ACTIV-2 and Operation Warp Speed: An Interview With COVID-19 Investigator, Davey Smith, MD

Davey Smith, MD, provides insight into current and future research opportunities targeting SARS-CoV-2.

The phase 2 ACTIV-2 trial (A Study for Outpatients With COVID; Identifier: NCT04518410) was recently launched at the University of California, San Diego, with a goal of assessing the safety and efficacy of potential therapies for coronavirus disease 2019 (COVID-19).  The trial is part of NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) initiative designed to speed prevention and treatment efforts targeting SARS-CoV-2.

Davey Smith, MD, MAS, professor of medicine and chief of the Division of Infectious Diseases and Global Public Health at the University of California, San Diego, met with Sara Gianella Weibel, MD, on behalf of Infectious Disease Advisor, to discuss where scientists are in the fight against SARS-CoV-2 and what might come next.

Sara Gianella Weibel, MD (she/her): How have your life and daily work schedule changed since the start of the COVID-19 pandemic? 

Davey Smith, MD (he/his):  Like many people, the pandemic has completely interrupted my daily schedule. My clinical work in the hospital is always very busy because we have to take care of many patients with COVID. My other job in the lab has also changed significantly. The current regulations at our university allow only a limited number of people to be in the lab at any one time, and so I work mostly from home to allow more people who do the actual bench work to be there in person. I also started a new clinical trial for COVID-19, and this has kept me working about 10 to 12 hours a day with innumerable conference calls. We are trying to get it up and running at record speed.

Dr Gianella Weibel: How well do scientists understand the novel coronavirus? What areas require more research?

Dr Smith: Scientists have learned more about SARS-CoV-2 pathogenesis in the past few months than any other new viral pathogen in history. Every week, some groundbreaking research paper comes out that deepens our understanding of viral transmission, infection, and disease, but more research is needed, especially translated research. Much of this work was directly informed by the scientific and technological advances created during HIV research, which highlights the importance of foundational research, which cuts across pathogens.

Dr Gianella Weibel: What type of COVID-19 research are you currently working on?

Dr Smith: We are working in a number of different areas. As a translational virologist, I am particularly interested in understanding how the virus attacks the human body and how it interacts with the immune system. We collect blood from people who have been exposed to the virus, and we follow them over time. We then try to tease out in the lab what’s going on with the virus and why some people get sick and other people don’t. Another part of my research is to actually run a clinical trial to identify a therapy to prevent people from getting sick with COVID-19.

At the moment, we only have limited medications for hospitalized people who are very sick. For example, medications like remdesivir or steroids (like dexamethasone) can be used to keep people from dying once they get severely sick. But we don’t have any therapy that can prevent people from progressing once they start to have symptoms, so that they do not need to go to the hospital in the first place. In summary, the trial that I’m leading is open to people who have COVID-19 but are not yet sick enough to require hospitalization.

The ACTIV-2 trial has been designed as a master platform adaptive trial and part of Operation Warp Speed. We will test a number of different candidate drugs in our pipeline until we find 1 or more drugs that work, and then we keep going until we find even better ones. As an adaptive trial, its protocol can be continuously updated as we learn more about the biology and about the immune response, to make it more efficient and flexible. In the beginning, we schedule numerous visits and evaluations, and we collect numerous different time points and specimens. But we might find out later that we do not need all those things and we can update the trial protocol to make it more efficient and to hone down on exactly what is needed over time.

Dr Gianella Weibel: What is Operation Warp Speed and how are you involved in it?

Dr Smith: Operation Warp Speed was initiated to facilitate and accelerate the development, manufacturing, and distribution of COVID-19 vaccines, therapeutics, and diagnostics. I don’t really like the name because it sounds as though we are going really fast, which could imply that we are conducting bad research. This is absolutely not true; we are conducting great research.  We are spending a lot of time on it, but it is very condensed, and I am getting less sleep.

Dr Gianella Weibel: Are you working on a vaccine trial? Do you think a vaccine to protect against COVID-19 will be available soon?

Dr Smith: We are conducting vaccine trials at UC San Diego, and I am helping my colleagues to get those off the ground. I understand that there is a lot of excitement around a vaccine, and people think that a vaccine it going to be what gets us out of this pandemic. The research is moving very fast and scientists are doing it the right way by testing all vaccine candidates very rigorously.  Nevertheless, I don’t think a vaccine is going to be available to the general population until sometime next year.

However, let me be clear about vaccines. Right now, the US Food and Drug Administration (FDA) has said that they will allow a vaccine to be approved if it is at least 50% effective. This means that even after getting the vaccine, if I were to be exposed, I will still have a 50% chance of getting infected. What this also means is that we will still need treatments. We learned early on from the HIV epidemic that effective therapies work to reduce transmission and to extend people’s lives. Although we never found a vaccine for HIV, we were able to use biomedical interventions — like treatments and prophylaxis — to start working on how to end the HIV epidemic. We should do the same with SARS-CoV-2.

