TWiV 663 The joy of vax

This Week in Virology

Host: Vincent Racaniello

Guest: Daniel Griffin

Aired 19 September 2020

Vincent Racaniello: This Week in Virology, the podcast about viruses, the kind that make you sick.

[music]

VR: From MicrobeTV, this is TWiV, This Week in Virology, Episode 663, recorded on September 11th, 2020. I’m Vincent Racaniello, and you’re listening to the podcast all about viruses. Joining me today from New York State, Daniel Griffin.

Daniel Griffin: Hello, everybody.

VR: Welcome back, Daniel.

DG: Thank you. For those of the people that can see you on the YouTube, you’ve got quite the thing going. You’ve got this blue in the back. I see the guitar. It’s quite the effect.

VR: I’m fooling around, working on different backgrounds.

DG: No, I like it. It’s sharp.

VR: You got your books. I like the bricks in the wall. [chuckles] I heard you put those bricks in yourself?

DG: Yes, I did. [laughs]

VR: You’re quite the handyman. That’s great. Daniel, what’s been going on these days with COVID-19?

DG: All right. For our clinical update, I know we have a lot of busy clinicians that listen and so they want me to hit the points. We actually have a lot to cover, so I’m going to try to crank through this. You can always put it down to half speed if I talk too fast. Let me start with my traditional quotation. I think people will recognize this. This is a quotation by the famous or infamous Donald Rumsfeld. I pause as people probably say, “I know what he’s going to say.”

“There are known knowns. There are things we know we know. We also know there are known unknowns. That is to say, we know there are some things we do not know, but there are also unknown unknowns, the things we don’t know we don’t know.” I thought that was appropriate as we’re going to be talking about vaccines and the unknown unknowns before us. This week, I want to share a case and explain why – I always think, Vincent, I probably should just tell you, I think eventually, I’m going to be done doing these clinical updates because people will have it all.

Then a case like this happens. I’m like, “I got to keep going.” It reminds me of the mission statement of Parasites Without Borders. If people know what that mission statement is, probably “No” will be the answer. I wonder if even Dickson, you, Chuck, or Peter Hotez could off the cuff. Our mission statement is, “Getting knowledge to the people and places that needed it the most.” [crosstalk]

VR: That need it. Yes, I knew that. I knew that.

[laughter]

DG: You win. You get the gold star. [crosstalk]

VR: It’s a good statement.

DG: Apparently, there are still lots of people in places that need knowledge about COVID-19. When I tell this story, I want to be encouraging. People keep listening, but get some other people to listen too. I know clinicians feel like they’re perhaps too busy, but you’re not really too busy to be up to speed on COVID-19. Being up to speed I think really helps with better outcomes. Let me tell this story.

There’s a woman that I just admitted this Monday or was called a consult on. She was admitted this Monday. The story is as follows. This woman and her husband attended a wake and the wake was for the husband’s sister. The husband is in his 50s or I’m going to say was in his 50s, so understand why the tense changes. His sister dies up in Boston. She is brought back to the New York area for the wake. The wife is describing to me how upset her husband is. He’s crying. He’s got his face in his hands. He’s touching the casket. I don’t know how many people have been to a wake. This is actually, people are grieving.

After the wake, the husband starts to feel ill, starts to feel crummy, muscle aches, starts to run a fever, has some stomach upset, some loose stools. A few days later, the wife actually starts to get sick, similar symptoms; fever, feeling crummy, your basic viral syndrome. She then goes to see an urgent care. I am going to point out, it was not a ProHealth Urgent Care. If it was, I would be making an angry phone call. She goes there and they see her, they examine her, they do a blood test, and tell her, “Oh, you don’t have COVID. You’ll be just fine. It’s probably just a virus.”

She leaves. She goes home. Then she relates to me that her husband, he’s really doing worse than her. It’s Sunday, and Sunday she’s trying to convince her husband that he really needs to go and get seen because he’s not doing well. She is not doing well herself and basically, passes out on the bed. She wakes up to a loud thump. She looks around. She’s not sure where her husband is. She’s a little disoriented. She sees that the bathroom door is closed, so she goes over tries to open it, is unable to open it more than a little bit because then she realizes her husband has passed out in the bathroom.

