Fauci to Medscape: ‘We’re All In It Together and We’re Gonna Get Through It’

https://www.medscape.com/viewarticle/933619#vp_7

The huge spectrum of disease

I’ve dealt with viruses for the past 40 years, from HIV to Ebola to Zika to chikungunya to all of the others. But I’ve never seen a pathogen, and in this case a virus, with such an amazing spectrum of disease severity, going from 20% to 40% of the people who are infected having no symptoms, disproportionately leaning toward younger people. But then you have people who get mildly ill, ill enough to stay at home for a few weeks or to the point where it brings them to their knees and they have postviral syndromes, some that require hospitalizations. Some require intensive care, intubation, ventilation, and some die. Usually a virus that is good enough to kill you would make almost everybody at least a little bit sick. So we’re dealing with a serious virus here.

You have 20%-40% of the people not even getting any symptoms. And yet vulnerable people, the elderly and those with underlying conditions, can require hospitalization, intensive care, and some will even die. So it’s tough to get a consistent message that we’ve got to stop this virus; it’s a pandemic and it’s killing people.

has there been any definition of the immune response in these folks? We learn through these patient groups, like Long COVID. There have been only minimal formal publications about them. But has there been any extensive or any immune response that might explain why they have these lingering symptoms that go on for months that are quite troubling and sometimes even quite debilitating?

The one thing that we do know is, and I don’t even think this clarifies it anymore, is that when they were first looking at people who progressed rapidly — the ones who got sick, went to the hospital, they look like they’re okay, and then all of a sudden, dramatically, they just crash and go on ventilators — that was felt to be a hyperactive, aberrant immunologic and inflammatory response. And actually, I think it’s at least partially true, based on the data from the UK study in which dexamethasone in individuals on ventilators and those requiring oxygen — but not in early patients — significantly diminished the death rate.

So we do know that there’s a lot of cytokine secretion. If you measure IL-1 beta, IL-6, TNF, they’re all sky-high.

 

But I’m not so sure that gives you much insight because we know, prior to COVID, that when you get people in dire straits with a lot of inflammation, you get a bit of a cytokine storm anyway. So, yes, the immune system is aberrant.

But I think what you’re asking, and this is important, is, what is the nature of the protective immune system? Is it clearing virus and you have a hyperimmune and aberrant cytokine storm that’s giving you pathogenic symptomatology at the same time that you’re suppressing the virus? We don’t know. I have to tell you, I’m humbled by it that we don’t know. We have so many people who have gotten sick, and we can’t write a really good paper on delineating A-B-C-D or what’s going on. We just don’t know.

 

Vaccines -whats the prediction?

From the time the Chinese published the sequence on a public database, literally, it’s somewhat historic. They put it up on January 10th. On the 11th, in this room that I’m sitting in now, we had a meeting of our crew and said, “Let’s get on it. This is all hands on deck.” My vaccine research center, led by Dr Barney Graham, 2 days later got the viral sequence, got the gene, and stuck it in an mRNA, and we started developing the vaccine on January 15th — 5 days after the sequence went up. A phase 1 trial started 62 days later. It’s mind-boggling. It usually takes a couple of years before you do that. Then at the end of this month, July, we’re gonna start the phase 3 trial.

They are going into phase 3 trials sequentially, maybe a month or two after each other. The phase 3 trial for the Moderna mRNA starts at the end of July. A month or so later another will come on, and then another as we get into the fall, and then another as we get into the late fall. We are hopeful, since we’re harmonizing the approach, with protocols that are very similar so you don’t have completely different things. We’re looking at having a common data safety monitoring board, common primary and secondary endpoints, and common immunologic parameters that you measure. Therefore, if one trial is ahead of another and one shows real efficacy, you could bridge it by immunologic compatibility.

 

Whenever you do vaccine research — you guys know as well as I — you never can guarantee anything because there are always potholes and bumps in the road. But given what the phase 1 data looked like, published 2 days ago in The New England Journal of Medicine, the neutralizing antibodies were at a titer induced by a moderate dose of the vaccine that was comparable to or even better than convalescent plasma. As we all know, the gold standard for a vaccine is to induce a response that’s at least as good as natural infection. So if we could mimic that in the field and have a comparable clinical efficacy, I think by the end of this year, the very beginning of 2021, we could have one or more vaccines available for distribution of doses. That’s what I’m hoping for.

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It’s remarkable. I know that in the editorial accompanying the data on the Moderna vaccine in The New England Journal of Medicine, they said it was the compression of 6 years of work into 6 weeks or something like that. It’s just startling. One of the questions it brings up is the dissociation of the antibody IgG potent neutralizing capacity and the T-cell story, which, as you know, this week was somewhat marked by this preprint about the waning, disappearing antibodies in 90-some people in London, which raised concerns.

The antibody response traditionally in coronaviruses in general is nothing like measles, which lasts essentially for life. It isn’t even in the same ballpark. We had a bunch of papers to show that it has a relatively short duration of 6 months to a year or so. We need to get out further with COVID-19 to find out what’s applicable there and whether someone who gets infected and gets clinically ill has a much more durable response than someone who gets infected but has isolated replication of the virus in their upper airway. Clearly, there’s something going on systemically when people really get sick. What I think is going on, and we’re getting hints of this from the vaccine, is that you are getting a not-so-greatly-durable antibody response and a much more durable T-cell response, because if the T cells act the way we know they act in other diseases, they have a degree of durability. And they are interesting because they can essentially get multiple types of the virus that they can cross-react with, which is unlike the antibody, which is much, much more specific.

Reinfection

That’s been another controversy: whether people can have reinfection or whether it’s just that they never have mounted an adequate response. Can you address that?

