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Michel Nussenzweig: Antibody hunter

Brazilian-born immunologist searches the plasma of patients who have survived COVID-19 for proteins capable of fighting the novel coronavirus

Nussenzweig, in his laboratory where he studies other inactivated viruses and attempts to identify antibodies that will neutralize SARS-CoV-2

Rockefeller University

In January, when the escalation of novel coronavirus infections was still just beginning in China, immunologist Michel Nussenzweig realized that the world was facing an unusual situation and it was time for him to act. “It was clear that this would be a big problem because of the person-to-person transmission and the speed with which it was spreading,” says the researcher, who coordinates the Laboratory of Molecular Immunology at Rockefeller University in New York.

Over the following weeks, Nussenzweig and his team of 50 scientists temporarily put aside the research they had been working on. Instead, they began searching for antibodies (proteins synthesized by the immune system) in the blood of COVID-19 survivors that would be capable of neutralizing the novel coronavirus. To accomplish this, the researchers are counting on small donations of blood from 100 people who had the disease caused by the SARS-CoV-2 virus and were cured. As of the end of March, about 30 volunteers had already donated.

Michel is the son of two Brazilian immunology researchers. His father Victor, and mother Ruth Nussenzweig (1928–2018), both studied malaria. Born in São Paulo in 1955, he spent most of his life in the United States, where he moved in the 1960s with his parents, who were being persecuted by the Brazilian military dictatorship. He graduated in medicine from New York University and earned a doctorate in immunology from Rockefeller University, where he has been a professor since 1990.

In his doctoral studies, conducted under the supervision of Canadian immunologist Ralph Steinman (1943–2011), winner of the 2011 Nobel Prize for Physiology or Medicine, Nussenzweig found that one type of defense cell—dendritic cells—are responsible for activating T lymphocytes, which attack cells infected by viruses and bacteria. More recently, Nussenzweig and his team have identified antibodies that are highly effective at neutralizing HIV in people infected with the virus, but who haven’t developed AIDS. Produced in the laboratory, these antibodies have been shown to reduce the amount of HIV in the blood in human testing. This same strategy will now be used to create a backup plan to defend against the new coronavirus.

In the following interview, given via Zoom on April 9, the researcher talks about the attempt to find antibodies effective against SARS-CoV-2, the risks and benefits of plasma transfusion, which is starting to be tested in Brazil and other countries, and how the pandemic has changed daily life at his lab and made research more collaborative.

When did you decide it was time to study the novel coronavirus?
I started thinking that we should do something about the virus in January, when it became clear that this would be a big problem because of the human-to-human transmission and the rapidity with which it was spreading in China. It was very obvious that this was something different from previous viruses in this category, such as those that cause SARS [Severe Acute Respiratory Syndrome, which appeared in 2002] and MERS [Middle East Respiratory Syndrome, identified in 2012].

What projects were you working on at that time?
We were studying human immune responses, specifically antibody responses to HIV, hepatitis, and the tick-borne encephalitis virus, which is prevalent in Europe. We had to stop everything because the university closed. About three or four weeks ago, the entire team, which is 50 people, began to dedicate itself to the new coronavirus.

Most people with COVID-19 are sick for seven to ten days and then get better. A few get much worse after this period

How did this affect the routine in the laboratory?
It’s changed the way we’re doing science because it’s so interactive. Not everyone on the team comes to the lab, because we don’t want it full of people. Those who do come wear masks, gloves, and lab coats. In addition, we are collaborating with several other labs. There are two virology laboratories here at Rockefeller University; there’s a crystallography-protein chemistry lab at California Institute of Technology [Caltech]; there’s a laboratory doing protein chemistry at the Chan Zuckerberg Initiative; and another at the University of California at San Francisco. And we’re talking to people around the world all the time about what they’re learning. So science has responded to this in an amazing way that I’ve never seen before, which is very, very collaborative, with everybody working together to try and understand as quickly as possible what is happening, and find prevention methods and cures.

