In the history of medicine, a vaccine has rarely been developed in less than five years. One of the fastest developing ones was the current Mumps vaccine, isolated in 1963 from a child's throat wash called Jeryl Lynn. Over the next few months, the virus was systematically "weakened" in the laboratory by her father, a biomedical scientist, called Maurice Hilleman. Such a weakened or weakened virus stimulates an immune response, but does not cause the disease; The immune response protects against future infections with the actual virus. Human trials were conducted over the next two years and the vaccine was approved by Merck in December 1967.
The development of antiviral drugs has generally also taken decades. effective combinations of them take even longer. The first cases of AIDS were described in the early 1980s; It took over a decade to develop and validate the highly effective triple drug cocktails that are the mainstay of therapy today. We are still developing new classes of drugs against H.I.V., and in particular there is no vaccine against this disease. And yet the often-cited goal for developing a vaccine against SARS-CoV-2, the virus that causes Covid-19, is 12 months, 18 outside.
Doing this is arguably the most important scientific endeavor for generations. The Times has put together a round table (of course, virtually) to help us understand the crazy complexity of the challenge and the extraordinary collaboration that has already inspired it. The group included a virologist; a vaccine scientist; an immunologist and oncologist; a biotech scientist and inventor; and a former head of the Food and Drug Administration.
Siddhartha Mukherjee is an associate professor of medicine at Columbia University and a cancer doctor and researcher. He is the author of "The Emperor of All Diseases: A Biography of Cancer", which was awarded the Pulitzer Prize for General Nonfiction in 2011, and "The Gene: An Intimate Story". He was recently appointed to Governor Andrew Cuomo's Blue Ribbon Commission to redefine New York.
Dan Barouch is director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center in Boston and professor of medicine at Harvard Medical School.
Margaret (Peggy) Hamburg is the Secretary of State for the National Academy of Medicine. From 2009 to 2015 she was Commissioner for the Food and Drug Administration.
Susan R. Weiss is a professor and vice chair of the Department of Microbiology at the University of Pennsylvania and co-director of the Penn Center for Research on Coronaviruses and Other Emerging Pathogens.
George Yancopoulos is co-founder, president and scientific director of Regeneron.
Photo illustration by Mike McQuade
George Yancopoulos: Most people do not know that the successful invention and development of new drugs or vaccines is quantifiably one of the most difficult things that people try. This is reflected in the numbers. Although there are thousands of large medical institutions and thousands of biotech and biopharmaceutical companies that involve millions of researchers and hundreds of billions of dollars annually – and all are working on new vaccines and medicines – the vast majority of efforts at the FDA fail only 20 to 50 new drugs approved each year. And each of the rare success stories usually occurs over many years, often a decade or two.
Peggy Hamburg: With Covid-19 we are moving at record speed in the history of vaccine development.
Siddhartha Mukherjee: Can you give a number of how quickly we can develop an effective vaccine? Is the 12 to 18 month period we heard realistic?
Dan Barouch: The hope is that it will be within a year, but this is in no way guaranteed. This projection is refined over time – and a year requires that everything runs smoothly from that point on. That has never been done before. And security cannot be compromised.
Hamburg: Realistically, the 12 to 18 months that most people said would be a pretty good marker, but still optimistic.
Susan R. Weiss: I agree.
Mukherjee: In order to consider whether there is a way to speed up this process, let's first talk about how the search for a vaccine usually works. Dan, what is the general principle of what a vaccine is and how it works?
Barouch: The aim of a vaccine is to trigger an immune response against a virus or a bacterium. Later, when a vaccinated person is exposed to the actual virus or bacterium, the immune system quickly blocks or controls the pathogen so that the person does not get sick. The immune cells that make antibodies are called B cells. Once triggered by a vaccine to elicit an immune response, some of these B cells can last for years and are always ready to produce antibodies against the pathogen when it is encountered, protecting them from the disease over a longer period of time.
Hamburg: Under normal conditions, the development of drugs and vaccines begins with "preclinical" work – basic research – to identify the type of disease in question.
White: In virology laboratories like mine, we try to identify the viral proteins that a vaccine could target, usually the protein that recognizes and binds to the host cell receptor. All corona viruses have a so-called spike protein, which gives the virus its corona-like morphology, the "crown-like shape" that can be visualized with an electron microscope. To penetrate a cell, the spike protein binds to a receptor – usually another protein – on the cell's outer membrane. This ultimately leads to the genetic material of the virus, in this case an RNA-protein complex, being internalized in the cell. And once that happens, replication can begin and a person can get sick. If you can identify the viral protein that interacts with the cellular receptor, you can try creating a vaccine. This spike protein is a particularly attractive candidate for a vaccine because it is a protein that adheres most clearly outside the surface of the virus and is therefore the part of the virus that is most visible to the immune system.
