 40 percent of infected people seem to have no symptoms. They can pass the virus quickly and unsuspectingly to friends and family members who might be more vulnerable to becoming seriously ill. That’s why we should all be wearing masks when we go out of the house—none of us can be sure we’re not that asymptomatic carrier of the virus.

This new phase makes fast, accessible, affordable diagnostic testing a critical first step in helping people and communities. In recognition of this need, NIH’s Rapid Acceleration of Diagnostics (RADx) initiative, just initiated in late April, has issued an urgent call to the nation’s inventors and innovators to develop fast, easy-to-use tests for SARS-CoV-2, the novel coronavirus that causes COVID-19. It brought a tremendous response, and NIH selected about 100 of the best concepts for an intense one-week “shark-tank” technology evaluation process.

Moving ahead at an unprecedented pace, NIH last week announced the first RADx projects to come through the deep dive with flying colors and enter the scale-up process necessary to provide additional rapid testing capacity to the U.S. public. As part of the RADx initiative, seven biomedical technology companies will receive a total of $248.7 million in federal stimulus funding to accelerate their efforts to scale up new lab-based and point-of-care technologies.

Four of these projects will aim to bolster the nation’s lab-based COVID-19 diagnostics capacity by tens of thousands of tests per day as soon as September and by millions by the end of the year. The other three will expand point-of-care testing for COVID-19, making results more rapidly and readily available in doctor’s offices, urgent care clinics, long-term care facilities, schools, child care centers, or even at home.

This is only a start, and we expect that more RADx projects will advance in the coming months and begin scaling up for wide-scale use. In the meantime, here’s an overview of the first seven projects developed through the initiative, which NIH is carrying out in partnership with the Office of the Assistant Secretary of Health, the Biomedical Advanced Research and Development Authority, and the Department of Defense:

Point-of-Care Testing Approaches

Mesa Biotech. Hand-held testing device detects the genetic material of SARS-CoV-2. Results are read from a removable, single-use cartridge in 30 minutes.

Quidel. Test kit detects protein (viral antigen) from SARS-CoV-2. Electronic analyzers provide results within 15 minutes. The U.S. Department of Health and Human Service has identified this technology for possible use in nursing homes.

Talis Biomedical. Compact testing instrument uses a multiplexed cartridge to detect the genetic material of SARS-CoV-2 through isothermal amplification. Optical detection system delivers results in under 30 minutes.

Lab-based Testing Approaches

Ginkgo Bioworks. Automated system uses next-generation sequencing to scan patient samples for SARS-CoV-2’s genetic material. This system will be scaled up to make it possible to process tens of thousands of tests simultaneously and deliver results within one to two days. The company’s goal is to scale up to 50,000 tests per day in September and 100,000 per day by the end of 2020.

Helix OpCo. By combining bulk shipping of test kits and patient samples, automation, and next-generation sequencing of genetic material, the company’s goal is to process up to 50,000 samples per day by the end of September and 100,000 per day by the end of 2020.

Fluidigm. Microfluidics platform with the capacity to process thousands of polymerase chain reaction (PCR) tests for SARS-CoV-2 genetic material per day. The company’s goal is to scale up this platform and deploy advanced integrated fluidic chips to provide tens to hundreds of thousands of new tests per day in the fall of 2020. Most tests will use saliva.

Mammoth Biosciences. System uses innovative CRISPR gene-editing technology to detect key pieces of SARS-CoV-2 genetic material in patient samples. The company’s goal is to provide a multi-fold increase in testing capacity in commercial laboratories.

At the same time, on the treatment front, significant strides continue to be made by a remarkable public-private partnership called Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV). Since its formation in May, the partnership, which involves 20 biopharmaceutical companies, academic experts, and multiple federal agencies, has evaluated hundreds of therapeutic agents with potential application for COVID-19 and prioritized the most promising candidates.

Among the most exciting approaches are monoclonal antibodies (mAbs), which are biologic drugs derived from neutralizing antibodies isolated from people who’ve survived COVID-19. This week, the partnership launched two trials (one for COVID-19 inpatients, the other for COVID-19 outpatients) of a mAB called LY-CoV555, which was developed by Eli Lilly and Company, Indianapolis, IN. It was discovered by Lilly’s development partner AbCellera Biologics Inc. Vancouver, Canada, in collaboration with the NIH’s National Institute of Allergy and Infectious Diseases (NIAID). In addition to the support from ACTIV, both of the newly launched studies also receive support for Operation Warp Speed, the government’s multi-agency effort against COVID-19.

