Answering Your Questions About A COVID-19 Vaccine

As we continue to navigate these unprecedented times, KCBS Radio is getting the answers to your questions about the coronavirus pandemic. Every morning at 9:20 a.m. Monday-Friday we're doing an "Ask An Expert" segment with a focus on a different aspect of this situation each day.

Today we're talking about the work on a possible vaccine after the nation's top infectious disease expert Dr. Anthony Fauci said Thursday it is “conceivable” the U.S. could begin to roll out a coronavirus vaccine by December. Our expert today is Dr. Joel Ernst, UCSF professor of medicine and Chief of UCSF’s Division of Experimental Medicine.

Let's start, if you wouldn't mind, by sketching the landscape a bit because it seems like a dizzying week of stories with so many different vaccine research projects underway. Can you kind of categorize broadly what sort of work is being done around vaccines and how it's being done?

The good news is there's a lot of activity and a lot of different options. Many of them include traditional approaches to making vaccines. In other words, one approach that's being used is to grow the coronavirus, the SARS-CoV-2 virus, inactivate it with a chemical and then just inject that as a vaccine. Now that is really the very same approach that was taken with the Salk polio vaccine, and that worked very very well. That's a kind of old-fashioned but still effective way.

There are more contemporary approaches, including administration of DNA engineered in such a way that it's not the virus itself, but a viral protein is encoded in the DNA. That's injected into a person usually by the muscle and then the protein is produced by the person's own cells. It's recognized as a viral protein and not a self-protein and that induces an immune response.

There's a similar approach, and that was one of the topics of one of the press releases earlier this week and that's an RNA-based vaccine where RNA is the intermediate between DNA and protein. There are others including using a different virus, in other words a virus that we know a lot about that can be crippled in such a way that it doesn't cause human disease but engineered so that it expresses a SARS-CoV-2 or COVID-19 protein, and those are increasingly used as approaches to making new vaccines. And then there are purified protein vaccines like we have for hepatitis-B or for tetanus, and then some refinements of those that include a specialized arrangement that works very well for the human papillomavirus vaccines.

So it sounds like there's almost a painter's palette of colors; you have a lot of different approaches. Are any of them, from where you sit, more likely or less likely to produce a quick answer?

It's too early to tell, because there are a lot of factors involved. First, any vaccine has to be safe. Second, it has to be effective - in other words it needs to raise the kind of immune response that our bodies need to fight off the infection. And third it needs to be produced, for a pandemic like this, in massive quantities: billions of doses. And so I think it's probably not going to be any one single vaccine that meets all those criteria and makes it across the finish line first. I think we're going to probably have quite a few vaccines and some of them may have advantages that we recognize with more study, that'll take a longer time.

And just this morning as we were preparing for this segment, we had yet another story breaking. This one a paper published in "The Lancet" by researchers out of Wuhan, China who say their vaccine candidate was - let me run some words past you and you can explain what these mean, because we're all going to have to learn these - "well tolerated at all doses," what does that mean?

It means that when they injected the vaccine into their human volunteer subjects who are otherwise healthy people, there weren't any really horrible side effects. Typically, we've all had this experience that our arm hurts after we've been injected but then the pain goes away and that's that. So what it means by "well tolerated" is that there weren't really any serious side effects that were observed in the volunteers that received the vaccine.

Ok, they say it produced "neutralizing antibodies and T-cell response." That means what?

Neutralizing antibodies are antibodies that will bind the virus and bind it in such a way that it blocks the ability of the virus to bind to our cells. Viruses can't replicate on their own. Viruses are really helpless unless they're inside of our cells. And so the first step that a virus needs to use in order to be successful is to bind to, generally, a specific receptor on one of our cells, and then use that receptor protein to get inside the cell. So neutralizing antibodies block that initial event. In other cases, neutralizing antibodies are both necessary and sufficient for vaccine-induced protection. We don't know yet whether that's the case for SARS-CoV-2. 

And when they say the vaccine is "immunogenic at 28 days post-vaccination," how do we read that?