Mukherjee: What different approaches can you take when looking for vaccines?
Barouch: A proven vaccine approach is a completely inactivated virus vaccine. In this case, the actual virus is grown in the laboratory, for example in cells or eggs, and then "inactivated" with chemicals or another method of production, but is not able to infect cells, but is still able to trigger an immune response. Sinovac Biotech, a company in China, currently has an inactivated SARS-CoV-2 vaccine in clinical trials. The pros are that there is a long clinical history of several vaccines that have been successful in this regard, such as the inactivated polio vaccine and the inactivated flu vaccine. The disadvantages are that there are always some security aspects to prove that the virus has been completely inactivated. If the virus is not completely inactivated, there is a risk that it will actually cause the disease.
Because of these problems, many groups are working on approaches called gene-based vaccines. Gene-based vaccines such as DNA vaccines and RNA vaccines do not consist of the entire virus particle. Rather, these vaccines use only a small part – sometimes only one gene – of the virus.
This still leaves open the question of how this gene can get into human cells. A vector-based vaccine uses a delivery vehicle – an example would be a recombinant adenovirus, a "harmless virus" carrier like a cold virus – to deliver the protein into a person's cells. For example, you can take the spike protein DNA from SARS-CoV-2 and use genetic engineering techniques to “sew it together” into the DNA of the harmless cold virus. The virus delivers the spike protein DNA in cells, but cannot replicate in cells, making it a safe delivery system. Still other approaches use purified proteins like the spike protein itself as vaccines.
Yancopoulos: This gene-based approach was used in the case of Ebola. Scientists found that the protein that the virus uses to penetrate human cells is known as GP protein. They were able to make a very successful vaccine. They actually used genetic engineering to assemble the GP protein into a benign virus. When this virus infected cells, it formed the GP protein, and the body recognized this protein as "foreign" and made antibodies against it.
Mukherjee: There is also the idea of getting rid of the "harmless" virus entirely and using only a section of a viral gene as an inoculum. As soon as the sequence of the SARS-CoV-2 genome became available in January, it became possible to design such a virus gene snippet. For reasons that we still do not fully understand, the body's own cells take up this viral gene without a carrier and produce viral protein from it. Why and how cells absorb this so-called naked DNA or RNA is still being worked out, but the viral protein is recognized as "foreign" because it has never been seen by the body and the host raises antibodies against it. And since it is not transmitted by a virus, this type of vaccine can be easier to manufacture at first, although it can be difficult to scale up. This is the approach Moderna is taking to make a vaccine. In Moderna's case, it's about using RNA as an inoculum.
But what is the current track record of a real human vaccine against a real human disease using these genetic techniques?
Barouch: There are currently no approved DNA or RNA vaccines. Some of them were tested in early clinical trials for safety and ability to elicit an immune response. However, they have not been tested in large-scale efficacy studies, mass-produced, or approved for clinical use.
Mukherjee: Yes, so we have to be very careful with these vaccines. The data discussed by Moderna in May suggest that your vaccine can raise antibodies in humans. This happened in eight patients. Whether this protects against SARS-CoV-2 and how long the protection lasts is an open question. This is all the more so as older people need special protection and we need to understand how much of this or similar vaccines elicit long-term immunity in older people, where the immune system may already be somewhat weakened.
Once you have a vaccine you want to test, start animal testing. What animals are coronavirus vaccines and medications tested on? And how do scientists know which ones to use?
White: An ideal animal model is one that reproduces human disease as accurately as possible – for example, observing clinical symptoms that are similar to human symptoms, virus replication is observed in similar organs, the immune response that reflects in humans, and so on. In addition, an animal model is often used to show whether a virus can be transmitted from an infected to a non-infected animal. Scientists use animal models to understand how the virus causes disease. They are also useful for determining whether a vaccine is successful in preventing infection, or whether a drug can reduce or eliminate the disease. With Covid-19 there is currently a hamster model that apparently is quite well suited to mimicking the disease, as well as promising research results with mice, ferrets and also non-human primates. Neither of these models is perfect, but each of them says something about the immune response and can be useful for testing the effectiveness of the vaccine and for antiviral therapy.