LY-CoV555 was derived from the immune cells of one of the very first survivors of COVID-19 in the United States. It targets the spike protein on the surface of SARS-CoV-2, blocking it from attaching to human cells.

The first trial, which will look at both the safety and efficacy of the mAb for treating COVID-19, will involve about 300 individuals with mild to moderate COVID-19 who are hospitalized at facilities that are part of existing clinical trial networks. These volunteers will receive either an intravenous infusion of LY-CoV555 or a placebo solution. Five days later, their condition will be evaluated. If the initial data indicate that LY-CoV555 is safe and effective, the trial will transition immediately—and seamlessly—to enrolling an additional 700 participants with COVID-19, including some who are severely ill.

The second trial, which will evaluate how LY-CoV555 affects the early course of COVID-19, will involve 220 individuals with mild to moderate COVID-19 who don’t need to be hospitalized. In this study, participants will randomly receive either an intravenous infusion of LY-CoV555 or a placebo solution, and will be carefully monitored over the next 28 days. If the data indicate that LY-CoV555 is safe and shortens the course of COVID-19, the trial will then enroll an additional 1,780 outpatient volunteers and transition to a study that will more broadly evaluate its effectiveness.

Both trials are later expected to expand to include other experimental therapies under the same master study protocol. Master protocols allow coordinated and efficient evaluation of multiple investigational agents at multiple sites as the agents become available. These protocols are designed with a flexible, rapidly responsive framework to identify interventions that work, while reducing administrative burden and cost.

In addition, Lilly this week started a separate large-scale safety and efficacy trial to see if LY-CoV555 can be used to prevent COVID-19 in high-risk residents and staff at long-term care facilities. The study isn’t part of ACTIV.

NIH-funded researchers have been extremely busy over the past seven months, pursuing every avenue we can to detect, treat, and, ultimately, end this devasting pandemic. Far more work remains to be done, but as RADx and ACTIV exemplify, we’re making rapid progress through collaboration and a strong, sustained investment in scientific innovation.

Links:

Coronavirus (COVID-19) (NIH)

Rapid Acceleration of Diagnostics (RADx)

Video: NIH RADx Delivering New COVID-19 Testing Technologies to Meet U.S. Demand (YouTube)

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)

Explaining Operation Warp Speed (U.S. Department of Health and Human Resources/Washington, D.C.)

NIH delivering new COVID-19 testing technologies to meet U.S. demand,” NIH news release,” July 31, 2020.

NIH launches clinical trial to test antibody treatment in hospitalized COVID-19 patients,” NIH new release, August 4, 2020.

NIH clinical trial to test antibodies and other experimental therapeutics for mild and moderate COVID-19,” NIH news release, August 4, 2020.


Researchers Publish Encouraging Early Data on COVID-19 Vaccine

Posted on by

Diagram of how mRNA vaccine works
Credit: NIH

People all around the globe are anxiously awaiting development of a safe, effective vaccine to protect against the deadly threat of coronavirus disease 2019 (COVID-19). Evidence is growing that biomedical research is on track to provide such help, and to do so in record time.

Just two days ago, in a paper in the New England Journal of Medicine [1], researchers presented encouraging results from the vaccine that’s furthest along in U.S. human testing: an innovative approach from NIH’s Vaccine Research Center (VRC), in partnership with Moderna Inc., Cambridge, MA [1]. The centerpiece of this vaccine is a small, non-infectious snippet of messenger RNA (mRNA). Injecting this mRNA into muscle will spur a person’s own body to make a key viral protein, which, in turn, will encourage the production of protective antibodies against SARS-CoV-2—the novel coronavirus that causes COVID-19.

While it generally takes five to 10 years to develop a vaccine against a new infectious agent, we simply don’t have that time with a pandemic as devastating as COVID-19. Upon learning of the COVID-19 outbreak in China early this year, and seeing the genome sequence of SARS-CoV-2 appear on the internet, researchers with NIH’s National Institute of Allergy and Infectious Diseases (NIAID) carefully studied the viral instructions, focusing on the portion that codes for a spike protein that the virus uses to bind to and infect human cells.

Because of their experience with the original SARS virus back in the 2000s, they thought a similar approach to vaccine development would work and modified an existing design to reflect the different sequence of the SARS-CoV-2 spike protein. Literally within days, they had created a vaccine in the lab. They then went on to work with Moderna, a biotech firm that’s produced personalized cancer vaccines. All told, it took just 66 days from the time the genome sequence was made available in January to the start of the first-in-human study described in the new peer-reviewed paper.

