- Welcome everyone to Wednesday Nite @ the Lab.

I'm Tom Zinnen, I work at the UW-Madison Biotechnology Center.

I also work for the Division of Extension Wisconsin 4H, and on behalf of those folks and our other co-organizers, PBS Wisconsin, the Wisconsin Alumni Association, and the UW Madison-Science Alliance, thanks again for coming to Wednesday Nite @ the Lab.

We do this every Wednesday night by Zoom, 50 times a year.

Tonight, it's my pleasure to introduce to you Mary Hayney.

She's a professor at the School of Pharmacy here at UW-Madison.

She was born in Easton, Minnesota and went to Good Counsel Academy and Delavan Minnesota High School.

Then she went to Creighton University in pre-pharmacy, then went to the University of Minnesota to get her doctorate of pharmacy.

Then she post-doced at the Mayo Clinic, and in 1997, came here to UW-Madison to serve on the faculty.

Tonight, she's gonna speak with us about insights into the development of COVID vaccines.

Would you please join me in welcoming Mary Hayney to Wednesday Nite @ the Lab.

- Thanks, Tom.

My presentation today is entitled "Vaccines for COVID-19: Our Shot at Ending the Pandemic."

I'm gonna start with a little bit about what pandemics are, but I'm gonna take a little bit of liberty and talk about significant disease outbreaks from history as well.

Let's start with the one that is probably most famous.

It happened in the mid 1300s, and it was called Black Death.

It was caused by a bacteria named Yersinia pestis, and it is estimated that a third to half of the entire population of Europe died during that disease outbreak.

Some other pandemics that I wanted to talk about is one that was important for the Americas, and it was the 16th century, when many settlers from Europe came to North America and brought with them their infectious diseases.

And it is estimated that some of these infectious diseases wiped out as many as 90% of the Indigenous population.

Another one, this isn't a pandemic, but I think it's interesting from the American history point of view.

In 1793, there was a yellow fever outbreak in Philadelphia.

Yellow fever is a mosquito-borne disease, and there were about 5,000 people who died that summer, and interestingly, and of course you'll go "Yeah," it subsided in the fall when frost came and the mosquitoes died.

Influenza was an important pandemic, which is maybe the other one you might think of, and I'm gonna talk more about that one coming up, but in 1889 and 1890, there was an influenza pandemic that started in Russia and swept across Europe with an estimated 1 million deaths.

Another pandemic, I think I'm exaggerating a little bit about this one being a pandemic, but certainly it did cause worldwide endemic death, and certainly disability is polio.

In 1916 was about when polio started in the world, really interestingly, and there were sporadic outbreaks until 1955 and then after that, there was a vaccine available.

This diagram that I've put up is a map of the world that shows the individual cases of polio in the entire world in 2020.

So we are putting dots for individual cases.

Therefore, we are on the verge of polio eradication from the world.

Another one that you will be very familiar with, we just celebrated-- celebrated, is that the right word?

The 100th anniversary of the Spanish flu.

Spanish flu is also an interesting name for it, but that is the one that came about.

And it is estimated that this influenza outbreak caused 500 million cases and at least 50 million deaths.

Other influenza pandemics are listed on this slide, so I'm gonna go out of order a little bit.

There was a 1957-58 one, a 1968 one, and then of course, many of us will remember the 2009 H1N1 influenza pandemic.

The first two caused about a million deaths worldwide, and about 100,000 deaths in the United States.

And the H1N1 influenza pandemic, interestingly, affected young people more than the old people.

And it is estimated that about 80% of the deaths were in people under the age of 65.

Again, I have a relatively wide range of how many deaths that influenza outbreak caused, but we don't have a good way to know.

And then another pandemic, it's a worldwide disease, started in 1981, or that was at least when it was first recognized widely, is HIV/AIDS, and there've been 35 million people who have died of this.

It has now become an endemic disease, and has particularly affected Sub-Saharan Africa.

The next one, again, was a localized disease outbreak, which was Ebola with almost 29,000 cases reported, and 11,000 of those died.

The next disease outbreak I wanted to talk about, which is actually one that spread to many areas of the world, is Zika.

Zika was first known and discovered in the 1940s, but it came to South America in 2015 and spread into North America as well.

It still continues to go on and cause diseases, cases of disease, and we don't really know the total impact of Zika virus yet.

So we're in a current pandemic again, and I think that we obviously know the effects of the coronavirus pandemic.

It is a global outbreak of disease.