Mukherjee: Dan, you worked with the monkey model and a genetically modified vaccine. Can you tell us more about it?
Barouch: We are working with Johnson & Johnson to develop a SARS CoV-2 vaccine. This vaccine is a recombinant adenovirus vector – a cold virus that has been engineered to be harmless – to deliver the spike protein to the cells. This is an efficient way to induce strong immune responses to a pathogen and also triggers permanent immune responses.
There are two important scientific questions related to vaccine development that are critical. Is there evidence that the natural immunity triggered by an infection protects against a later encounter with the virus? And then of course there is the question of which vaccines should be tested and how effective they will be. We have just published some preliminary answers to these questions in the animal model for monkeys.
In the first experiment, we infected nine monkeys with SARS-CoV-2 in the nose and lungs. All animals developed viral pneumonia similar to human disease, except that the monkey disease was mild and all animals recovered. 35 days later, we exposed the animals to the virus a second time – and found that all the animals were protected. There was no virus or very low virus concentrations in the lungs. This is an important question because in the past it has proven to be much easier to develop vaccines if there is a natural protective immunity to the virus. For H.I.V. for example, there is no natural protective immunity, and this is part of the reason why H.I.V. Vaccines were so difficult to develop.
In the second study, we developed a number of prototype vaccines. These were vaccines with "naked DNA" – those without delivery vehicles. These are not the vaccines we want to bring to the clinic, but these prototype DNA vaccines can teach us a lot about the immune responses needed to protect against this virus. We used six different versions of the spike protein gene – some encode all of the protein, others with smaller pieces. 25 monkeys received these vaccines and 10 received saline as a control only. Each monkey received two shots of vaccination. Six weeks after the first shot, they were exposed to the virus and we found that vaccinated animals were protected from SARS-CoV-2. Eight of the 25 animals had no virus after exposure and the remaining animals showed low virus concentrations. Most importantly, the amount of antibodies induced by the vaccine correlates with the level of protection. This biomarker can therefore be useful to monitor vaccine studies in the future. The full-length spike protein seemed to work best.
The implications of these two studies are that both natural immunity and vaccine-induced immunity may exist in primates and that the amount of antibody can serve as a useful marker for the effectiveness of the vaccine. But of course these are animal studies and we have to examine these questions in humans.
Mukherjee: What happens next to turn this data into a real vaccine?
Barouch: DNA encoding the full length spike protein was sutured into the common cold virus vector to more efficiently transport the spike protein DNA into cells. This is the basis of the vaccine that we are developing with J. & J.
Mukherjee: In addition to the J. & J. and Moderna vaccines, there are several other programs. One is the Oxford program. What do we know about it
Barouch: The Oxford vaccine is based on a chimpanzee cold virus and also encodes the spike protein. Early data show that the vaccine in monkeys after exposure to SARS-CoV-2 was able to reduce the amount of virus in the lungs but not in the nose. This vaccine has started early human testing, but we are still waiting for final data. Several vaccines are also in clinical trials in China, including Sinovac's inactivated virus vaccine and another vaccine based on a human cold virus.
Photo illustration by Mike McQuade
Mukherjee: What happens next if you know the vaccine you want to test?
Barouch: Vaccine development for a new pathogen traditionally takes many years or even decades. The process involves manufacturing on a small scale; Clinical studies in phases 1, 2 and 3; and then regulatory approval and large-scale manufacturing. For SARS-CoV-2, the goal is to significantly compress these schedules without compromising security. This is critical for any vaccine that is given to a large number of people.
Hamburg: And there are many hurdles that appear on the way. Sometimes developers have a good idea, but can't turn it into a usable vaccine. Or you have unexpected side effects in early human studies. Worse, you may find security or effectiveness issues below, or you may not be able to reliably scale manufacturing or have regulatory issues.
Mukherjee: Guide us through human testing.
Yancopoulos: The first human studies are called phase 1 studies and consist of small "safety studies" that examine increasing doses of the medicine to prove that you can achieve an effective level of the medicine without any obvious harm. This usually takes a few months to a year or two. If you are satisfied that the phase 1 study found that an effective amount of the drug did not cause obvious harm (albeit with the small number of patients in phase 1), proceed to the next phase of the studies, phase 2, continue Ensure safety with larger numbers of patients and at the same time show that your medication has a beneficial effect.