In the NIH-supported phase 1 human clinical trial, researchers found the vaccine, called mRNA-1273, to be safe and generally well tolerated. Importantly, human volunteers also developed significant quantities of neutralizing antibodies that target the virus in the right place to block it from infecting their cells.

Conducted at Kaiser Permanente Washington Health Research Institute, Seattle; and Emory University School of Medicine, Atlanta, the trial led by Kaiser Permanente’s Lisa Jackson involved healthy adult volunteers. Each volunteer received two vaccinations in the upper arm at one of three doses, given approximately one month apart.

The volunteers will be tracked for a full year, allowing researchers to monitor their health and antibody production. However, the recently published paper provides interim data on the phase 1 trial’s first 45 participants, ages 18 to 55, for the first 57 days after their second vaccination. The data revealed:

• No volunteers suffered serious adverse events.

• Optimal dose to elicit high levels of neutralizing antibody activity, while also protecting patient safety, appears to be 100 micrograms. Doses administered in the phase 1 trial were either 25, 100, or 250 micrograms.

• More than half of the volunteers reported fatigue, headache, chills, muscle aches, or pain at the injection site. Those symptoms were most common after the second vaccination and in volunteers who received the highest vaccine dose. That dose will not be used in larger trials.

• Two doses of 100 micrograms of the vaccine prompted a robust immune response, which was last measured 43 days after the second dose. These responses were actually above the average levels seen in blood samples from people who had recovered from COVID-19.

These encouraging results are being used to inform the next rounds of human testing of the mRNA-1273 vaccine. A phase 2 clinical trial is already well on its way to recruiting 600 healthy adults.This study will continue to profile the vaccine’s safety, as well as its ability to trigger an immune response.

Meanwhile, later this month, a phase 3 clinical trial will begin enrolling 30,000 volunteers, with particular focus on recruitment in regions and populations that have been particularly hard hit by the virus.

The design of that trial, referred to as a “master protocol,” had major contributions from the Accelerating COVID-19 Therapeutic Interventions and Vaccine (ACTIV) initiative, a remarkable public-private partnership involving 20 biopharmaceutical companies, academic experts, and multiple federal agencies. Now, a coordinated effort across the U.S. government, called Operation Warp Speed, is supporting rapid conduct of these clinical trials and making sure that millions of doses of any successful vaccine will be ready if the vaccine proves save and effective.

Results of this first phase 3 trial are expected in a few months. If you are interested in volunteering for these or other prevention trials, please check out NIH’s new COVID-19 clinical trials network.

There’s still a lot of work that remains to be done, and anything can happen en route to the finish line. But by pulling together, and leaning on the very best science, I am confident that we will be able rise to the challenge of ending this pandemic that has devastated so many lives.

Reference:

[1] A SARS-CoV-2 mRNA Vaccine—Preliminary Report. Jackson LA, Anderson EJ, Rouphael NG, Ledgerwood JE, Graham BS, Beigel JH, et al. NEJM. 2020 July 14. [Publication ahead of print]

Links:

Coronavirus (COVID-19) (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 Launches Clinical Trials Network to Test COVID-19 Vaccines and Other Prevention Tools,” NIAID News Release, NIH, July 8, 2020.

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) (NIH)

Explaining Operation Warp Speed (U.S. Department of Health and Human Services, Washington, DC)

NIH Support: National Institute of Allergy and Infectious Diseases


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

Posted on by

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)


Finding Antibodies that Neutralize SARS-CoV-2

Posted on by

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


Searching for Ways to Prevent Life-Threatening Blood Clots in COVID-19

Posted on by

At Home with Gary Gibbons

Six months into the coronavirus disease 2019 (COVID-19) pandemic, researchers still have much to learn about the many ways in which COVID-19 can wreak devastation on the human body. Among the many mysteries is exactly how SARS-CoV-2, which is the novel coronavirus that causes COVID-19, triggers the formation of blood clots that can lead to strokes and other life-threatening complications, even in younger people.

Recently, I had a chance to talk with Dr. Gary Gibbons, Director of NIH’s Heart, Lung, and Blood Institute (NHLBI) about what research is being done to tackle this baffling complication of COVID-19. Our conversation took place via videoconference, with him connecting from his home in Washington, D.C., and me linking in from my home just up the road in Maryland. Here’s a condensed transcript of our chat:

Collins: I’m going to start by asking about the SARS-CoV-2-induced blood clotting not only in the lungs, but in other parts of the body. What do we know about the virus that would explain this?