She calls EMS and they arrive to find her husband dead in the bathroom. Husband is taken away. She stays at home. The next day, it was actually one of her family members goes to visit, finds her down on the ground. She’s admitted this time, not a blood test but a swab is done. As I think, we can all imagine, it comes back positive for COVID-19. She’s now in the hospital. She’s hypoxic. She’s on oxygen. She’s been started on remdesivir. We’ve started steroids. She was actually progressing. We actually added tocilizumab today.

You wouldn’t think in the New York area that people would miss this diagnosis, you wouldn’t think that they would do a serology blood test. I feel like we have to keep doing this and get other people to listen because whoever this person was at that urgent care, that’s a miss and somebody’s dead and somebody else is quite sick in the hospital. All right. Just wanted to start off with that.

Now, news. I was told last week that I’m not very good at the whole good news thing, so I’m just going to call this section “news.” The first part is good news. This was reiterated on September 9th. The New York Department of Financial Services reported that they’re extending the action requiring all New York health insurers to waive all costs associated with COVID-19. New York insurers must waive the cost-sharing for COVID-19 testing, in-network telehealth visits until November 9th, so no co-pays, no patient.

In New York, if there’s a concern about COVID-19, if you need COVID-19 testing, you go, you get it done, you don’t pay for it. I think that that’s important. There was an interesting study in Open Forum Infectious Diseases that actually described a tenfold higher rate of ICU admissions for people with COVID-19 that had fever that continued past nine days. Just the more we can do to know what’s ahead of us. This journal is the open access journal of the Infectious Diseases Society of America, and it’s nice to have more information.

Now, the bad news. With school reopenings, we are seeing more younger individuals with COVID-19. Actually, did an interview today about the number of rising cases that we’re seeing in Suffolk County. Actually, the majority of positives over the last month were in people under the age of 30. 40% of the positives here in Nassau County were under the age of 30. When the kids get COVID-19, they spread it to the teachers, they spread it to the parents. We now have had teachers die in Missouri, Iowa, Mississippi, South Carolina, and many other states.

Just a reminder. It’s not just the kids, but the communities they’re at risk if we don’t reopen properly. To say that, there was an article that just was published in JAMA Internal Medicine, actually, just yesterday and it was, “Clinical outcomes in young adults hospitalized with COVID-19.” This article looked at young individuals where a couple of things we’re realizing were not true. One myth that young people are immune and don’t need to worry and can’t transmit it. Now, it’s very clear that that’s not true.

Young people can get COVID-19. Young people can give other people COVID-19. Young individuals can become infected with SARS-CoV-2 and they can share that virus with other individuals. What happens when they get COVID-19? This article looked at over 3,000 individuals aged 18 to 34, non-pregnant, and they found that 21%, so a fifth of them, required ICU level care, 10% ended up on a ventilator, about 3% died, and about 3% by the time the hospital stay was over, they were not well enough to go home. They actually had to go to rehabilitation centers. This is 18 to 34-year-olds. These are pretty young folks. Another, and we’ll get back to this, just to include, I think everyone is probably aware at this point of the AstraZeneca trial that was stopped. It sounds like this was a case of transverse myelitis, but I’m going to return to this when we discuss vaccines and adverse effects and such. Transmission testing and schools, I think it’s important that we keep talking about this. One of the scenarios that’s been coming up recently, which I don’t think is a problem, I think it’s people are starting to think this through a little bit better. I think that that’s fine.

This is what do you do with the false positives when you’re testing a low prevalence situation, low prevalence population. As mentioned, we’re running into this. We see this on a daily basis in the movie industry, and all these large organizations that have now incorporated testing. There was a recent article where they were basically saying this means we can’t use tests that are not 100% specific, but just to run through this, What are people talking about if you’re really getting the rapid testing out there?

If you test 100 million people a day, and it’s 98% specific, so that means 2 million false positives a day, you’ve got to repeat the test on those 2 million people. Whatever that number below 100 is your specificity. If you approach this with orthogonal testing, you do a second test, you reduce that by again, that 90 or 98%. This is something we’re already working with as we incorporate this in screening. Some people say, “Oh, just tell those people to stay home for the day.” Maybe that’s fine for a college student. You try doing that to some entertainment executive and they would rather you take that eight minutes to do a second test to sort out if it’s true or not.

This is in no way a game-changer. Too many times the world has ended, but this does not end the world and does not disrupt the paradigm. Eventually, we’re going to get this– not only we’re going to get this paper out, but I think I’ve been talking to people about how the research and development group at UnitedHealth Group is looking at, “How often do you need to test? What are the implications of different levels of sensitivity, specificity?”