For example, phase 2 could show that a drug lowers “bad cholesterol”. However, this does not necessarily mean that heart attacks are prevented. Only if you conduct very large, well-controlled phase 3 studies can you demonstrate that lowering "bad cholesterol" can also prevent heart attacks and save lives. For example, for the heart disease medication Praluent developed by my company, we were able to show that in phase 2 studies with a few hundred patients it effectively lowered "bad cholesterol" but the phase 3 study that was required to show that it prevented heart attacks The improved survival included about 20,000 patients and about five years.
Mukherjee: In what you have just described, phase 1 alone can last up to two years. How can we speed up the whole process?
Hamburg: Well, we cannot give up the rigor of science. And we can't give up the ethics of our studies either. But frankly, we can ask developers to take more risks themselves. Vaccine development can be costly and success uncertain. Compared to a drug that anyone can take every day, the return on investment is quite high compared to the risk of failed development for vaccines. With vaccines often viewed as a public good and protecting both people and communities, there can be significant pressure on companies to limit vaccine prices. Therefore, a company rarely has a “blockbuster” vaccine, such as cancer treatment, an ulcer medication, or a cholesterol-lowering drug. There are also liability issues because you give a healthy person a vaccine to protect them from disease rather than treating an existing problem. The compromise between development risk and benefit therefore often does not favor vaccines. To manage these risks, tests with different vaccine candidates are usually carried out step by step.
Barouch: For Covid-19, developers speak of performing as many steps as possible in parallel and not sequentially. For example, several vaccine manufacturers are willing to take enormous financial risks – they plan to produce on a large scale before they know whether the vaccine is working or not.
There may be half a dozen vaccines reaching phase 3. How do we choose which ones go forward? Do we prioritize vaccines that are similar to those that have previously been tested on humans and have shown safety and efficacy? Or are we turning to vaccines that can be mass-produced quickly and safely? Ultimately, prioritization is a complicated process that involves many decisions. The F.D.A. must be involved, as well as governments and regulators and stakeholders around the world. There are questions about security, effectiveness, manufacturability, and scalability that need to be addressed.
Hamburg: Obviously we are looking for those that work in the first studies. But we don't just need a vaccine that works. We need one that can be reliably scaled to be manufactured in very large quantities. Ideally, it is one that does not require multiple doses to be effective, certainly not beyond a two-dose regime. And ideally, no cold storage would be required, making it more accessible in low-resource environments. In addition to safety and effectiveness, there are also properties of a vaccine that will play a role.
Mukherjee: Are there other ways to speed up the process? Typically, you go into phase 3 trials, for example, giving 15,000 people the vaccine you are testing and 15,000 people a placebo. And then wait and see how many of those with the vaccine have the disease compared to the numbers given the placebo. But of course that takes a long time. You have to wait months or years to see this natural experiment. An ethical possibility that some experts have questioned is the use of so-called “challenge” studies, in which young, healthy people are vaccinated and then deliberately exposed to the virus. This would only happen if the safety of the vaccine was established and there was evidence that there was an immune response. But what are the ethical concerns about speeding up a vaccination process?
Barouch: It is considered ethical for certain pathogens to conduct human studies, but typically only for pathogens for which there is a highly effective treatment. For example, there is a very widespread and effectively used human challenge model for malaria, in which vaccines or other interventions can be tested. Volunteers can be vaccinated with malaria and, if they develop the disease, treated quickly so that they don't really get sick.
Mukherjee: Why can't we do that for Covid-19?
Barouch: The dilemma for Covid-19 is that curative therapy is currently not available. So if a volunteer becomes seriously ill in a potential human challenges study, there may be no way to cure that person. Indeed, far from it: the medication in our armor is not perfect, and therefore we have no guarantee that we could "save" someone who became seriously ill.
White: I'm not an ethicist, but I feel that trying to challenge is too dangerous. Young people can get pretty sick and die from Covid-19.
Mukherjee: If we could develop a drug or antibody that could alleviate the disease, we would still have to think about the ethical concerns of a human challenge. There is also the question of who volunteers for such a challenge. There was a whole story – extremely worried – in which minorities were used as test subjects without their understanding or consent. How do we ensure that volunteers understand consent? How do we ensure that they are not given perverse incentives? A young person might think that if vaccinated and challenged, he has an “immunity pass” against the disease. But what if they actually get sick and we don't have effective therapy? The question of a challenge experiment therefore requires both deep ethical thinking – who, what, how many – and scientific thinking: is there a strategy to "save" a patient if the challenge led to a real illness?