Gibbons: It seems like every few weeks another page gets turned on COVID-19, and we learn even more about how this virus affects the body. Blood clots are one of the startling and, unfortunately, devastating complications that emerged as patients were cared for, particularly in New York City. It became apparent that certain individuals had difficulty getting enough oxygen into their system. The difficulty couldn’t be explained entirely by the extent of the pneumonia affecting the lungs’ ability to exchange oxygen.

It turned out that, in addition to the pneumonia, blood clots in the lungs were compromising oxygenation. But some patients also had clotting, or thrombotic, complications in their veins and arteries in other parts of the body. Quite puzzling. There were episodes of relatively young individuals in their 30s and 40s presenting with strokes related to blood clots affecting the arterial circulation to the brain.

We’re still trying to understand what promotes the clotting. One clue involves the endothelial cells that form the inner lining of our blood vessels. These cells have on their surface a protein called the angiotensin-converting enzyme 2 (ACE2) receptor, and this clue is important for two reasons. One, the virus attaches to the ACE2 receptor, using it as an entry point to infect cells. Two, endothelial-lined blood vessels extend to every organ in the body. Taken together, it seems that some COVID-19 complications relate to the virus attaching to endothelial cells, not only in the lungs, but in the heart and multiple organs.

Collins: So, starting in the respiratory tree, the virus somehow breaks through into a blood vessel and then gets spread around the body. There have been strange reports of people with COVID-19 who may not get really sick, but their toes look frostbitten. Is “COVID toes,” as some people call it, also part of this same syndrome?

Gibbons: We’re still in the early days of learning about this virus. But I think this offers a further clue that the virus not only affects large vessels but small vessels. In fact, clots have been reported at the capillary level, and that’s fairly unusual. It’s suggestive that an interaction is taking place between the platelets and the endothelial surface.

Normally, there’s a tightly regulated balance in the bloodstream between pro-coagulant and anticoagulant proteins to prevent clotting and keep the blood flowing. But when you cut your finger, for example, you get activation for blood clots in the form of a protein mesh. It looks like a fishing net that can help seal the injury. In addition, platelets in the blood stream help to plug the holes in that fishing net and create a real seal of a blood vessel.

Well, imagine it happening in those small vessels, which usually have a non-stick endothelial surface, almost like Teflon, that prevents clotting. Then the virus comes along and tips the balance toward promoting clot formation. This disturbs the Teflon-like property of the endothelial lining and makes it sticky. It’s incredible the tricks this virus has learned by binding onto one of these molecules in the endothelial lining.

Collins: Who are the COVID-19 patients most at risk for this clotting problem?

Gibbons: Unfortunately, it appears right now that older adults are among the most vulnerable. They have a lot of the risks for the formation of these blood clots. What’s notable is these thrombotic complications are also happening to relatively young adults or middle-aged individuals who don’t have a lot of other chronic conditions, or comorbidities, to put them at higher risk for severe disease. Again, it’s suggestive that this virus is doing something that is particular to the coagulation system.

Collins: We’d love to have a way of identifying in advance the people who are most likely to get into trouble with blood clotting. They might be the ones you’d want to start on an intervention, even before you have evidence that things are getting out of control. Do you have any kind of biomarker to tell you which patients might benefit from early intervention?

Gibbons: Biomarkers are being actively studied. What we do know from some earlier observations is that you can assess the balance of clotting and anticlotting factors in the blood by measuring a biomarker called D-dimer. It’s basically a protein fragment, a degradation product, from a prior clot. It tells you a bit about the system’s activity in forming and dissolving clots.
If there’s a lot of D-dimer activity, it suggests a coagulation cascade is jazzed up. In those patients, it’s probably a clue that this is a big trigger in terms of coagulation and thrombosis. So, D-dimer levels could maybe tell us which patients need really aggressive full anticoagulation.

Collins: Have people tried empirically using blood thinners for people who seem to be getting into trouble with this clotting problem?