Today, actually we’re talking more about putting an online calculator. Different groups can go online and say, “What are my tests available? How many people do I want to test? What’s the sensitivity specificity?” Then they can actually look at the impact. If I test every day, if I test every 3, 7, 14, if I do no testing, and actually figure out, “How many tests do I need to do? At what frequency? At what sensitivity or specificity to prevent what number of infections?” I think this is all moving forward and it’s all very exciting. I look forward to the widespread use of the lick-a-sticks.

VR: Let me show you this photograph, which was taken by Amy. This is a rapid test center opening up on Columbus Avenue in New York City. It says 15-minute tests. I believe it’s a LAMP-based test of some sort. You’re not familiar with or involved with this in any way, are you?

DG: Not that particular– My father is in real estate, he actually is involved with renting– We’ll call them retail locations. Actually, people are realizing there is a huge demand for testing. Boy, wouldn’t it be great to get a test result? Ideal is this situation where you do the lick-a-stick.

As I brought up before, there’s interest in sports and theaters and other wanting to open up and wanting to have the ability to have people be tested before they come in the doors. There’s a huge demand for these places. Actually, shops have been closed for other reasons. There’s empty stores. Now people are saying, “I’ll jump in. I’ll have a nurse, I’ll have a physician, I’ll get one of these machines, and I’ll start providing testing services.” We’re going to need lots of tests.

VR: They’re going to charge for them obviously, right?

DG: We do live in a capitalist society, Vincent. [laughs]

VR: Oh, I forgot that part.

DG: You forgot for a second.

VR: Is insurance going to pay for that?

DG: That was the interesting thing about this statement that just came out by New York State again, just reinforcing that they’re well aware that a lot of the testing is now being done for screening purpose. I thought this was really reassuring. They didn’t come out and say, “Oh, we’re only going to test X, Y, and Z criteria.” They said, “COVID testing is still 100% covered. No amount of money goes to that patient.” This is really positive. At least in New York, it’s very clear that you can keep testing. The governor, everyone wants us to test, so continue.

All right, vaccines, this is the meat of what we’re going to talk about today. There’s certainly that possibility, I’m going to say that vaccines certainly, I’m going to keep qualifying myself here, may be available in the U.S. without the normal amount of information about safety that we’re used to, and just to give this context. A lot of our clinicians are now being asked to extend their expertise outside of what they normally do.

I mean, normally, as clinicians, most of us deal with diagnosis, treatment. I think our pediatrician colleagues are better and more knowledgeable about vaccines, but now we all need to be a little bit more knowledgeable. The typical length of study for these Phase III clinical trials has historically been one to four years. I don’t think anyone is expecting we’re going to wait four years before we release vaccines. What are we concerned might happen? We’re concerned about these adverse events, they might be mild, they might be severe.

There are some great articles out there starting to look through this, but let me do my primer. For clinicians– actually, for general public, I think this is of interest. There are in general, historically, there have been Phase I, Phase II and Phase III trials. I touched on this last time, Phase I are safety trials, a small number of people. Phase II are an expanded trial with a slightly increased number of people and a broader age range. They termed these trials, Phase I/II, they’re really just– We jump into Phase II.

I’m not sure how you do a I/II. They’re doing Phase II trials, they’re just skipping the ones. They’ve moved up to hundreds of people of broader range, and they’re looking at both safety and immune stimulation. What we really care about are Phase III efficacy trials. I call them efficacy trials, they’re called that. These are placebo-controlled trials. They look at efficacy. Even though they’re called efficacy trials, they’re also looking for the less common side effects. Vaccines might have side effects in the range of one per 100,000. One per million, things like that.

Let’s talk about the vaccines. We’re going to go into each one of these in more detail, but I’m going to break them down into four groups. We’re going to talk about the whole virus vaccines, inactivated and attenuated. I’m going to avoid using the word live, even though the CDC throws that every so often when they start talking about stuff. Viral vector vaccines, replicating and non-replicating. Nucleic acid vaccines, they’re DNA and RNA vaccines. There are protein-based vaccines or protein subunit and virus-like particle.

Very brief mention of immunity, and everyone should listen to Immune, they’ll get a great background. I think Brianne Barker has an online immunology course that my wife says she’s going to take, so I’ll direct people there as well. In a nutshell, we have our B cells that make antibodies, which are– I would say, antibodies are these proteins that hopefully neutralize viruses. We have T cells that are able to detect if a cell has been infected with a virus, and then they actually destroy those cells.