Hamburg: There is also the question of the extent to which a challenge study on young healthy patients tells us what we need to know. When we conduct a study in these least risk patients, do we get enough information about the value of the vaccine in the elderly, who in many ways are the primary target for this vaccine?
Barouch: Absolutely. The problem for Human Challenge trials that goes beyond ethical issues is that a controlled Human Challenge experiment does not necessarily show how a vaccine actually behaves in the real world. Participants in such challenge studies would likely be young, healthy, least risky people. Therefore, the data generated may not be applicable to older and vulnerable groups who need to be protected with a vaccine. There can also be different doses and different virus variants.
Mukherjee: Peggy, is there anything we should do while waiting for all of these tests?
Hamburg: Well, I think we definitely have to think about the scale-up and manufacturing problems, as we said earlier. Another issue we need to think about is working with the communities where these large-scale Phase 3 studies are being conducted. Some are conducted in the United States, but others are located in other locations around the world – in locations with fewer resources that may not have the clinical research infrastructure we have here, regardless of whether we have enough trained researchers or sophisticated health are care services they need, such as laboratory and diagnostic tools, and basic things like cooling and cold storage.
Mukherjee: To speed up the vaccine development process, we have three things ahead of us: we have cleaner and probably safer vaccine manufacturing technologies; We know the viral proteins that are likely to trigger a good immune response. and we know how to measure this immune response with much greater accuracy in people who have been given a test dose of the vaccine. We hope that all of this will speed up the Phase 1 security trials, some of which started between March and May, so that they can be completed in four to six months. We then look at a period of approximately 12 months to test the vaccine in real human populations. So it seems that we are approaching the 18-month marker. Dan, how do you see the time it takes to actually use the vaccine in the world population once we have it?
Barouch: There are two schedules that are important. One of them is the infrastructure and schedule required to produce a large number of vaccine doses, as well as a separate, possibly different, schedule to actually use the vaccine.
Hamburg: With regard to manufacturing, you have probably heard of Bill Gates' decision to invest in a number of different types of manufacturing capacity to cover the different categories of vaccines without knowing which of the different types of vaccine candidates are actually used to make it across the finish line.
Mukherjee: Correct so that once the “winner” is identified, the winner can go forward without having to wait for capacity.
Barouch: The reason to increase this capacity in advance is that different vaccines are made very differently. Beispielsweise ist der Herstellungsprozess für einen RNA-Impfstoff völlig anders als für einen Impfstoff auf Basis eines Adenovirusvektors. Um einen Impfstoff schnell einsetzen zu können, nachdem die klinische Wirksamkeit nachgewiesen wurde, muss mit der Herstellung mehrerer Impfstoffkandidaten in großem Maßstab begonnen werden, bevor die Wirksamkeit des Impfstoffs nachgewiesen werden kann.
Hamburg: Aber selbst wenn diese Initiative voranschreitet, kann es in der Öffentlichkeit zu Missverständnissen über die Herausforderungen von Scale-up und Fertigung kommen. Sobald ein Impfstoff zugelassen ist, wird er am nächsten Tag nicht mehr für jeden verfügbar sein, der ihn möchte.
Mukherjee: Erzähl uns davon. This is important.
Hamburg: Die Herstellung muss qualitativ hochwertig und konsistent erfolgen. Es werden Materialien benötigt, die nur begrenzt verfügbar sein können, z. B. die Fläschchen und Stopfen, die Sie zum Verpacken benötigen. Und dann gibt es Ketten für die Verteilung, und manchmal müssen Impfstoffe bei sehr niedrigen Temperaturen eingefroren werden. Sie müssen also alle wichtigen Systeme für Herstellung, Verpackung, Lieferung und Vertrieb in Betrieb nehmen und die Lieferketten fließen lassen, um tatsächlich einen zugelassenen Impfstoff in die Körper der Personen zu bringen, die ihn benötigen.
Mukherjee: Und dann kehrt dies zur Verteilung und Inokulation des Impfstoffs und den darauf folgenden epidemiologischen Studien zurück.
