Jacob Heilbrunn: How does the COVID-19 crisis end?

Paul Offit: German chancellor Angela Merkel said it best: “We need to get to a doubling time of longer than ten days.” The number of hospital admissions and deaths caused by COVID-19, those doubling intervals, is more than ten days. For example, on March 26 we had one thousand deaths; on March 28, two thousand. That’s a doubling time of two days. By April 1 we had four thousand deaths. That means we had a doubling time of four days. If you can get to a ten-day doubling time, it is likely that hospital discharges will exceed admissions and you can say that you accomplished what you wanted—no longer overwhelming the healthcare system. That’s what you are worried about—not that you can’t take care of these patients, but that you can’t take care of any patients.

Once you get there, things can loosen up and you can go back to work even though there still may be cases and deaths. But that is not the goal. The goal is to not overwhelm the health system and allow us to go back to work. When do we get there? I’m going to predict that by the end of April, things start to look better and we start to see a gradual increase in our doubling times.

Heilbrunn: Do you think we are likely to reach the high end of the predictions of deaths? Or is that just unknowable?

Offit: It’s surprising, isn’t it? We know that lockdowns, or sheltering in place, works. China, Singapore, Japan, and South Korea were all able to pretty much end the spread of this virus while knowing that there had to be tens of millions of people in those countries who were still susceptible. Yet still, they were able to end it—that’s a good sign.

Now Vice President Mike Pence has said that he thinks we are mimicking Italy. Italy has 13,000 deaths right now and they are roughly one-fifth our size. That would come out to 65,000 deaths, but they are predicting as many as 240,000 deaths. Which means that Italy would have to have 50,000 deaths, for us to be Italy. It’s just surprising that it could get that bad; even though Italy is still suffering deaths, it looks like their doubling time is about eight days. So it should be coming off this curve and I don’t see this 240,000 death estimate. I don’t see that. But they are also close to the data, so they could be seeing something I’m not.

We did many things wrong. We were slow to ban travel from China. We were very slow to do testing—South Korea had already done 150,000 tests by the time we had done fewer than 500. We were slow to lockdown. We had a president who, if anything, tried to play this down: “We've got it under control, it’s only a few cases, don’t worry about it.” And we were very slow to supply protective gear, ventilators, etc. so people were not getting the care they need or being protected in the manner they need to be. So we’ve done a lot of things wrong. As a consequence, we are doing worse than most countries.

Heilbrunn: So you would have banned travel from China earlier? President Donald Trump keeps bragging that he did it quickly.

Offit: Right, but if you look a little more closely at how that played out, he had to be convinced to do that. He didn’t want to offend his friend President Xi [Jinping]. China was not a good actor here. We should not have had to have a whistleblower to tell us that there was a novel virus that was killing people in Wuhan. They should have been quick to tell the world that this was going on so the world could prepare for it. They didn’t do that. But the moment it did become clear, Trump was very slow to ban travel. But once the virus was here, once there was community spread, it didn’t really matter.

You can make the same case for what is happening in New York. We were pretty slow to ban travel from Europe, when clearly there were problems in Spain, Italy, and France. I suspect that may be the reason that New York suffers so much now—there was a lot of travel from COVID-heavy territories, regions, or countries, coming into LaGuardia, coming into JFK.

Heilbrunn: You were the co-inventor of the rotavirus vaccine. How critical do you think it is that we develop a vaccine against the coronavirus? Or do you think the virus will largely burn itself out?

Offit: We certainly should not assume that it will burn itself out. We should make a vaccine as quickly, efficiently, and safely as possible. There is some good news about the vaccine. Human trial studies done decades ago show that if you are inoculated with one of the four strains of human coronavirus that circulates in our country every year and are challenged with that virus a year later, you are protected. Good. That means that there is protection—it’s probably years, not decades—but that’s a good sign. You also know which protein you are interested in. You are interested in that spike protein—the glycoprotein—that’s the protein that attaches to cells. If you can prevent the virus from attaching to cells, then you can’t get infected. And we live in an age of recombinant DNA technology where we can make that protein itself in a manner similar to the Hepatitis-B or HPV vaccine, or we can use either messenger RNA or DNA vaccines that express that protein.

So the messenger RNA approach is the one being used by Moderna and that is already in the human trials that Dr. Anthony Fauci has talked about. But they are really at the beginning of this process. You still don’t have an immunological correlate of protection; you still don’t really have a dose. The forty-five people who are being tested in Washington state have been divided into three groups of fifteen and each given a different dose. They started with a low dose, then they moved to a middle dose, and now they are moving to a higher dose. But that’s only fifteen people in each group. Really, to do this right, you would need thousands of people to make sure you are giving the right dose—not too much or too little. I presume that they will move to that, but it takes time.

Heilbrunn: What is a realistic timeline for a vaccine?

Offit: You want to make sure that a vaccine induces an immune response that you think will be safe. I’m assuming that they are not doing animal-model studies because it seems that they moved very quickly to human trials. It would have been nice to do animal-model studies. While mice aren’t bad, they do give you hints to what could be potential safety problems. But it looks like that is not happening.