Dr Gianella Weibel: It looks like a number of therapeutic agents will be available before the vaccine. Could this help cut down on the number of people who might die from this disease? 

Dr Smith: The therapies will very likely come before the vaccine. We are going to need these therapies, even once we have a vaccine. In reality, I think that we could actually get out of this pandemic, even if we never get a vaccine. We would need to use therapies smartly and get people on them quickly. The therapies would need to work fast enough to keep people from getting sick and from spreading the virus. In this way, we could control the spread of the infection within our communities, similar to what we did with HIV therapy and HIV prophylaxis using treatments.

Dr Gianella Weibel: What are your thoughts on testing? 

Dr Smith: Testing has been problematic from the very beginning. We keep running into issues and we just do not seem to learn from our mistakes. We do not test nearly enough people, and this is because we do not have enough supplies or capability. What this means is that we are essentially blind to how bad the pandemic, and we don’t really know how it is spreading.  Without this information, we are unable to institute effective epidemic control procedures like contact tracing. In reality, if we had a really good test that we could use extensively, then we should be able to control the virus, even without a vaccine or without a therapy, by using contact tracing, isolation, and quarantine procedures.

Dr Gianella Weibel: What do you think is our strongest weapon against COVID-19? 

Dr Smith: Our most effective weapons against COVID-19 right now are basic testing, contact tracing, isolation, and masking. These methods have worked well with other types of infection.  Also, parts of the world where people have used these tactics consistently on a community level were able to get the infection under control and keep viral spread low. But for it to work, everybody needs to do their part. People have to wear a mask. People have to get tested, isolate, and quarantine, as needed. Any break from these protocols means that we could have new outbreaks that we may not be able to control. But clearly those procedures alone are not going to work everywhere, and other methods — like developing treatments, prophylaxis, and a vaccine — are still needed. And then, once we have all those tools together, we hopefully can get the epidemic under control.

Dr Gianella Weibel: What do you want people to know about COVID-19?

Dr Smith: The main thing that I want people to know is that we are all in this together, and we need everyone helping to get over it. For example, people who are young and healthy are probably not going to get very sick if they are exposed to SARS-CoV-2. But we still need their help because it is becoming increasingly clear that young and healthy people can spread the virus to older people. We all can do our part to help contain the virus by wearing masks, washing our hands, and keeping ourselves safe with appropriate social distancing procedures.

We also need to move the science forward. We need healthy volunteers for vaccine trials. In addition, if someone gets infected, they should consider participating in treatment trials so that we can figure out what new treatments might be useful for COVID-19.

Importantly, despite making up a large percentage of COVID-19 deaths, underrepresented populations are not seeing adequate enrollment in clinical trials for potential coronavirus treatments and vaccine. It is very important for COVID-19 trials to adequately enroll underrepresented populations, prioritizing their inclusion, developing a formal diversity strategy, and during site selection, working with institutions that have connected with underrepresented communities and possess the infrastructure to conduct research.

I think that if we do not ensure diversity in our COVID-19 clinical research studies to uniformly demonstrate efficacy across populations, then we may miss an important signal of efficacy or an important signal of toxicity, which could be devastating.

Dr Gianella Weibel: What are your thoughts about the current state of the COVID-19 pandemic in our country? 

Dr Smith: In my opinion, politics and science just do not mix well. At the very beginning of this pandemic, clinicians (including myself) thought that hydroxychloroquine may be used to treat COVID-19 in people who were early in their infection. There was good rationale for the use of this inexpensive and relatively safe drug. Scientists started to design a large clinical trial, which would have been the only way to determine if this drug was safe and effective in various populations. Since we did not know for sure, the only setting for the use of this drug should have been a clinical trial.

Unfortunately, the FDA put out an emergency use authorization to permit the use of this drug without definitive proof that it actually worked. In addition, politicians started advertising the drug and it became a political issue. Physicians started using it to treat people in very late stages of the disease because there was nothing else available. Eventually, it became obvious that the drug didn’t help people in the very late stages of infection and, in fact, it may have caused harm.  That outcome should have been expected from the outset because during the late stages of COVID-19, the main problem is the immune system and not so much the virus, and hydroxychloroquine was more likely to work directly against the virus.

This is an example of politics getting in the way of science: eventually, the FDA had to revise the emergency use authorization because they didn’t really do the research to figure out if hydroxychloroquine worked or not. Because the politics are so divided right now, there is no way to complete a trial of the medication for people early in the disease, so we will probably never know if it was useful for that situation.

A similar situation is happening with convalescent plasma. Clinical trials are ongoing to see if convalescent plasma works for COVID-19 and under what conditions; however, as a result of political pressure, the FDA granted an emergency use authorization allowing anybody who wanted convalescent plasma to use it outside of a clinical trial. So here again we have a therapy that has not been proven to work and yet has been given the green light for treatment. I worry that we may never find an answer to whether or not convalescent plasma works for COVID-19 because of the same issues that occurred with hydroxychloroquine.


Sara Gianella Weibel, MD, and Davey Smith, MD, have no relevant relationships to disclose.