Gibbons: There’s a paper out of the Mount Sinai in New York City that looked at thousands of patients being treated for COVID-19 [1]. Based on clinical practice and judgments, one of the striking findings is that those who were fully anticoagulated had better survival than those who were not. Now, this was not a randomized, controlled clinical trial, where some were given full anticoagulation and others were not. It was just an observational study that showed an association. But this study indicated indirectly that by giving the blood thinners, changing that thrombotic risk, maybe it’s possible to reduce morbidity and mortality. That’s why we need to do a randomized, controlled clinical trial to see if it can be used to reduce these case fatality rates.

Collins: You and your colleagues got together and came up with a design for such a clinical trial. Tell us about that.

Gibbons: My institute studies the heart, lung, and blood. The virus attacks all three. So, our community has a compelling need to lean in and study COVID-19. Recently, NIH helped to launch a public-private partnership called Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV). As the name spells out, this initiative provides is a clinical platform to generate life-saving treatments as we wait for the development of a vaccine.

Through ACTIV, a protocol is now in the final stages of review for a clinical trial that will involve a network of hospitals and explore the question: is it sufficient to try a low-dose thrombo-prophylactic, or clot preventative, approach versus full anticoagulation? Some think patients ought to have full anticoagulation, but that’s not without risk. So, we want to put that question to the test. As part of that, we’ll also learn more about biomarkers and what could be predictive of individuals getting the greatest benefit.

If we find that fully anticoagulating patients prevents clots, then that’s great. But it begs the question: what happens when patients go home? Is it sufficient to just turn off the drip and let them go their merry way? Should they have a low dose thrombo-prophylactic regimen for a period of time? If so, how long? Or should they be fully anticoagulated with oral anticoagulation for a certain period of time? All these and other questions still remain.

Collins: This can make a huge difference. If you’re admitted to the hospital with COVID-19, that means you’re pretty sick and, based on the numbers that I’ve seen, your chance of dying is about 12 percent if nothing else happens. If we can find something like an anticoagulant that would reduce that risk substantially, we can have a huge impact on reducing deaths from COVID-19. How soon can we get this trial going, Gary?

Gibbons: We have a sense of urgency that clearly this pandemic is taking too many lives and time is of the essence. So, we’ve indeed had a very streamlined process. We’re leveraging the fact that we have clinical trial networks, where regardless of what they were planning to do, it’s all hands on deck. As a result, we’re able to move faster to align with that sense of urgency. We hope that we can be off to a quick launch within the next two to three weeks with the anticoagulation trials.

Collins: This is good because people are waiting on the vaccines, but realistically we won’t know whether the vaccines are working for several more months, and having them available for lots of people will be at the very end of this year or early 2021 at best. Meanwhile, people still are going to be getting sick with COVID-19. We want to be able to have as many therapeutic options as possible to offer to them. And this seems like a pretty exciting one to try and move forward as quickly as possible. You and your colleagues deserve a lot of credit for bringing this to everybody’s attention.

But before we sign off, I have to raise another issue of deep significance. Gary, I think both of us are struggling not only with the impact of COVID-19 on the world, but the profound sorrow, grief, frustration, and anger that surrounds the death of George Floyd. This brings into acute focus the far too numerous other circumstances where African Americans have been mistreated and subjected to tragic outcomes.

This troubling time also shines a light on the health disparities that affect our nation in so many ways. We can see what COVID-19 has done to certain underrepresented groups who have borne an undue share of the burden, and have suffered injustices at the hands of society. It’s been tough for many of us to admit that our country is far from treating everyone equally, but it’s a learning opportunity and a call to redouble our efforts to find solutions.

Gary, you’ve been a wonderful leader in that conversation for a long time. I want to thank you both for what you’re doing scientifically and for your willingness to speak the truth and stand up for what’s right and fair. It’s been great talking to you about all these issues.

Gibbons: Thank you. We appreciate this opportunity to fulfill NIH’s mission of turning scientific discovery into better health for all. If there’s any moment that our nation needs us, this is it.

Reference:

[1] Association of Treatment Dose Anticoagulation With In-Hospital Survival Among Hospitalized Patients With COVID-19. Paranjpe I, Fuster V, Lala A, Russak A, Glicksberg BS, Levin MA, Charney AW, Narula J, Fayad ZA, Bagiella E, Zhao S, Nadkarni GN. J Am Coll Cardiol. 2020 May 5;S0735-1097(20)35218-9.

Links:

Coronavirus (COVID-19) (NIH)

Rising to the Challenge of COVID-19: The NHLBI Community Response,” Director’s Messages, National Heart, Lung, and Blood Institute/NIH, April 29, 2020.

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) (NIH)


Next Page