What that means is that the vaccine was given to the volunteers in the study and then their blood was sampled at various time points afterward. And by immunogenic, it just means that there was a measurable immune response to the viral antigen that was contained in the vaccine. And in this case it's the so-called "spike glycoprotein" in the drawings that we've all seen of the SARS-CoV-2. It's that red knobby thing that sticks out of the sphere.

That thing is real?

It's real! That's really what the virus looks like. 

Alright, so let's get on the questions from listeners: many companies are developing vaccines. At some point there may be multiple vaccines. Who will decide which is the one to be distributed?

That's a tough question. I think it's a work in progress. First of all, hopefully there is a lot of global cooperation. I think that right now that global cooperation hasn't been negotiated, so right now I think a vaccine that's developed and produced in a given country is probably going to be the vaccine that that country uses first. And I think there will be expert panels that decide, "this vaccine is either safer or more economical or more effective than that vaccine." That might help rank them.

But it's also possible that there will be multiple vaccines appropriate in different populations. For example, there might be one vaccine that's particularly good in older individuals and another vaccine that might be better or less expensive to produce and appropriate for younger individuals.

What is different about COVID-19 which makes us think we can identify a vaccine when we haven’t been able to for HIV after 35 years of trying?

One huge difference is that HIV has an extraordinary amount of variation in its structure. In other words without going into a lot of detail, HIV mutates a lot, very frequently, at an extraordinary rate. And it takes advantage of that mutation rate to alter itself so that if we've developed an immune response to HIV or an HIV protein, the next round of viral replication can just generate a mutant that avoids recognition by that immune response, such as an antibody.

With SARS-CoV-2, for a number of reasons the molecular biology of the virus is different than for HIV. So that mutation rate is not nearly as high. There are some other subtleties to HIV including that some of the best target epitopes, they're called - in other words the structural part of the protein that you would really like to have an antibody recognize - are covered up and only unfold when the virus binds to a cell. And that doesn't seem to be the case in SARS-CoV-2.

Am I too skeptical? I keep hearing all this talk about a vaccine for this coronavirus but isn't the common cold caused by a coronavirus and we don't have a vaccine for that?

That's correct. Now I should make the point that most common colds are caused by viruses other than coronaviruses. In other words, coronaviruses cause a minority of human upper respiratory infections or colds. And so the massive number of different viruses that can cause colds is a real obstacle to making vaccines against common colds. It's really impractical at this point to make a vaccine that would protect against every single virus that can cause a cold.

So the effort to make anti-coronavirus vaccines for common cold protection has not been particularly robust. And so as you can tell, the efforts to make a vaccine that prevents COVID-19 is extremely robust.

With a positive result from eight people tested with a possible vaccine - I think this question is probably talking about the Moderna story from earlier this week - what would a phase two trial look like? There’s been a lot of hype about something being ready by September, is that realistic?

First of all I should just say a phase one study - which is what was announced in that press release on Monday of the Moderna vaccine - is meant to determine safety in a small group of subjects and also to determine whether there are immune responses. That's the immunogenicity part.

A phase two trial will be expanded and that includes a larger number of people, a more diverse group of people that is in the volunteer group. For example in the next round, older people would be included. In the Moderna trial that was announced on Monday it was only people up to the age of 55 years, and we know people above the age of 55 years are the most susceptible to bad outcomes with COVID-19. Then in addition, a phase two trial will allow more studies of the types of immune response: antibody responses, T-cell response, that sort of thing. And then in so-called "phase 2-B" trials you can start getting information about the potential efficacy. That is, the ability of a vaccine to prevent infection and disease.

This next question is one I've been wanting to ask too, as we all digest so much information. Over the last two weeks we've seen a new study seemingly every day about a possible vaccine. How do we figure out how to read these, look for keywords to decide which studies are legit and which are a little early?

They're all early. (laughs) But I think some keywords to look at are "peer reviewed". “The Lancet" study that you mentioned earlier was in a rigorously peer reviewed journal called "The Lancet". And so I think when peer review happens the journal will get an article submitted to it and the journal sends the article out to a panel of experts - people who have expertise and knowledge in the field - they read it, they look at the data, they look at the conclusions. They may have questions about it; in some cases serious reservations about it, and they might reject the manuscript. And then something that makes it through that peer review process, especially for a journal like "The Lancet" you can be pretty sure it was rigorously examined. The experiment's being designed and done properly and also interpreted properly.