Your team plans to collect blood from people who have recovered from COVID-19 and synthesize some of the antibodies they produce in the laboratory. How do you know what type of antibody to use?
We’ve asked people to voluntarily donate blood, between 100 and 200 milliliters. We separate the plasma, in which the antibodies are found, from the blood cells. In particular, we’re interested in the B lymphocytes, which are the antibody-producing cells. We use plasma to test the ability of antibodies to neutralize the virus. What we’ve found in all the other viral diseases we’ve studied is that human beings have different abilities to produce antibodies against viruses. So, just as we’re all different in many ways, from our physiques to our intellects, there is also a wide spectrum of immune responses. By testing the plasma’s neutralizing potential, we try to find the people who fight the virus best. The next step is to use the isolated protein from the virus surface to find the cells that make the antibodies with the greatest neutralizing power. The cells that produce them are then isolated, and the section of genetic material that encodes only the antibody is copied and used to synthesize the monoclonal antibodies in the laboratory, which originate from a single B lymphocyte. Then, we test whether they are able to neutralize the virus.

What else is done with the antibodies?
We also use the antibodies to map where on the virus that it’s sensitive to the immune system, where the immune system can act. By doing that we get some insight into which regions of the virus could be used to produce vaccines, by triggering the immune system’s response. Different antibodies adhere to different parts of the virus, so we can use them together. Once we have that information, we can make choices, such as writing a scientific article and publishing it. Or, if the antibodies’ neutralizing activity is good enough, we can try to produce them, and that means looking for a company to synthesize them for clinical use. Alternatively, we can also license the antibody production to a company. Our preference is to pay a company to make the antibodies, at least in the first phase, so we can study what happens and understand what the antibody is actually doing in people, without a commercial requirement to make money from it.

Why do you believe this strategy can work against the coronavirus?
It’s worked very well for HIV. We were able to find antibodies that are very potent, very broad, produce them for clinical use, test them in patients all the way through Phase 2 of clinical trials [drugs and vaccines must go through three stages of testing on humans before they are approved for marketing and large-scale use], and show that they are efficacious in combating the virus. We’ve already tested them on 300 people. We’re in the late planning stages of a large, Phase 3 clinical trial, with thousands of people, to be conducted with support from the Bill and Melinda Gates Foundation. The goal is to see if these antibodies can prevent HIV infection. Rockefeller University has licensed them to a major pharmaceutical company, Gilead. Whether the same strategy will be effective against coronavirus is another story; we cannot know until we try it. And is it worth trying? I think that question depends on whether or not we have an effective vaccine or therapy in the next six months. If we do not, the antibodies will almost certainly work, I believe, and will serve as a backup plan in case other things fail.

So, it won’t be the treatment of first choice. And it will take time to find effective antibodies against the coronavirus, correct?
It will absolutely take time to achieve, and it won’t be the first choice. But, vaccines don’t always work. We know that from dengue. We know that from a lot of HIV vaccines. It is not clear how a coronavirus vaccine will work. It may protect some people, or it may be like the dengue vaccine, and be harmful to some people. So having a backup plan is not a bad idea.

In Brazil and other countries, some research groups are trying to take plasma from people who have recovered from Covid-19 to infuse it in critically ill patients. What are the risks and benefits of this strategy?
Plasma therapy has a very long history. It was invented around the late 19th century. In fact, one of the first Nobel prizes was given for these types of passive therapies [German physiologist Emil von Behring received the Nobel Prize for Physiology or Medicine in 1901 for developing a therapy using blood serum against diphtheria]. But those passive therapies were primarily for toxins [toxic compounds] produced by the diphtheria bacteria. It saved a lot of people and was widely used to fight pneumonia and other infectious diseases around the time of the First World War. But as soon as antibiotics became available that form of therapy basically stopped for infectious diseases. In Brazil and other countries, you still use it to treat snakebites—and it’s quite effective against these toxins. In the case of COVID-19, it would be using a nineteenth century solution to a twenty-first century problem. If we are in a war, plasma therapy is a World War I weapon, and antibody therapy with monoclonals is a nuclear, guided ballistic missile.