It starts as an epidemic, which is a localized disease outbreak, and then when it becomes worldwide, it becomes a pandemic.

The World Health Organization declares the pandemic.

It declared the pandemic for SARS-CoV-2, which is the virus that causes COVID-19, in mid March in 2020.

It's typically caused by a new infection, new meaning new to the population, because the population has very little immunity to it, which makes it easy to transmit from person to person.

So we have the opportunity now to talk about COVID-19 vaccines.

I feel so lucky to do that, because who would have thought we would be able to have a vaccine in just a few months?

Well, a few months, nine months following the first call for a COVID-- that COVID was a disease and a pandemic.

So I want to assure you that the vaccine licensure and development process was followed carefully for the COVID-19 vaccines.

So let's talk about what that process is, and then I'm going to apply that process to how the COVID-19 vaccines were developed.

So every vaccine starts with a preclinical phase, a phase in which most of the work is done just in the laboratory.

Then phase one, two, three, and after phase three, the vaccine will be licensed, or in the case for the COVID-19 vaccines, it has an emergency use authorization.

I'll talk more about all of these individual parts coming up, starting with phase one.

Phase one starts with a new vaccine, and you get a IND submitted to the FDA, the Food and Drug Administration.

So the Food and Drug Administration is involved right away.

An IND is an investigational new drug application.

And so that allows scientists to start testing the drug in humans.

And so you get a very small number of healthy humans, typically healthy humans, who maybe are not at any particular risk for the disease in question.

The main goal of phase one trials is safety and tolerability, and maybe you'll get a little bit of immunogenicity, or does this vaccine induce an immune response?

And then we also look at different doses, different schedules.

This is where those kind of data or information associated with the vaccine come from, is in these early phase one trials.

Now typically, phase one trials take 8 to 12 months.

They're often done in academic settings or a small biotech startup kind of setting.

But it also can be done in large pharmaceutical companies as well.

Phase two studies typically involve larger numbers of volunteers, somewhere between 50 and 500 people.

And they usually are a mix of low risk and higher risk individuals from the population where the phase three trials will be done.

I know I'm getting ahead of myself by starting to talk about phase three while I'm still trying to talk about phase two, but bear with me for a second.

The main goal of phase two trials is to generate safety data.

We really want to know that this vaccine does not cause harm.

It also gives us an opportunity to work with vaccine formulations, make sure that we can make it again and again in a new batch.

You know, that's a critical component of a pharmaceutical agent.

You also might get some preliminary data on efficacy.

And these trials typically take 18 to 24 months because of screening, enrolling larger numbers of participants.

Phase three trials are typically those large ones that we hear about.

And I'm in fact gonna talk about phase three trials almost exclusively when I talk to you about the vaccines that are available for the use, to prevent COVID right now.

They're blinded and randomized.

Blinded means that the individuals won't know which group they got, they're assigned to, whether it's placebo or active vaccine, and neither will the investigators.

There's only one person in a data closet somewhere who knows who got what, and they don't tell.

So it's, typically they involve thousands of participants, and in fact, the COVID-19 trials typically had tens of thousands of participants from this target population who are at risk for the disease.

The goal of the phase three trials is primarily to determine vaccine efficacy and vaccine safety, and this then can lead to licensure application.

In phase three trials, particularly for vaccines anyway, we need a key component is surveillance.

We need to know when people are getting disease, and we need to know how much disease there is in the population.

And so we need active and passive surveillance for disease.

We need to look for cases.

So you can see that we needed to be able to know a lot about COVID-19 and who was getting COVID-19, where the cases were, and how many cases that could be accrued.

This, in fact, the large COVID outbreaks in the summer actually speeded along the development of the vaccines because the vaccines need to collect so many cases, or in this case, on the slide, I've written a specified number of events, in this case meaning cases of disease have to occur in the study population in order to make, to hit the study endpoint.

So then the study becomes unblinded, and we see in which group each case might have been.

And so what investigators and scientists are hoping for is that the cases are primarily in the placebo group and not in the vaccine group.

That would indicate that the vaccine probably protected or likely protected people from infection.

These trials typically take years to complete.

The Food and Drug Administration is involved in vaccine licensure, and as our expert recommendation bodies.

So let's start with the Food and Drug Administration, or the FDA.

They review data regarding the safety and efficacy of vaccines.

They use advisory panels.

These advisory panels are typically made up of experts in the area.

So they give advice to the FDA.