When something hasn't been peer reviewed, it's anybody's guess. We'd like to think that press releases are correct as they're stated, but without the rigor and scrutiny of peer review you can never quite be as sure prior to that step.

I assume you're the kind of guy who does peer reviewing. What's that process like?

Oh it can be pretty rough. First of all it takes time. Second, virtually all peer review is done by people like me and we essentially do it as volunteers. In other words we've got our full time jobs but as part of our additional activities we peer review manuscripts for journals - partly because we need our own manuscripts peer reviewed - and so it's kind of a large volunteer effort. And sometimes a peer reviewer will find something that they find unappealing about a particular study and they can stop the publication. Other times the authors may be given the opportunity to respond to the questions or concerns raised by reviewers. So generally it's a back-and-forth process. Many times it takes weeks and often months. Obviously in the present pandemic crisis the peer review process is being rapidly accelerated.

When the vaccine is finally approved - or multiple vaccines - will it be readily available to everyone like a flu shot? Do you think it will be like an annual shot?

So let me answer the last question first, "do I think it'll be an annual shot" because it raises an extremely important question that we just don't have an answer to right now, and that is how long-lived is immunity to SARS-CoV-2? Either from infection or from any of the candidate vaccines?

There's evidence from the experience with SARS-CoV-1 and from MERS that human immunity that develops after those infections might be short-lived. It might be as short as a year or two. And that's unsettling. Now, we would like to be able to do better than that with a vaccine but I think it's too early to tell how durable or how long-lived immunity will be after any of the vaccines are being examined. Obviously you can't know that without studying responses over a period of time. 

So will we need another injection every year? Possibly. Will it be for the same reason as influenza? Influenza vaccination needs to be repeated every year because the influenza virus changes every year. The SARS-CoV-2 virus doesn't have the machinery to change at the frequency that the flu virus does. I think the answer is still out. We will presumably know in a year or so whether re-vaccination is going to be necessary.

There's been so much talk about what immunity is, whether antibodies confer it or not. So this questioner wants to know, does that have any bearing on whether a vaccine is going to be successful?

We'll find out. We can't really know that until we have evidence on so-called efficacy, and that is, does this vaccine block infection and disease? For one thing that we don't know, is we see papers and we see the press releases that say a given vaccine induced neutralizing antibodies. That's certainly something we want to hear, but it depends on the quantities of those neutralizing antibodies.

For example, with the flu vaccine the effective immune response induced by the vaccine requires neutralizing antibodies to be present in the serum that you can still measure after you've diluted the serum out 40-fold. In other words, one part serum and 39 parts some kind of buffer. It measures the quantity of the antibodies. And so we don't know from any of the studies done so far, how high did the antibody titers have to be in order to provide protection? And we won't know that until we've got much more time, much more experience and the opportunity to study efficacy either in communities or in so-called human challenge models.

Vaccine versus antigen: please explain in the long-term which would be more beneficial?

So an antigen is a protein or other component - usually a protein - that is part of a vaccine. In other words, a vaccine needs an antigen that's appropriate for the pathogen that you're interested in. It needs a delivery system. In others words, it needs to be in a viral vector or a piece of DNA or a piece of RNA. And the third thing that is necessary is so-called adjuvant, which is a chemical - sometimes naturally derived, sometimes synthetic - that boosts the immune response, that really instructs the immune response to respond optimally to that so-called antigen. So an antigen is one component of a vaccine and it's the component that the immune system recognizes and targets.

Let me ask you one more. And this is not straight down your alley but this question is being asked a lot so let me throw it out there. This questioner says, recently I heard President Trump was taking hydroxychloroquine. Are there side effects, and if so can you describe them?

Well there certainly are side effects. And we've heard a lot about the one that's probably the most hazardous, and that is cardiac toxicity. So hydroxychloroquine can disturb cardiac rhythm in people and there are fatalities of people who have those disturbances in cardiac rhythm because of hydroxychloroquine. So it's not a drug to be taken lightly, it's not a drug to be taken without physician supervision and good monitoring.