You can imagine my bias towards the antibodies neutralizing that virus before it gets in. What I like to say is that there’s B cells, there’s T cells, but then there’s B and T cells working together and that’s ideal. How do you get B and T cells to work together because B cells don’t make great antibodies unless they cooperate with T cells? This is my bipartisan thing, not only do we all have to get along and work together, but the immune system has to as well. What brings all these people together? Who’s the great compromiser?

Who’s going to help us all? It’s this wonderful antigen-presenting cell. The most famous is the dendritic cell. I’m going to tell a little story about the dendritic cell. The dendritic cell was a cell that a lot of people weren’t sure existed. It was actually Ralph Steinman who won the Nobel Prize for this, and talk about a brilliant man. I had lunch with this man and there were four or five of us having lunch together about three months before he died. I was working on some B cells. We had a little bit of a conversation.

Off the cuff, something that had taken me two years to discover, He said, “I think that this subset that you’re talking about would probably have these three markers on the surface.” I just sat back and said, “Boy, why am I in this game when there are people as brilliant as this gentleman?” Because he was completely right. There are people that really– This all makes sense. I will say as a lowly clinician, a lot of those people are working on these vaccines, so I am quite optimistic. What happens is these antigen-presenting cells, they do a couple of things. The big thing they do is within a cell, when we’re making proteins, the proteins are always being chopped up into little segments and they’re being displayed like flags on the surface of the cell. This is going to be another story, and this is the head of the Nobel Prize Committee was telling me this story. I was hanging out with a lot of Nobel Prize winners one year. This was in the past. He was talking about a story in Sweden where they were worried that the Russians were sending subs into their water.

They spent a lot of money and they made this book that had pictures of all the potential foreign submarines that might be coming into their waters. Everyone was supposed to carry this 200-page beautiful book around with them. So whenever they were out sailing on the water, they could quickly look through and if they recognized one of these. Then finally, someone realized, like, “Instead of showing us all these hundreds of different submarines, why don’t you just show us the pictures of what Swedish submarines look like?”

What happens is the T cells, basically, they’re fine as long as they see that you’re you, but then if they see something that’s not you, that’s what gets them to trigger, to freak out. In this whole process, these antigen-presenting cells are going to help educate T cells, the T cells are going to help educate B cells. At the end of the day, we’re going to have B cells making antibodies that hopefully will neutralize the virus. We’re going to have T cells that are helping the B cells do a good job of that, the T helper cells making all the right cytokines, etc., and we’re going to have T cells that are going around hopefully destroying any virally infected cells.

Now, how does all this magic happen? How do we make it happen? That’s vaccines. I know on the last comments, there was some comments, “Oh my gosh, if the TWiV people become anti-vaxxers.” I’m going to say no. [chuckles] I love vaccines, but I like vaccines that work, vaccines we can trust. Let’s talk about the whole virus vaccines. The simplest here is to grow up a whole bunch of virus and then use something like formaldehyde and basically prevent the virus from having the ability to be active. Here, you’re just basically giving the raw material.

The other approach is you take a virus that has somehow been made wimpy, attenuated. This can either be genetically engineered or passaged through. The virus goes in, and this is enough to go around. It can replicate. You don’t have to put quite as much in, but you do have to be a little careful because if someone is immunosuppressed, what might seem like a wimpy virus to Vincent and myself might not be so wimpy to someone without an immune system. The advantages of the attenuated is you don’t need to make quite as much because it can make more once it’s injected.

The advantage and disadvantage of the inactivated is you need to make a whole bunch more, but you don’t have to worry about the replication going on. Now, things get a little bit fancier. Instead of this, you can actually make up your own viral constructs, your own viral vaccines. Here, what you can do, and this is something I enjoy doing for many years, I’m going to say I enjoyed it. There at Columbia, just down the hall from Vincent, is you actually, you mix and match and you might take a certain viral construct and then introduce a protein or the spike gene, for instance, from another virus.

In this sense, you’re taking maybe an adenovirus construct and then sticking the genetic code for the spike, so that now you have what looks like an adenovirus except it’s studded with the proteins from the payload from what you’re after. You can set these up in a way where they really just get into one cell and then produce all the proteins and that’s where it goes, or you can actually set these up where they can replicate. Again, you can look at and think about the differences there. It really relates back to how much do you have to put in.