They'll review all of the study data and look at it very, very carefully, and then make a recommendation to the FDA for licensure, or in this case, let's talk a little bit about emergency use authorization, or EUA.

Probably a new term in everybody's vocabulary is the EUA.

This is actually a relatively new strategy.

It's only been around since the early 2000s to make products available to the public very quickly during an emergency.

And, of course, the COVID-19 pandemic is certainly an emergency.

It allows the FDA to weigh risks that are known.

Actually, I guess I should start with what the slide says, which weigh known and potential benefits of the product against the risks of the product.

And please know that an EUA is based on very high-quality data.

It doesn't mean, the EUA doesn't mean that the vaccines are not proven or that the data is, that data are suspect.

In fact, the EUA is based on very high-quality data, or the EUA would not be granted.

A second group that's incredibly important in our use of vaccines in the United States, including the COVID-19 vaccines, is the Advisory Committee on Immunization Practices.

This is a committee of the CDC, or the Centers for Disease Control and Prevention, and this committee makes recommendations on how to use vaccines to control diseases in the United States.

The recommendations stand as public health advice to reduce the incidence of vaccine preventable diseases, and then of course, to promote safe use of vaccines.

The COVID-19 vaccine recommendations from the ACIP were made within days following the EUA.

Their recommendations included priority groups.

In fact, like who should be first in line to get the vaccines.

So you might remember, the first people who got... for whom COVID-19 vaccines were recommended included healthcare workers and individuals who lived in long-term care facilities.

And the reasons for this is, in advance, the ACIP put together a committee that decided what, on what, how are we gonna decide who gets the vaccines first?

So they chose these ethical principles to maximize benefits, minimize harms, promote justice, and mitigate health disparities.

Those were their guiding principles.

So you can see it's natural that individuals in long-term care facilities, I'll use that one as the example, would get vaccine first, because they were a very important group in outbreaks as well as deaths associated with outbreaks.

So now moving on to Operation Warp Speed, because how did we then apply these vaccine licensure and EUA and study principles to the development of the COVID vaccine?

So first, although I don't love the name Operation Warp Speed, it was what was chosen, so we'll go with it.

I won't try to change it at this point.

Operation Warp Speed was overseen by the Department of Health and Human Services, as well as the Department of Defense, and vaccines weren't the only thing under their auspices.

They also had a big role in developing of diagnostics.

Remember, when we didn't have this, we didn't have this disease before early 2020.

Therefore, we wouldn't have a strategy or any tests to diagnose it.

So those had to come really quickly.

We've also done pretty well, although not as well as I had hoped, in the therapeutics or drugs that can be used to treat COVID-19 when people are infected.

And then finally, vaccines, which are gonna be the drug or the agent in this Operation Warp Speed effort that reaches the most people.

In fact, we'd like to reach everyone in the whole world.

The reason that this was able to be done so quickly is because it was done with investment, monetary investment, and big people effort as well.

And it was also done with a significant amount of cooperation and coordination with many, many partners, both public and private.

The federal government oversaw the whole process, including the protocols that were used for studying the vaccines as well as the other agents, but I'm gonna focus on vaccines.

In fact, the protocols, the study protocols were made public.

Now, ordinarily, when you do studies, such as these phase three clinical trials, the protocols are the property of the company that's sponsoring the trial, and you sign a confidentiality agreement if you happen to be an investigator associated with this, with the study, but in this case, and very differently from the, you know, way we usually do things, the protocols were overseen by the federal government and were public.

You could find those protocols on the internet.

But here's the really important thing that I want you to know is that no steps were eliminated.

The steps proceeded simultaneously.

So for instance, phase one trials and phase two trials were going on at the same time.

And planning for the phase three trials were being done while the phase two trials were still being conducted.

While the phase three trials were ongoing, vaccine production was already underway.

The vaccines were being made and packaged.

Now you can see that, should the vaccine fail to meet its efficacy goal, those vaccines would have been wasted.

So you could see there was significant financial risk associated with this, but please know that human risk or the risk associated with the product or adverse events were not, are not part of that risk, when I talk about risk.

There are a couple of hundred COVID-19 vaccines that are in development or in various phases.

So you can see that there are four vaccines that are approved.

This is global data.

There are no approved vaccines in the United States.

We have the authorized vaccines.

We have three authorized vaccines at this time, and those vaccines, I'm gonna go through each one of those.

But look, we have a lot of other vaccines that are still coming, and some interesting ones that are coming and will probably soon be available in the United States.