Hamburg: Ja, ich denke, wir müssen Systeme schaffen, um eine faire und gerechte und auf die öffentliche Gesundheit ausgerichtete Verteilung des Impfstoffs sicherzustellen. Eine Sorge, die viele haben, ist, dass es einen großen nationalistischen Druck für die Länder geben wird, zu versuchen, so viel Impfstoff wie möglich für die Verwendung innerhalb ihrer eigenen Grenzen zu beschaffen, doch letztendlich hängt die Sicherheit eines Landes oder einer Gemeinschaft von der Adressierung und dem Schutz ab gegen dieses Virus auf der ganzen Welt.
Fotoillustration von Mike McQuade
Yancopoulos: Wie wir bereits gesagt haben, könnte es bei all den Herausforderungen bei der Entwicklung, Erprobung, Herstellung und dem Vertrieb eines sicheren und wirksamen Impfstoffs – egal wie viel Aufwand so viele Wissenschaftler und Unternehmen in das Problem stecken – noch Jahre oder sogar länger dauern. Aus diesem Grund ist es so wichtig, parallel zusätzliche Anstrengungen zu unternehmen, um sich gegen diese Pandemie zu wehren. Wenn wir ein bis zwei Jahre oder länger keinen sicheren und wirksamen Impfstoff haben, müssen wir andere Behandlungen als Brücke zu einem Impfstoff entwickeln, damit die Gesellschaft einen Weg zur Wiedereröffnung und Funktionsweise finden kann, während wir auf einen warten Impfstoff.
Mukherjee: Also lasst uns rückwärts arbeiten, während wir hektisch auf den Impfstoff hinarbeiten. Was können wir jetzt tun, das hilft? Wie können wir uns von unserem Aufenthaltsort – Isolieren, Quarantäne, Maske, Entfernung – zu einer Therapie bewegen, die uns mit dem Impfstoff verbindet?
Yancopoulos: Die Welt hat sich für das Medikament Remdesivir interessiert, das den Prozess der RNA-Replikation hemmt und nachweislich in vielen Viren aktiv ist, die diese Mechanismen nutzen, um sich selbst zu replizieren.
Mukherjee: Eine erste Studie aus China, die im Lancet veröffentlicht wurde, zeigte einen eher enttäuschenden Effekt von Remdesivir. Es gab einen Hinweis auf eine klinische Verbesserung bei behandelten Patienten im Vergleich zu Kontrollen, die jedoch statistisch nicht signifikant war. Bei diesem Prozess gab es jedoch mehrere Probleme. In diese Studie wurden Patienten eingeschlossen, bei denen Symptome von einem Tag bis zu 12 Tagen auftraten, sodass das Spektrum der Schwere der Erkrankung sehr breit war. Und obwohl die Studie eine Placebo-Kontrolle hatte, hatte sie nicht viele Patienten: 236 insgesamt, 158 in der Behandlung und 78 in Placebo. Ende Mai gab es eine Studie der National Institutes of Health, die im New England Journal of Medicine veröffentlicht wurde und zeigte, dass Remdesivir eine – wenn auch wieder bescheidene – Wirkung auf Krankenhauspatienten haben könnte. Die Anzahl der Tage, die Patienten im Krankenhaus verbrachten, wurde reduziert, und die Studie deutete erneut darauf hin, dass die Mortalität von 11,9 Prozent in der Placebogruppe auf 7,1 Prozent in der behandelten Gruppe sank, obwohl dies statistisch nicht signifikant war. But again, this was a study that involved a very broad range of patients — some with moderate lung damage and some on ventilators.
Hamburg: Until there’s a vaccine, I don’t think there’s going to be one magic bullet for treating this thing, and we’re certainly not going to find that magic-bullet drug treatment in a repurposed drug pulled off the shelf.
Yancopoulos: History has told us that. Repurposed drugs are usually not panaceas.
Hamburg: And meanwhile, every day we are learning more about this virus, its life cycle and the complexity of how it causes disease. We initially thought of Covid-19 as a lung disease, and then realized that many of the people who became seriously ill had their disease course worsened by a hyperactive immune response. Now we realize that many other vital organs can be seriously compromised, including the kidneys, the gut and the brain, and that something about this virus is triggering a very dangerous hypercoagulability syndrome, where the blood starts clotting in dangerous ways. And there’s an apparent association of this novel coronavirus with a very serious hyperimmune syndrome in children, the so-called Kawasaki-like syndrome.
I think we need to draw on our best scientific understanding and the work of virologists like Susan to identify where are the targets for intervention, for what will likely be a combination therapy that addresses different points in the life cycle of the virus and the human immune response.