Now, it gets, I’ll say, to the IKEA vaccines, but these are worse than IKEA. These are the nucleic acid vaccines. This is when you go to IKEA, they don’t even give you the parts to the chair. They just give you the blueprints and you’ve got to go cut the wood yourself. They can give you the DNA vaccines. Here, you’re basically going to get DNA, which is this got to get into the nucleus, and this is I think tough for those of us that are far from our cellular biology.

You take DNA. The DNA has to get into the nucleus and then the nucleus– the DNA is turned into RNA. The RNA is going to come out and then it’s going to be made into the proteins. A shorter thing here, and something that a lot of folks are working on now, is you just go right to the RNA. The RNA doesn’t have to get into the nucleus, which is good and bad.

One of the good things by not getting into the nucleus is that being in the cytoplasm, it can be directly turned into those proteins and now can start making those proteins, proteins that are expressed in, hopefully, a form that the B cells will recognize and react to, but also, all the little amino acids are being chopped up, displayed on the surface. Those antigen-presenting cells, those dendritic cells, can educate the T cells and we can get both the T cell response and an education of our B cells, so we get a better B cell response.

Then the last one, we’re almost there, this is not that hard, is our protein-based vaccines. This is you really just cut to the end. You say, “You know what? I want antibodies. I want T cells against the spike protein, so I’m just going to give either the person a whole bunch of spike protein,” that’s the protein subunit approach, or you could actually make these viral-like particles where it’s really just an envelope of a virus studded with the protein subunits. Again, it’s going to go through the same process. You’re going to get your dendritic cells involved and they’re going to help our B cells, they’re going to help our T cells, and they’re going to get everyone to work together.

VR: Can I put you on the spot, Daniel?

DG: Please do.

VR: Give us examples of licensed vaccines with all these, starting from inactivated vaccines.

DG: Oh my gosh. You are putting me on the spot.

VR: What do I work on, Daniel?

DG: You work on polio. This will be a good one. Polio, we’ve got oral polio that’s attenuated, so that’s perfect. Then we got that injectable stuff.

VR: That’s right. Very good. Two licensed vaccines. How about a vectored vaccine? Do you know of a licensed vectored vaccine?

DG: Licensed vectored vaccine? Now, I guess the Ebola one is actually a licensed vector vaccine.

VR: It is, absolutely right. That’s right. Also, the dengue vaccine, DENGVAXIA is also vectored. It’s vectored in a yellow fever virus vaccine backbone. How about a nucleic acid, are there any licensed nucleic acids? [crosstalk]

DG: Now, the mRNA, there’s none for people. There are, I believe, some in the veterinary world.

VR: That’s right. There’s a West Nile for horses that’s a DNA vaccine, yes. All right. How about a virus-like particle? [chuckles]

DG: Now, you are putting me on the spot. I think I’ve reached the limit of my knowledge, Vincent.

VR: Human papillomavirus vaccine– [crosstalk]

DG: Oh, that’s excellent.

VR: And the hepatitis B virus vaccine and purified protein subunits. This is a vaccine you’ll get over 50 years of age.

DG: Oh. Is this the shingles vaccine?

VR: Yes, the new one, the SHINGRIX glycoprotein, adjuvanted glycoprotein, right?

DG: Yes.

VR: Okay, good job.

DG: One day when I reach 50. [laughter] Fortunately, that’s in the rearview mirror.

VR: I have to say, Daniel, my health insurance is UnitedHealth Care and I can get SHINGRIX flu vaccine free at my local pharmacy because of that. They take care of it.

DG: Oh, that’s fantastic. It’s good company.

[laughter]

VR: Apparently. Now, all these approaches are being used for SARS-CoV-2, right?

DG: They are, actually. I went through a little bit of the different ones because you could say, “What if I want to go down the whole virus vaccine pathway?” There’s a bunch of people working on that, viral vectors. You’ve got a bunch of people working on that. The RNA vaccines we’re hearing a lot about, those as well. Everyone is using all these different platforms. There are over 200 vaccines in development. I want to talk a little bit about, first I’m going to say, “How do I volunteer for a vaccine trial?” And talk to people a little bit about that.