I'm gonna start with the mRNA vaccines, and it's because they did it chronologically, it's which vaccine was available first, so that's how I chose which vaccine to present first.

We think of mRNA vaccines as being brand new, cutting edge.

How did this happen?

But they're not that new.

They have been studied for more than 10 years, and they have been targeted at diseases like influenza, cytomegalovirus, that's a infection that causes disease in people who are immunosuppressed, like solid organ transplant patients.

Also, it's a particular threat to pregnant females for their fetuses, similar to Zika virus.

Rabies, and also has been a target for maybe development of a cancer vaccine.

Early efforts with these mRNA vaccines were plagued by mRNA's instability.

So I'm gonna guess there's a few of you out there who have worked with mRNA in the lab, or as an experiment somewhere along the line, and mRNA can just disappear.

It's a very unstable molecule in that it just rapidly degrades.

So we needed to come up with a strategy that would prevent it from rapidly degrading so that we could use it as a vaccine.

But important things, about the mRNA vaccine platform anyway, is that they're are non-infectious.

There is no part of the pathogen in that vaccine.

MRNA is not integrating, meaning it doesn't get into your DNA, doesn't change the DNA.

In fact, it doesn't even enter the nucleus of the cell.

MRNA, as I mentioned already, is degraded by natural cellular processes, and in fact, if you put it in a beaker on the bench, it might degrade on its own.

Its duration can be regulated by specific modifications and changing the delivery method.

And then we don't have immunity to the vector as a consideration.

I'll talk more about immunity to the vector coming up when I talk about the adenovirus vaccines, or the viral vector vaccine.

This is a diagram that shows you how mRNA vaccines work.

Firstly, I'm gonna start at about 7 o'clock on that slide, where you have the machine in the lower left-hand corner.

That is a, best I can... machine that would make nucleic acid and hook 'em together for us.

So it takes the As, Ts, Cs and Gs, and in this case, there's probably some Us in it, and hooks 'em together as a messenger RNA.

That messenger RNA is then, once it's synthesized, it's coated in a lipid, mice cell kind of thing.

And that lipid coat protects the messenger RNA from being degraded in storage.

And then it becomes a vaccine.

And in addition, the lipid coat, once it's injected into the person, helps the messenger RNA get into the cell 'cause it's like a soap.

It'll get through the cell membrane.

Then the messenger RNA leaves the lipid coat and gets translated into a protein.

And in this case, this messenger RNA codes for the coronavirus spike, and that spike protein is a dominant protein to which we make an immune response.

So that immune response is made by the cells once they recognize the spike protein.

So in this case, I didn't draw out the whole immune response, but rather I have an antigen-presenting cell, which looks like the spider and is labeled an APC, presenting that coronavirus peptide or spike protein to the other cells of the immune system, which they'll make cellular immune responses, as well as antibody responses.

Another huge advantage of messenger RNA is that it is easy to modify it to either increase a translation in the cytoplasm, and it's actually pretty easy to rapidly upscale and relatively inexpensively produce the mRNA.

So there are two mRNAs available for use in the United States.

The first one is the Pfizer vaccine.

It's a two-dose series.

It was studied in about 30,000 participants in a large clinical trial.

Notice that it included 18 to 85-year-olds.

The Moderna vaccine is also a two-dose vaccine, and it had about 30,000 people in its study, and it too included 18-year-olds up past people over the age of 65 with no upper limit of age.

The vaccines, both of them induced great immune responses.

They induced robust neutralizing antibody responses.

A neutralizing antibody response is exactly kind of like how it sounds.

It's a response, an antibody response that can neutralize the virus and prevent it from, you know, prevent it from causing infection.

Some cellular immune responses are also done, including a CD4, and a Th polarization is also a CD4 type response, and that is oriented more toward a cellular immune response.

So this kind of essentially covers all of the immune responses that might be necessary for making a vigorous immune response to a virus infection.

The Moderna vaccine is given at a 28-day interval, about a month apart, and was found in clinical trials to be about 95% effective.

The Pfizer vaccine has a 21-day interval, three weeks, and was found to be about 95% effective.

And then, I also have some real world effectiveness data.

The mRNA vaccine, so it was either vaccine, it was administered first to some healthcare providers.

About 4,000 healthcare providers were swabbed every week for coronavirus.

Essentially, they had a COVID-19 test every week, whether they were symptomatic or not, and in fact, if they became symptomatic, they were swabbed again.

But they were swabbed about every week.