Mukherjee: What about using antibodies to tide us through this period? As we’ve discussed, the entire purpose of vaccines is to induce the body to make its own “protective antibodies” that bind and kill the virus. George, you have pioneered ways of making these same type of “anti-viral antibodies” outside the body, manufacturing them and purifying them and then giving them back to individuals — so these people now have antibodies against the virus. It’s like they have already been vaccinated: They now have antibodies but without needing to go through the actual vaccine step.
Yancopoulos: Right. Earlier I mentioned Ebola. Over the past 10 to 20 years, we have developed a series of technologies that are designed to make antibodies against many disease targets, including viruses. These technologies were used by our scientists to develop a cocktail of three antibodies to bind and block the GP protein of Ebola — the GP protein is the Ebola equivalent of the spike protein — our so-called REGN-EB3 cocktail, and this treatment was very effective in patients already infected with Ebola, as shown by the World Health Organization in a clinical trial. And now we have used these same technologies to rapidly make an antibody cocktail — REGN-COV2 — that binds and blocks the spike protein of Covid-19.
Mukherjee: Explain what that means.
Yancopoulos: You can almost think of it as a temporary vaccine. Instead of waiting for a vaccine that will make the body make its own antibodies against the virus, we can make exactly those kinds of antibodies and inject them into people.
Mukherjee: And how long would that take?
Yancopoulos: For Ebola, we went from starting the project to being in clinical trials in just nine months. With Covid-19, we’ve cut that in almost half: We have already made thousands and thousands of these antibodies and started to grow them up and tested them for blocking the virus. And we plan to start human trials in June. We will conduct three types of trials. First, prophylaxis, in which we give REGN-COV2 to patients not yet infected but at high-risk and hopefully show we can prevent infection — much like a vaccine would hope to do but not inducing the “permanent immunity” that a vaccine can confer. Then, we will give REGN-COV2 to patients recently infected, who are asymptomatic and/or who don’t have severe disease, and see if we can rapidly “cure” them and eliminate the virus and prevent them from progressing to the severe-and-critical stage that would require hospitalization and ventilation. Then, finally, we would give the REGN-COV2 to severe-and-critical-stage patients, who are in the hospital, many on ventilators, with poor prognosis, and hopefully show we can rescue them, get them off ventilators and save their lives.
Mukherjee: And how long would the antibodies last in terms of protection?
Yancopoulos: We hope each injection should last at least a month, if not several months. Beyond this antibody cocktail, there are quite a few drugs that are being repurposed to see if they have potential in Covid-19. One particularly promising story that came out of China was that blocking the inflammation that seems to be causing the lung problems in Covid-19 — in particular by blocking an inflammatory factor called interleukin-6, or IL-6, that is an important driver of the inflammation in rheumatoid arthritis — might help patients with lung problems due to Covid-19. This promise was based on a small, uncontrolled but positive experience in China. We are now doing large Phase 3 trials to definitively test whether our IL-6 blocking drug — which as I said is already approved for treating the inflammation in rheumatoid arthritis — may help with the lung inflammation in Covid-19 patients who are critically ill. But if you look at either repurposed drugs like remdesivir or even the IL-6 blocking approach, those are not the sort of drugs that I think would make Dan happy, because they are just incremental.
Hamburg: Or me.
Yancopoulos: Or anybody. But they could provide a benefit. Every life that’s saved or every disease course that’s shortened is important.
Mukherjee: But the incremental effects that you are describing may be because the trials are still being run on patients with moderate to severe disease and in particular on hospitalized patients. In virtually every infectious disease, the use of antibacterials or antivirals or even antibodies against a virus early in the course of disease is better. In terms of remdesivir, it’s possible that the drug is much more likely to be efficacious when used early than late, and in fact, the published trial from the N.I.H. has a hint of that. As we just said, thus far, the trials have generally involved a broad spectrum of patients — hospitalized patients and some of the sickest — and the benefits have been modest. But experts such as Francisco Marty, an infectious-disease doctor at Brigham and Women’s Hospital, have argued that this was precisely the wrong population to use the drug. By the time you have lung inflammation and tissue injury, killing the virus is not enough. It’s too late; the body has turned on itself, and an antiviral drug cannot tackle the inflammation. And so a second fleet of trials is being designed to evaluate whether the drug might be more successful if given as early as possible — for instance, as soon as you have detected the virus and the oxygen level has begun to drop, particularly in high-risk patients. It would invert the paradigm: Rather than quarantine and sit at home, you would get the drug sooner rather than later. Infectious-disease doctors, such as Marty, have early evidence that this strategy works: Patients given early remdesivir recover and do not progress to the fulminant lung disease. A group of us, including Marty, are in conversations with the Gates Foundation and others to launch trials of such a strategy.