Then, I’m also going to talk a little bit about something that will relate to volunteering for a vaccine trial, but also, “What do you do if a vaccine might be released without that one to four years of safety data that we’re used to?” Just to go through, you actually can sign up. I’m going to actually encourage people to sign up who are listening now. I don’t know the full demographics of our listeners, but one of the things about vaccine studies is you need large numbers. You need 30,000 people or more. 30,000 is what a lot of these trials are shooting for. They can’t be 30,000 white guys in their 20s. This needs to be– I’m looking at Vincent. He’s not a white guy in his 20s. [chuckles] You need people of different ages. You need people of different genetic backgrounds. If you are a white guy in their 20s, you need women, you need people of color, you need all the different groups. If you want to sign up or go through the eligibility screening for the Moderna vaccine, you go to a website. You go to www.modernatx.com. If you want to sign up for one of the Pfizer studies, you go to covidvaccinestudy.com.

These are catchy. If you want to sign up for the AstraZeneca when they start enrolling folks again, you go to c19vaccinestudy.com. If you just want to sign up to be alerted to any vaccine trials, you go to coronaviruspreventionnetwork.org. Basically, I’d encourage our listeners if you are interested in being part of this effort, if you’re interested in being part of this, go hop onto your computer because, you know what?

The trials need that whole diversity to fill because there’s a several-step process here. You need to screen the people, you need to enroll them in the trial, they need to get vaccinated. Sometimes I hear, “Oh, the site is going to vaccinate 50 people a day,” and I do the math and I’m like, “That’s 50 times 30, 1,500. We’re going for 30,000.” You need lots of sites, lots of people getting vaccinated, to get to that first step.

Some of the vaccines require a booster, so a month to enroll and then a month when you’re vaccinating everyone, and then a month later when you’re doing a booster if needed, and then you need exposures. Most of these studies are powered with a 30,000 for 200 infections or more. Once you get to 200, we should be starting to get in a realm of potentially some statistical significance.

VR: To get 200, you’re saying 30,000 is a good enrollment number?

DG: There’s two reasons why we want the 30,000 because there’s two sides to the vaccine study. One is you want efficacy data and you need about 200 infections before you can really start getting the power to determine that, but you need 30,000 because you want to start picking up these less common events. Historically, I’m going to get into these. We’ve been willing to tolerate a certain incidence of side effects, but if you don’t have 30,000 people in your trial, you’re not going to start seeing this issue.

You rolled me right into my next topic, which is, “How do you make a decision with limited data, and how do you decide whether or not to be enrolled in one of these trials?”

I wanted to put this in context. Different vaccines have different safety profiles and we’re willing to accept different risks based upon the context. I wanted to use smallpox vaccination as an example. This vaccine involves getting injected with an active vaccinia virus.

Let’s suppose, as we ran into a number of years back, you’re about to send your troops into some area of conflict, perhaps it’s in the Middle East. We have some information that maybe later turns out not to be true, that your troops might be exposed to smallpox based upon a bio-weapons attack. When you look through, they say, “Oh, a certain percent of people have ‘mild vaccine-related symptoms,’ which was 30% of people got so sick that they missed days of work, three days of work on average.” That’s a little more, in my mind, than mild.

If you say, “If you get this vaccine, anticipate missing a few days of work like a 1 in 3 chance of that.” We saw a certain number of deaths. We saw a certain number of people had brain inflammation. When you start doing the math and you say, “Oh, we give this to 300 million people, 300 million Americans.” And you start saying, “Oh, well, these are rare events.” But those rare events start to add up. If you give smallpox vaccine to 300 million Americans, you end up with 72,000 cases of disseminated vaccinia. You end up with 300 deaths.

You end up with 360 cases of encephalitis or brain inflammation. There are different things to be thinking about when you look at vaccines. That’s a vaccine that’s available. We now use a diluted vaccine, but you’ve got to start asking, “What are the risks I’m willing to take if I’m going to be in a different situation?” If I’m an ER worker in a part of the country that doesn’t have good personal protective equipment stockpiles and I feel like my chances are quite high, what risks might I take?

What are these risks? The minor adverse effects, in general, are, say, pain, fever, muscle aches, headaches. Then we’re all starting to learn about the serious adverse effects, death, that’s maybe as bad as it gets, Guillain-Barré syndrome, this is the rapid onset of ascending paralysis over hours to weeks with about 15% of people affected requiring mechanical ventilation. In general, this is thought to be caused by auto-reactive antibodies triggered either by natural infection or vaccination. Although most people fully recover over weeks to years, about a third never fully recover, and about 7%, 8% die. That’s something to worry about.