And interestingly, the vaccine was about 90% effective.

So they were about nine-- Those who were immunized and fully vaccinated were about 90% less likely to get infected compared to individuals who were not immunized.

Great news, and this is just real-world data.

I want to talk a little bit about adverse events, because I think that's something that's really important to think about, and it is a concern of many people regarding these vaccines.

Interestingly, older people have less vigorous immune response, or less vigorous adverse events following the vaccine.

So those who are over 56 years of age had milder and less frequent adverse events.

Reactogenicity, which is a word that means an adverse event immediately following the vaccine.

But they were, those adverse events were typically mild to moderate and short-lived, a day or two.

The incidence of discontinuation of the vaccine series due to adverse events was low.

And interestingly, it was similar in the vaccine and the placebo groups.

So those are really important, that's a really important adverse event for me as a scientist to monitor, because if the adverse event was so bad after the first vaccine dose, most people who have really bad reaction aren't gonna get the second dose.

But in this case, there was no difference between those who got the vaccine or those who got the placebo who refused to get the second dose.

The main adverse events associated with the Pfizer vaccine were pain, headache, chills, and fever.

The Moderna vaccine had actually quite a similar adverse event profile, but because the trials were were not exactly the same, I can report them in different ways.

Let's start with grade three local reactions.

Those are local reactions that happen at the injection site.

And I've defined the grade three at the bottom of this slide, and you'll see that the grade three local reaction requires narcotics for pain or has caused a significant discomfort, at rest, redness or induration, meaning redness with swelling, of about 10 centimeters or more.

Or that it prevents daily activity.

So you can see grade three reactions happened more frequently after the second dose compared to the first dose.

Local adverse events had an onset day one.

So remember, day zero is the day of the vaccine, day one this is the day after the vaccine was administered.

Typically onset at day one and lasted two days after dose one, and three days after dose two.

What I'm telling you is that dose two is a little bit worse than dose one for the Moderna vaccine.

A fever, about 1% after dose one and almost 15% after dose two.

Systemic reactions, reactions that kind of affect a whole body.

Muscle aches, fever would be included in that, persisting beyond seven days were about 12% in the vaccine group.

Now that sounds kind of high, but it was almost 10% in the placebo group.

So I think we just have a lot of systemic reactions that we might report following in a vaccine, or maybe we just all have a lot of systemic reactions that we report any day.

One other adverse event that I want to spend a little time talking about with the messenger RNA vaccines is anaphylaxis.

Anaphylaxis is an allergic reaction that is life-threatening, and this was noted actually very shortly after the vaccines became available in the public, following the EUA.

There were no anaphylaxis episodes in the clinical trials, but when we put it out in millions, you'll be able to find these things.

So the most recent report showed about, a risk of about five per million in the Pfizer group, and about two and a half per million in the Moderna group.

Now, the ordinary rate of anaphylaxis following vaccines in, you know, previous to the COVID-19 vaccines, I would teach the students that it's about one and a half cases of anaphylaxis per million doses of vaccine.

So it's a really rare side effect.

Now, of course, we've dramatically increased that risk with the messenger RNA vaccines, but please know, take a step back and really look at these numbers.

The risk is still incredibly low.

We try to find some risk factors associated with anaphylaxis with these vaccines, and about a third of them had had a prior episode of anaphylaxis.

So for those of you who have already received your COVID vaccine, or for those of you who will, you'll get a question about anaphylaxis or your experience with serious allergic reactions.

All of the cases in this series required some kind of treatment.

Epinephrin is virtually the magic bullet for treatment of anaphylaxis, and over 90% of people did receive a dose of epinephrin.

Please know that although we screen for anaphylaxis, we, you know, only about a third would have this risk factor of a previous episode of anaphylaxis, but know that those people who are vaccinating and providing vaccines are ready to make an emergency response should someone in their care be, experience a case of anaphylaxis following vaccine.

So they're ready.

They monitor people for a period of time following the vaccine, and they can make an emergency response should it be needed.

So current contraindications to the messenger RNA vaccines do include allergy.

I want to take another step now and talk about the third type of vaccine, the third vaccine that is, is available in the United States, and it is a viral vector vaccine.

So starting with the spaceship-looking thing, that's my diagram of a virus, that's an adenovirus.

This adenovirus, though, has been significantly engineered.

One is that it is replication deficient.

When a virus is replication deficient, that means it can't multiply and make more of itself.

That part of its genome has been disabled.