Why are plasma therapy and monoclonal antibody therapy different if both are based on the action of antibodies?
Take, for example, the plasma of 100 people. Some people—and I don’t know who’s who—some people have a little bit of antibody, some people have no antibody, some people have bad antibodies that make the disease worse, just like dengue. And some people have good antibodies.  Now I mix these antibodies and give it to somebody else, just a little bit. Is that good or bad? Will it be effective in neutralizing the virus? I don’t know. It might be good. It might be bad. It might do nothing. Chances are, it will do nothing, even though there are some components in there that are good. In some people. And if you’re giving it to people when they are very ill it’s not at all clear that such plasma therapy is going to help them. It might help them before they get very ill. I’m not saying that it shouldn’t be tried, but, if doctors and researchers are going to try this—first of all they have to be very careful, number one. And number two, they should try to do it in some controlled manner, so we can learn whether or not it is any good. Or whether it’s actually doing harm.

What I’m most hopeful for is that there is some small-molecule drug that will act on the virus

For that matter, antibodies are generally thought of as a good thing, but can they be toxic and do harm?
It’s believed that the worst cases of dengue, the hemorrhagic fevers, are caused by antibodies, and not the virus. Some people produce antibodies that are not neutralizing. Or they are neutralizing against some varieties of the virus, but not others. Those antibodies, instead of neutralizing the virus, can actually enhance the disease, by facilitating the entry of the virus into cells that are not normally infected. So antibodies can be harmful, and dengue is an example.

So this could also happen in plasma therapy?
In theory, yes. In reality, we really hope it doesn’t, because it would be a nightmare.

Why is it so difficult to fight viruses?
There are lots of viruses that we fight very, very well. And every virus is completely different, in which parts of the body it attacks, how it interacts with the immune system, how the immune system is able to see it. Many, many people are doing a very good job fighting this virus. But of course when a large enough number of people are infected, and a small percentage of them don’t fight it very well, then it’s a tragedy.

Is it well known how the human body combats the new coronavirus?
No, we really don’t have a good understanding of how this fight takes place, or why some people do badly. But there’s something very unusual, and very interesting, about it because the typical course when people get infected with the novel coronavirus is they develop a fever and have some problems, but they’re not really sick for a week to ten days. Then, the people who do get really sick go down the tubes—they develop pneumonia, have trouble breathing, and have to be intubated. That whole syndrome is associated with something called cytokine storm, an immunological phenomenon where the immune system is overactive. So, it may be that what’s going on there is all about the virus, or it could be that it’s all about the way the immune system is dealing with the virus. Most people are sick for seven to ten days and then it all goes away, but in a few people, after that period they do very badly. And that’s associated with this immune hyperactivity, which leads to the secretion of cytokines, typically IL [interleukin] 6, IL 1, TNF [tumor necrosis factor] and GM-CSF [granulocyte-macrophage colony-stimulating factor]. There’s something important going on immunologically we don’t understand; we don’t know why that’s happening in these people, and sorting through that phenomenon will be important in learning how to prevent it.

What other strategies could work against this coronavirus?
What I’m most hopeful for is that there is some small-molecule drug that will act on the virus. There are plenty of pharmacological targets in this coronavirus, including proteases and polymerases [enzymes that, respectively, digest proteins and synthesize copies of viral genetic material]. There’s a polymerase that’s very unique to it called RNA replicase. There should be drugs that can inhibit this virus. I’m hopeful that this molecule will be identified quickly and that those drugs will be available soon, and minimize the human suffering. That’s one approach. There’s the vaccine approach, which is a good approach to take, there’s the plasma therapy approach, which is something we can do immediately—so people should try it, in a controlled fashion. And then there’s monoclonal antibodies, which is one of the parts of this armamentarium; and there are different levels of sophistication and requirements for making them available to doctors.

The state of New York has been the most affected in the United States. It’s recorded about 80,000 cases and 10,000 deaths as of April 7. Did you ever imagine that something like this could happen? What’s the scariest thing about this pandemic?
No, I didn’t. You know, it is frightening, but I think people should not be so frightened, they should just be careful. If they follow the simple advice about washing hands, about wearing a mask, about social distancing, avoiding groups of people, and minimizing contacts, then they will minimize the chances of being infected. And I think just educating people about how to avoid this is very important.

Have you been following the news from Brazil?
Not very much. I know that there was some initial reluctance to enforce or even advise about social distancing, which I think was a terrible mistake. I hope that the politicians there are realizing that this is actually a serious problem.