Transverse myelitis, something which may be the affect that we saw reported in this vaccine study, the AstraZeneca, and it’s not clear that this is related to the vaccine or just something– We see this about 1 in 100,000 individuals. You enroll enough people, you got a one in three chances someone in your trial is just going to have this. Here is where you’re having inflammation of the myelin and the spinal cord. This can be either caused by a virus itself, adenovirus itself can actually cause this.

It can be caused by antibodies. It also can be caused by T cells that are targeted. Encephalitis, brain inflammation. Then the last thing that we’re not going to necessarily know about for a year is the antibody-dependent enhancement. This is where initially you have a great level of antibody, it’s protective, but once those antibodies drop below a certain level, this is what we see in dengue, if you get exposed, you’re much worse off than having never been vaccinated.

The reason you need that 30,000 and the reason, ideally, you have a year, is you’re not going to get that last one until you’re out about a year and you see what happens when those antibody levels fall below a certain level and these people get exposed. Are they going to get sicker? Maybe there is a requirement that we’ve really got to revaccinate those people to avoid that last. Since there are some rumors that there might be some vaccines out a little bit sooner than we’re used to, people may actually be starting to make these decisions in this kind of a context.

VR: Daniel, what’s the death rate with the smallpox vaccine? I think you mentioned it.

DG: 1 in 241 million, so it’s very low.

VR: That’s not something you would pick up in a 30,000-person trial.

DG: Yes, I think it’s about 1 in one million. It’s 1 in one million deaths. With smallpox, if I remember correctly, our emailers can write in and tell me if that’s true, but yes, it’s 1 in one million. If you do a 30,000 trial, you’re not going to see that.

VR: Even if death is 1 in 100,000, any serious complications like Guillain-Barré, I think, is 1 in 100,000 for flu vaccine. You don’t pick it up.

DG: Actually, that’s the classic for Guillain-Barré is 1 in 100,000, so you’re most likely not going to see it. I think that brings up the swine flu, which [President] Ford really was worried about. He thought we were about to be in a pandemic. There were 45 million people who were vaccinated and there about 450 people that ended up developing Guillain-Barré. Just to be honest, you have to look at those numbers. 45 million, 450, I mean, it sounded when you read the articles like thousands of Americas were paralyzed. 450 is a tragedy. We’re losing 1,000 people a day to COVID-19. The math might be a little different in the middle of this pandemic.

VR: Sure. You have to balance the lethality of COVID-19 with whatever the vaccine is going to do, right?

DG: Yes. I think that we’re in a slightly different world than we historically have been with vaccines. There will be certain people in high-risk situations who say, “I would rather take that risk of a vaccine than that risk of not getting a vaccine.” I don’t think we’re anti-vaxxers, I think we’re just– My whole goal is to educate people and let them make their own decisions. Bad decision is what keeps me in business.

VR: We also on TWiV talk about the risks and benefits a lot and people can get informed in a deep way, not in two minutes from your local news. Listen to TWiV and Daniel and all of us.

DG: I think there’s a lot of important information people will benefit from having.

VR: Daniel, if you had a choice, which vaccine would you want: an activated, attenuated, vectored, subunit, or virus-like particles since they will all be available?

DG: I know everyone like skirts this, but I’m going to answer it. I have to admit, I’m not just thinking about the moment, but I’m thinking about the future. I really like the idea of the mRNA vaccines because I feel this is a vaccine that, going forward, if we get that platform working, as we saw, it may be something you can very quickly get out there and start testing. I know that it makes people immediately think of Moderna. They’ve got the mRNA. It’s built into their name. Pfizer also has an mRNA vaccine out there.

Pfizer has a much longer track record of getting vaccines out there. I don’t think Moderna has ever produced a vaccine or licensed one before, but that’s okay. Yes. I have to say, not just thinking about this pandemic, but just thinking about, let’s say, the future of mankind. It would be great to have a good vaccine platform that we were ready to deploy. I like the mRNA approach. I worry a little bit, I’ll tell you in all honesty, about using adenovirus as a vector, as a platform because adenoviruses, they’re not without risks.

VR: Alan Dove recently said he wants the vaccine that Tony Fauci gets.

DG: [laughs] I like that. Our last section, and then we’re going to end it. I always like to talk about understanding the course of COVID-19. The patients are still suffering for months after the acute phase of COVID. They could at least take some solace that this pervasive myth, that this was just a short-term illness, is constantly being dispelled. There certainly are mental health impacts as well as physical. There’s a growing number of individuals who have issues months out.