So it is essentially just a case of DNA, and in that DNA, scientists have inserted some DNA for the coronavirus spike protein.

So they've inserted the gene for that.

Then this whole replication deficient virus is formulated into a vaccine and is administered.

The virus will enter the cell because adenoviruses do that.

The coronavirus gene, spike protein gene will be transcribed into RNA and then translated into a protein.

And you've heard this story before.

Then the mRNA that is made from the gene that was in the, inserted into the adenovirus is made into the spike protein.

The spike protein will then get presented on an antigen-presenting cell and will initiate an immune response to that spike protein.

But please know, because the adenovirus is there, it can also elicit an immune response to the adenovirus.

That is one of the implications and shortcomings, or possible shortcomings, anyway, of an adenovirus vector vaccine, or any viral vector vaccine.

You can make an immune response to the virus and no longer be able to use that as a vector for your gene of interest.

The viral vector vaccines that are furthest in clinical trials include the Johnson & Johnson, which now has an emergency use authorization.

And it is a replication-incompetent adenovirus number 26.

It was specifically chosen 'cause it hasn't widely circulated in humans.

The Astra-Zeneca or University of Oxford vaccine uses a chimp replication-deficient adenovirus.

So again, it did not circulate widely in the population.

And the Astra-Zeneca trial has not yet made it to the EUA phase.

It's currently with the FDA with some concerns over irregularities in how it's being reported.

You know, just, these could get ironed out very easily.

Interestingly, the Astra-Zeneca vaccine is being used widely in many countries around the world.

So I'm gonna give you some information about the Johnson & Johnson vaccine.

This vaccine is a single-dose vaccine.

Makes administration really easy, because you only have to do it one time.

There were 44,000 participants in a multinational study.

So including the United States, South Africa, Brazil, and then some other countries in South America.

And now the reason I wanted to specifically talk about South Africa and Brazil, or specifically mention them, is because these two countries have had coronavirus variants appear and appear during the vaccine trials.

I'll talk more about those coming up.

But the Johnson & Johnson vaccine was 67% effective against moderate to severe or critical COVID-19.

It was about 85% effective against severe or moderate disease and 100% effective in preventing death.

I think we have a good vaccine here.

In the United States, interestingly, it was 72% effective, but in South Africa where there were more variants, it was 64% effective.

And please know that this was against moderate to severe or critical disease.

And they were 86% and 82% effective against severe disease.

So it was any disease kind of starting up, or more serious disease.

Still pretty effective.

Adverse events to the Johnson & Johnson COVID-19 vaccine include injection site pain.

That's a very common adverse event with vaccination.

Headache, fatigue, and muscle aches, all in the 30 percents.

Nausea, 14%, fever, 13%.

There was one case of anaphylaxis reported with this vaccine in the clinical trials.

Another type of vaccine that is under development include the subunit protein vaccines.

This is an interesting technology used widely already for other vaccines, including the hepatitis B vaccine, the human papilloma virus vaccine.

There's an influenza vaccine that uses the subunit protein vaccine strategy as well.

And more recently, the newer shingles vaccine uses this type of technology.

They usually are combined with an adjuvant.

An adjuvant is a chemical that magnifies the immune response.

It's like giving that protein, that recombinant protein a microphone and saying, "Hey, immune system, pay attention to me."

The Novavax is a recombinant protein.

Again, it's a spike protein.

It's stuck on microscopic particles and adjuvanted.

It will require probably two doses.

It is finishing up phase three clinical trials in adults.

There are several subunit protein vaccines in phase two trials, so we'll probably see more of these.

The live attenuated or inactivated coronavirus vaccines are another strategy.

This is an old and tested strategy of a vaccine platform.

No vaccine is very far in development in the United States.

There are several using these technologies in phase two globally, and there are three in phase three in China.

I also promised to get back to the variants.

We know that the variants cause lower vaccine effectiveness in the Astra-Zeneca and the Johnson & Johnson vaccines.

And the reason we know that is because the variants were circulating during clinical trials.

So we know that they have less effectiveness against the variants, but still, I think I showed you relatively reassuring data that even though it's a little bit lower, it's still not bad.

There is laboratory evidence that the messenger RNA vaccines might offer protection against the variants, meaning that going back to that word, the neutralizing antibodies, the antibodies will still neutralize the variants.

It requires a higher concentration of them, though.

All of these vaccines appear to be less effective against the B.1.351 variant.

One really good news is the FDA is allowing a path for vaccine modifications to respond to the variants without redoing all of the large-scale clinical trials.