We need to get out of the anecdotal range and collect some real data because there are a lot of anecdotes about people who believe — and they might have; I’m not saying they haven’t — that they may have gotten reinfected. We have to be careful because what we do see sometimes is that people clear virus. Then they go back and get a PCR test later that’s finding residual nucleotides. But when you look at the cycle threshold, it’s unlikely that this is replication-competent virus. Other people recover and then get clinically ill, and they come back and it looks like it’s a positive test. Is it residual? Is it reinfection or is it exacerbation? The answer is, we don’t know. But if you look at the cohorts in general, if it’s occurring, Eric, it’s not occurring a lot. We’re not seeing a lot of people getting relapse or recurrence. So we need to get those people in whom it looks like it might be happening and study them very carefully.

One of the reasons why we haven’t seen a lot of studies on correlating PCR positivity with replication competence is because you’ve got to be in a biosafety lab-3 (BSL-3) to do that. Not everybody has a BSL-3. That’s the problem.

 

Mutations

It’s an RNA virus, and RNA viruses mutate all the time. So when you have a lot of disease, a lot of replication, it’s going to mutate.

Most of the time, it’s a mutation that has no phenotypic relevance. It just mutates, doesn’t change. There’s one interesting mutation that is being studied very carefully. It’s a mutation from a D at the 614 amino acid site to a G. People have looked at that, D614G, and have found that that mutation allows the virus to bind much more readily to the ACE2 receptor and therefore is likely associated with a more efficient transmission, though that’s an extrapolation that we need to confirm clinically. But the investigators found that the site of that mutation doesn’t interfere with the binding site of a neutralizing antibody on the spike. So even though it might actually make the virus more readily transmissible, it doesn’t appear to have any impact on what we’re doing with vaccines. So thank goodness for now that that’s the case.

Public perspectives regarding the pandemic

Abraham, I have a lot of thoughts but no solutions. It’s really frustrating when you have some public health interventions that historically in this outbreak have shown to be clearly effective, particularly when you don’t have any other tools because we don’t have a vaccine. You have a couple of therapies, but they’re mostly for advanced people. Yet we have such pushback on people not wanting to wear a mask. I don’t know whether that has to do with the American spirit, which in many respects serves us well — that independent drive that brought our ancestors over, leaving whatever country they came from. I don’t know what it is, but it’s a pushback on authority. And what I think it’s linked to is not only anti-authority, but it’s a bit linked to the disturbing anti-science trend that we have in this country, like, “You’re telling me it’s scientifically sound to do that. Well, I don’t want to do it because I want to make up my own mind and not listen to authority.” I can understand that that has a degree of attractiveness, independence. But, boy, when you’re in the middle of an outbreak, it’s doing such destructive damage. It’s time to let that go and join the club and wear a mask. Be a joiner as opposed to an independent entity.

Neuralizing antibodies

That’s also being used for neutralizing antibodies which are being tested in clinical trials. What do you think are the prospects for those in the months ahead? Will that come before a vaccine or around the same time?

Fauci: There’s no doubt. The monoclonal antibodies now are going into clinical trials both on an outpatient and an inpatient basis. So that’s really good. I’m very pleased to see that because that could be filling in one of the gaps that we have in therapeutics, Eric, because right now we have a couple of drugs for more advanced disease. We don’t have anything that we can readily give widespread, inexpensive, to get to somebody who gets symptomatic to prevent them from being hospitalized.

 

It would be really wonderful. And I think it’s doable to get something [that could be administered] either intravenously or even on a subQ or intramuscular injection, to essentially block the progression of the infection that would land a patient in a hospital. Remember — people forget this, but we had two monoclonal antibodies that were highly successful in Ebola. Remember that trial? Monoclonal anybody 114 and the Regeneron product. Both of those products had a highly significant impact on mortality.

What about if someone does get a monoclonal antibody or they’ve had the infection and then vaccines become available? Will people all get the same one or are they going to need different assays to know whether they should get this vaccine or that? How complicated is that going to be?

Message to the frontline clinicians

Dr Fauci, your speaking today to many, many physicians who listen to this podcast. Do you have any message for them specifically? Many of them are on the frontline. Many of them are great admirers of yours and are listening intently to your words. Anything that you’d like to say to them?

Fauci: Abraham, thanks for asking me. Two things. One, I just try to express how much I admire the real heroes on the front line for getting in there every day and essentially putting themselves at risk. I’m operating from a different vantage point where I am, but I almost miss the days of being in the trenches with you. So that’s the first thing.

The second thing is that, you know, this is so stressful for all of us. I think we have to remember that we’re gonna get through this. This is not something that’s gonna be forever. We’re gonna get through it. It’s gonna be over. And we’re going to look back and hopefully say we really gave it our best shot. And it’s gonna be over from two standpoints: It’s going to be over from a public health standpoint if we get it right, public health–wise.

But I think science and good biomedical research are also going to come to the rescue because we’re going to get a vaccine, hopefully sooner rather than later, and we will get effective therapeutics. So for the people on the frontlines and in the trenches, hang in there with us. We’re all in it together and we’re gonna get through it. So that’s my message to them.

Rapid diagnostics

Also exciting and on the frontier are the rapid diagnostic tests, where you can get these at the home or wherever in 20 minutes, 30 minutes, with the answer. What’s your sense about how that can be transformative? 

We’ve invested a half a billion dollars in the RadX [National Institutes of Health initiative] to get the diagnostics. It’s just what you say, Eric. That’s what we need. Enough of this nonsense of waiting to get it done and waiting 5 days to get it back. We’ve really got to have something where you go in, you get it, bingo. Everybody gets it. As many as you want, as quickly as you want. That’s the end game that we need. We’ve got to get much, much better than we are right now. We’ve got to be able to get tested immediately at the point of care and get back to diagnosis as rapidly and as cheaply as possible. No doubt.

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