Recently, I’ve seen a lot of individuals start to develop what are classic for migraine or vascular-type headaches, which is interesting. One of the theories behind migraines is that there’s this inflammatory trigger. These migraines that I’m seeing in these “long haulers,” people with a tail of COVID, seem to be responding to typical migraine therapies. The triptans, other therapy. I will end there. Again, I’m going to thank everyone.

A lot of people have been tremendous going to parasiteswithoutborders.com and helping us support Floating Doctors. Helping us give them the funds, so that they can keep these people from starving, give them whatever access to medical care that we can provide. These are the indigenous people in this remote part of Panama that I’ve worked with over the years. Many of them I know personally. Thank you for going to parasiteswithoutborders.com. For every dollar you donate, we’re doubling that. Thank you.

VR: Great. All right. I’ll just give you two quick questions.

DG: Are these going to be as hard as the vaccine ones?

VR: I don’t think so. First one was from Nathan, who is an urgent care PA from San Antonio, Texas, who, by the way, loves TWiV. He said, “Parasitology is my favorite ID infection.” He wants to know your thoughts on using indomethacin in place of other NSAIDs.

DG: Indomethacin?

VR: Indomethacin. He gives some evidence that it has some antiviral properties. He says this could be a two-handed therapeutic. What do you think about that?

DG: Now that we’re in September, hopefully, we’re not as ready to decide that indomethacin is an effective antiviral for SARS, as some people may have been back in March and April. I think it’s fine as we now know to use non-steroidal anti-inflammatory, whether it be ibuprofen, whether it be Naprosyn, whether it be indomethacin, whether it be aspirin. I think these actually can be helpful for some of the symptoms.

I’m not sure that indomethacin is going to have great potency. There’s tons of in vivo stuff out there for so many different things. It’d be great, at some point, to know if there were certain sorts of drugs on the shelf, so to speak, that could be helpful. I think it’s absolutely fine if you want to use this as your nonsteroidal anti-inflammatory of choice. I think the others seem to be effective as well.

VR: There is a clinical trial and recruiting in Arizona for, you’re going to love this, Daniel, hydroxychloroquine, indomethacin, and Zithromax for COVID-19. [laughs] All right. We’ll know because they’re all given together. All right, one more from–

DG: It would be better to not give them all together, but that be my two cents.

VR: Yes. There’s also one for ivermectin with zinc and vitamin D and vitamin C altogether. I just don’t know how you can figure anything out. All right. One more from Patty. All right. She has a dilemma, which I thought you could help with. Her husband’s mother passed away in June. The service is next week. The father is going to be there, he’s 92. She wants to know, “Is this a big risk for my husband to go visit his father whose wife just died? Then drive back and live with me. Will I be at risk? What should I do? Can it be done safely with distancing and masking?”

DG: Yes. So this is from Philadelphia. I was looking to see where you were because we do know that being outdoors is a much better way to approach things. Memorial services, wakes– I was worried about because, let’s be honest, you’re grieving, you’re upset. It’s not a great time to say, “I’m not going to reach out and hold you.” There’s physical contact when we comfort someone. This can be tough. When you physically get there, are you going to sit six feet away from your 92-year-old father who’s crying and just be like, “Hey, I’m six feet away with my mask on.”

I’m most concerned that you get in these situations and you may say, “Oh, we’re going to wear masks. We’re going to social distance.” But come on. This is someone you love, someone you care about. They’re hurting. It’s really hard to not just go over and give them a hug. How do you do this safely? You get tested. You let whoever it is that you work with, your doctor, know that this is a priority. It is a priority. A 92-year-old father may not live past this pandemic.

They may not survive until there’s vaccines and effective medication. We’re doing an article for– I think it was Reader’s Digest o Consumer Reports. Sorry to lump you two together. It was about how incredibly hard and socially isolating the pandemic has been on our seniors. Particularly, situations like this. If you’re an older individual, other older individuals are dying. You’re losing your friends. You’re socially distant from your grandchildren, your children. A great way to make this safe is to figure out a way to get tested and then go see your 92-year-old father and give him a hug.

VR: Probably everyone at the wake should be tested as well. [laughs]

DG: Yes.

VR: Ideally. Alright. Okay, that’s our weekly COVID-19 Clinical Report with Dr. Daniel Griffin. Thanks so much, Daniel.

[00:47:46] [END OF AUDIO]