Instead, it'll be more like the influenza vaccine that's reformulated every year.

We know that the influenza vaccine works as well as it does, and that the vaccine can just be reformulated using the same technology every year, just with a different virus.

So this will be, at least is the plan for how the coronavirus vaccine, so the COVID-19 vaccine, might be modified in response to variants that will very likely continue to pop up as more and more people get the infection, and maybe in response to pressure as more people are immune.

The next thing I want to talk about is vaccine storage.

And, of course, the ideal vaccine would induce an immune response in everyone, and be stable at room temperature.

Or, even better maybe, at any temperature.

However, we have no example of an ideal vaccine.

So right now, we're dealing with some vaccine storage challenges.

The best temperature for the Pfizer vaccine is minus 80 degrees Celsius.

That's really cold.

And that requires actually even a special freezer.

Ordinary freezer cannot get that cold.

These freezers are really common in research labs, but they're not common in places where vaccines are typically administered.

So that presented a challenge, initially at least, for the Pfizer vaccines.

The Pfizer vaccine is stable at a higher temperature or a warmer temperature, let me put that, 'cause we have trouble thinking when we're talking about negative numbers, for a short period of time.

And that's really how the vaccine got widely disseminated to start with.

The Moderna vaccine is stored at normal freezer temperatures, and normal freezer temperatures are doable for people who administer vaccines.

And the Johnson & Johnson vaccine is stored in a refrigerator.

So that's kind of like most vaccines are stored in a refrigerator and they are stored, you know, just like other vaccines, such as the influenza vaccine.

The next thing I want to move on and talk about is kind of things about, logical things about vaccination, first starting with herd immunity.

Herd immunity might be a new term to you as well.

Think about the new words you've learned in the last year.

Other terms for herd immunity include community immunity, community protection, and indirect protection.

Because some people really don't take offense at being herd immunity.

Herd immunity is protection conferred to susceptible individuals when a sufficient portion of the population is immune.

I'm gonna talk a little bit and show you some diagrams of this, but what does this mean?

Herd immunity is the amount of people who need to be immune in order to essentially stop widespread disease transmission or halt a pandemic.

And the herd immunity, the level that we need depends on the reproduction number, abbreviated R0.

The reproduction number is the number of people to which an infected person transmits the infection.

So this makes, you know, to have an R0 makes a lot of assumptions.

It assumes that there's equal mixing, that meaning the entire population mixes with the susceptible person.

And then, of course, I'm also gonna make an assumption when I show you these data that the R0 doesn't change.

And of course, the R0 is gonna change as the immunity in the population increases.

So it is estimated that for SARS-CoV-2, the R0 is between two and three.

Compare that to the R0 for measles.

Measles is the most infectious disease or contagious disease that we know of, and it has an R0 as high as 18.

So the herd immunity threshold is calculated as 1 minus 1 over R0.

This is a picture of the concept of herd immunity.

The red stick figures are people who are infected.

The green ones are those who are immune, and the white ones are those who are susceptible.

So now if you look at the diagram on the left, you'll see that the immune people and the susceptible people are freely mixing.

Now on the right-hand side of the diagram, we have way more immune people.

Most of the population is immune, and therefore, fewer people would be infected.

So the infected people, again in red, are separated physically and protected from the susceptible people by the immune people, thereby protecting the susceptible people.

This is a concept of herd immunity.

Let's talk a little bit more about R0s and herd immunity thresholds that we need for a variety of diseases.

I mentioned measles having an R0 of up to 18 before, but in this particular example of measuring measles immunity in the 1960s, the R0 was 14 and a half, but that translates into a herd immunity threshold of 94%.

I'm not gonna read all of these, but I wanna point out SARS-CoV-2.

This was from 2020.

I took the halfway between of two and a half, and that translates into an R0 of about 60%.

Meaning the herd immunity threshold is 60%.

Okay, what does that mean?

We need to achieve a community immunity level of about 60%.

So let's assume that about 10% have been infected, and that the vaccine confers about 70% protection.

So to achieve herd immunity, we need a vaccine uptake of at least 70%.

Let me show you that in graphic form.

So on the left hand, the black bar, that's current immune.

The population gets vaccinated, let's say 70% of people get vaccinated.

But remember, my vaccine estimate, effectiveness estimate was only 70%.

Therefore, only 70% of the 70% are immune.

So I've got 10% plus 49% is 59%.