When you are where they are now—which is about forty-five people tested—you do need to gradually expand that to thousands of people at the dose you think you’re looking at and make sure a significant percentage of the population is receiving that, and that that population represents the U.S. population. You want those people to develop an immune response that would protect them, even though you don’t, right now, have immunological correlate protection. We don’t know that, because we aren’t doing animal studies and we obviously aren’t doing human trial studies with this virus. Then you would need an efficacy trial, and that would best be done on healthcare workers.

Healthcare workers are the ones who are most likely to come in contact with COVID-19 patients, both by frequently being in contact and in close contact with them because they have to examine them. That would probably be the group with which to do an ethical trial, but that takes time. That takes years. For us, in the development of the Rotavirus vaccine, that took sixteen years before we got to the large, definitive, phase three trial. That was a placebo-controlled, prospective, eleven-country, four-year, $350 million trial, on 70,000 babies. That was a definitive phase three trial.

My sense is that they are moving along in this “break the glass mode,” which is to say that they will use fewer people in these studies and may bypass the FDA. They might just move to offer this. That said, to put this in perspective, Dr. Fauci is certainly right. The mRNA approach is very quickly scale-uppable. You can make very large numbers, remember you are talking about making billions, hundreds of millions of doses. But the mRNA still needs to be delivered in this complex lipid delivery system, which is not so easy to scale up. It could take a year to just scale up that part of it. And the filling takes time. Even if they use multi-dose vials, the filling alone could take a year. So, I don’t see eighteen months—Dr. Fauci could see something I don’t here, he is certainly closer to it—but I think eighteen months is a very, very, very optimistic timeline.

So, this gets back to your original question. Where are we eighteen months from now? Does this virus come back? Certainly, SARS or MERS, which were two previously novel coronaviruses, didn’t, but this is clearly a different virus. It’s clearly better adapted to growth and reproduction in the human population, so it may come back. We’ll see.

Heilbrunn: Are you worried about a recurrence of the virus in the fall? Or do you think that we will be in better shape by May? And will we have a better grasp on COVID-19 with more testing.

Offit: What you’re looking at now in terms of today’s number of cases—today is April 2 and you are looking at around 5,100 deaths so far—this is the effect of where we were three weeks ago. The virus’ incubation period is five to ten days, and then you get sick, maybe get sicker, then go to the hospital, maybe get intubated, and maybe you die. That takes about three weeks. So we are looking at what we did as a country three weeks ago. I think we are getting better at shutting down. Florida has just had a shutdown. There are a number of states that were hesitant to do that which are now shutting down. There would have been value for President Trump to have called for a nation-wide shutdown much earlier because I think we would be far more ahead of the game than we are now. What you are seeing now is more of an understanding that we have to shutdown to stop the spread. We will see the effect of that three weeks from now. By the end of April, I predict, we will start to see the falloff of this logarithmic, exponential growth curve.

Heilbrunn: What does all this imply for Americans’ attitudes towards vaccines? You had written a book called Autism’s False Prophets and about the suspicion of vaccines in America. What’s your take now?

Offit: I think vaccines are the hero of this story. It’s interesting that the most downloaded movie right now is Contagion, where vaccines were also the hero of that movie. People couldn’t wait to get the vaccine. People were lining up to get the vaccine. We want there to be a vaccine—and there is no reason to believe that we could not make a successful vaccine, I’m just questioning the timeline because you do want to make sure that it is as safe as it can be. You want to make sure that you have as much evidence that it’s safe as you can, you want it to be tested on thousands, preferably tens of thousands of people, before you give it to tens of millions of people.

You do the best you can pre-licensure to determine whether there is a safety issue, but it’s only post-licensure that you really learn that. And from what I’ve heard, this may not even go through a typical licensing process. I’m on the FDA’s so-called VRBPAC (Vaccine Related Biological Products Advisory Committee). Technically this vaccine would go through our committee first before it was licensed, but I’m not so sure that is even going to happen. It has already gone to clinical trials and after those, it may just go right to production and distribution. I am worried about that. Remember, a healthy person who is younger than forty-five years of age is very unlikely to die from this virus. You want to make sure that it’s safe before you put someone in a potentially unsafe position.

The only other thing I worry about, which I don’t think is likely at all but should be looked at, is called ADE (antibody-dependent enhancement)—which is similar to the Dengue vaccine—and that is people get the vaccine and then when they are exposed to the natural virus, the wild virus, they do worse. I don’t think that will happen, but you do want some information on that before you give it to tens or hundreds of millions of people.

Heilbrunn: Finally, what about anti-virals?

Offit: Drugs like hydroxychloroquine, azithromycin, remdesivir and favipiravir should also be tested. So we can see if these will help us decrease mortality.

Jacob Heilbrunn is the editor of the National Interest.

Dr. Paul Offit is the Director of the Vaccine Education Center and an attending physician in the Division of Infectious Diseases at Children’s Hospital of Philadelphia. His latest book is Overkill: When Modern Medicine Goes Too Far.

Image: Reuters.