And then there’s the question of combining drugs: Perhaps an antiviral drug would work even better if used in combination with antibodies. But all of this is logistically complex. All these drugs have to be given intravenously, so you have to go to an infusion center to get them. But I cannot emphasize enough the urgency of doing these early-treatment trials. It would be really a shame to give up a valuable drug in our very limited armamentarium because we couldn’t study the right patients. And the drug itself is in short supply, so every time it’s used on a patient that it would not benefit, we are losing ground. We need political support, financial support and support from Gilead, the manufacturer, to get this urgent early treatment trial done as soon as possible.
Susan, what is your sense of combining two targets? Maybe a replication inhibitor along with an antibody. And I know you’ve been involved with other laboratories, testing new drugs. What is your sense of the development of these drugs?
Weiss: That might turn out to be useful, but right now drugs are still being evaluated. Quite a few people are testing all kinds of F.D.A.-approved drugs and unapproved drugs against the virus. There are a lot of potential drug targets in the viral-replication cycle — that is, the enzymes that are needed to replicate the virus as well as the cellular factors needed for the virus to enter the cell. And I guess I feel like a lot of compounds may inhibit replication of the virus, especially in combination and aimed at multiple targets. But I don’t know how many of them will actually become drugs. In addition, replication inhibitors may not be enough to stop the virus after the early stages of infection, when the individual may be asymptomatic. We may need a combination of an antiviral drug to be effective early in the disease and an anti-inflammatory drug for the later “cytokine storm” phase of the disease.
Mukherjee: Yes, just because a compound inhibits the virus in a petri dish, doesn’t mean that it can immediately become an antiviral drug for human use. The compound might be toxic to humans. It might be degraded into an inactive substance by the body. Its dose might be so high that it’s impossible to administer. But I do think while we’re waiting for the antibodies and the vaccines, it seems reasonable to proceed with testing thousands of drugs against the virus — called “drug screening” — so that if something does come up, we might find a drug to combine with remdesivir or with antibodies, making an anti-viral cocktail.
From what I’ve been able to see, there is unusual urgency and cooperation among scientists in this effort.
Hamburg: It’s remarkable, in terms of the collaboration across disciplines and research institutions and sectors and borders. There’s been more openness and sharing than I’ve seen in past crises like Ebola or Zika or H1N1. Regulatory authorities around the world are coming together in ways that are very, very important to reduce barriers and to make sure that they’re bringing the best possible science to bear on decision making, trying to identify what are the critical questions that have to be asked and answered, what kind of study designs and preclinical work is going to be necessary, so that you don’t have companies facing different regulatory authorities with different standards and requests and approaches, so that the hard questions can be more effectively addressed through bringing together the best minds, wherever they are.
Weiss: I’ve never seen this before, either. Our C.D.C. permit to receive the virus, which is classified as a biosafety Level 3 agent, was approved in less than two days. We received at least two material-transfer agreements, which have to be signed by a number of institutional officials and sometimes lawyers, in a matter of hours. Both of those processes have taken much longer, sometimes weeks, in the past. This is just one sign of administrators and scientists collaborating with each other and acting extra efficiently to facilitate the science.
Barouch: I’ll just echo that. From a research perspective, I have never seen such collaborative spirit, such open sharing of materials, data, protocols, thoughts and ideas among academic groups, industry groups, government groups and the clinicians on the front lines.
Yancopoulos: I’ve seen unprecedented collaboration from all forces. I can get on the phone and call my counterpart, Mikael Dolsten, at Pfizer, and his first question is, “Well, what can we do to help?” Whether it’s scientists in academia, whether it’s people at biotech and pharma companies, whether it’s the doctors and health care workers who are at the epicenter at hospitals like Mount Sinai or Columbia in New York City, whether it’s the F.D.A. — we are all coming together, and things are happening at unprecedented rates because we realize that we have a common enemy.
Maria Toutoudaki/Getty Images (bottle); Jan Olofsson/EyeEm, via Getty Images (needle); Ilbusca/Getty Images (human figure); Guido Mieth/Getty Images (model); Hannah A. Bullock and Azaibi Tamin/C.D.C. (Covid-19).