So that's about where we are with calculating herd immunity.

You can do this for all kinds of different assumptions.

It doesn't have to be with the data that I've presented.

You could change it up and use it for the mRNA vaccines, which have been shown to be 90% effective.

I just used this one because it seems like the numbers work out, and it's cool.

The approach to herd immunity, though, has only been done through immunization strategies.

No infection has ever achieved herd immunity, not even measles, with as contagious as that is.

But the other thing I really, really need you to remember this aspect of herd immunity.

Herd immunity is a theoretical concept.

It is not a goal.

Herd immunity changes with nature.

It changes with the number of immune individuals.

It's gonna change with virus mutations.

And it's also, we also need to take into account durability of protection conferred by both natural infection and vaccine, and we don't know what that is.

So please, please, please don't think of herd immunity as a goal.

We still wanna get vaccine into everybody in order to maximize protection, okay?

So herd immunity, not the goal.

I mean, as a concept, it is, but herd immunity of 60% or 70% or whatever we calculate that to be, that is not the goal.

We wanna get vaccine into everybody.

Also want you to know that vaccine safety in the United States has the best system ever.

So these are just some diagrams that I put up of our different vaccine safety monitoring programs.

The first one is VAERS, or Vaccine Adverse Event Reporting System.

It's a passive reporting system.

Anybody can make a report about an adverse event following a vaccine.

And healthcare providers are required to make a report if a vaccine adverse event happens within 30 days.

The Clinical Immunization Safety Assessment is another system.

And the Vaccine Safety Data Link are both background systems, systems in the background that are constantly monitoring vaccine safety.

And then V-safe is a new system that was put in place right for the COVID-19 vaccine.

And back when you got vaccinated, or when you will get vaccinated, you'll get a handout about V-safe, and it's an app for your smartphone and you can report adverse events that happened to you.

Makes it personal, and you do your part for reporting vaccine adverse events.

And then finally, want to talk a little bit about the world and vaccinating the world.

COVAX is part of the World Health Organization's response to pandemics, and it is a multifaceted approach to make vaccines, well, and diagnostics and treatments available equitably to the world.

You'll know that even though a small proportion of the population lives in the developed world, we've hogged the vaccines so far.

So we want to figure out a way to get vaccines to the rest of the world, because we clearly know that, and this has been truly illustrated by the pandemic, that unless the entire world is protected, we remain at risk for disease outbreaks.

COVAX has a goal of providing 2 billion doses of vaccine.

So far, they have 1.1 billion purchased, but that doesn't mean they possess 1.1 billion, but they've purchased 1.1 billion.

So we have a strong barrier ahead of us.

What has happened as part of COVAX is that the developed world or wealthy countries are paying a premium for vaccines.

And then part of that premium goes to buy vaccines for countries that can't afford them.

So this is a strategy, I've put the link up here for you if you'd like to know more about it.

Okay, in summary, I've decided to end with questions.

So, and that's because there's a lot we don't know yet, and you know, so therefore, so many questions.

The timeline for completion of phase three trials for other vaccines, we don't really know yet.

Interestingly though, so far we've had really appropriate and really great transparent data sharing.

I can sit here and tell you about vaccines and their protocols and how they worked, and what adverse events were reported, and with great confidence that these reports have been made with good transparency.

The Advisory Committee on Immunization Practices got to very quickly see those data and make recommendations for vaccine use.

Places we still need to work on, though, are vaccine delivery logistics.

How do we get vaccines to the people of the United States, as well as to the people in the rest of the world?

Think about getting vaccines that require frozen temperatures or ultra cold or frozen temperatures to places that don't have reliable electricity.

So we have a long way to go yet.

I think we also need to work on public acceptance.

In every state in the United States, the immunization rates in Blacks lags behind the immunization of whites.

We need to make a special effort to close disparities for people who have been adversely affected or disproportionately affected by COVID-19 and get vaccines to them and on their terms.

We also need to continue to do research after the EUA and even into following licensure.

Then following, I think that I can close with the big impact that COVID-19 has had on the United States.

It has become the third leading cause of death in just one year.

You know, we didn't have COVID-19 that we widely know of anyway, in January 2020, but by the end of January 2020, COVID-19 was the third leading cause of death.

I think right there shows how important this information is and how we need to get vaccines in every arm.

I thank you so much for listening.

It's been a pleasure to be able to talk to you and bring you such good news about COVID-19 vaccines.

Roll up your sleeve, get the vaccine, and stay well.