Pfizer (NYSE:PFE) and its German partner BioNTech (NASDAQ:BNTX) reported incredible efficacy data from a phase 3 trial for their mRNA coronavirus vaccine candidate last Monday. While the 90% figure inspired much hope, investors should know this was interim data that have not yet been peer-reviewed. This week, Moderna (NASDAQ:MRNA) reported equally impressive results for its vaccine candidate that takes a similar approach.

We talked to Dr. Angela Rasmussen, a virologist and Associate Research Scientist at Columbia Center for Infection and Immunity, about what this hopeful development means for the world and for investors.

 

 

Corinne Cardina: I'm so excited to welcome Dr. Angela Rasmussen, a virologist and an Associate Research Scientist at Columbia Center for Infection and Immunity. Hi Angela, how are you?

Angela Rasmussen: I'm great. How are you doing Corinne?

Cardina: I'm so good. I'm so excited we're going to spend the next 30 minutes talking about coronavirus vaccine development. Starting, of course, with the big news from Monday. Fools, if you haven't heard, on Monday, Pfizer and BioNTech released a press release sharing new information about their COVID-19 vaccine candidate. So a little caveat. This data has not been peer-reviewed. This was a press release, it wasn't the raw data, but the market reacted very positively. It's been heralded as proof-of-concept for vaccines that take an mRNA approach. Right now, the early data indicates that the efficacy, meaning that it accomplishes the goal of preventing COVID-19 disease, it's more than 90%. For context, the Food and Drug Administration (FDA) had said 50% would be good enough. Dr. Angela, can you tell us a little bit about this news and what it means?

Rasmussen: Yes, this news is very encouraging. But I'd like to caution people that we should be a little hesitant to jump to conclusions that this is a complete game changer. The reason for that is that, so this trial enrolled almost 44,000 participants in this Phase 3 clinical trial. This interim data analysis was based on what are called events. An event is when somebody in a clinical trial, either in the control group which receives the placebo or in the group that receives the vaccine, gets a case of COVID. In this case they're looking at symptomatic COVID-19 cases. So people who not only have COVID, but also have symptoms of COVID disease, so not asymptomatic people. This was based on 94 events. That's considerably less than the 44,000 that have been enrolled. We don't know about how many people within those 94 cases were in the most high-risk groups. Obviously, if this holds up, as the trial proceeds, there are more events that we can make conclusions about efficacy on that will be wonderful and that's performing much better than expected. Most of the vaccine candidates, people said 50% is good enough for the FDA. We think that it will be 70% protective. So this obviously exceeds that, which is wonderful news. But that could, of course, change as more events are added to this trial. It's going to be particularly important to make sure that some of the events are occurring in participants who are in those risks groups, especially elderly folks. One of the things about flu vaccines that happens a lot is that older people actually need to get a different formulation of the flu vaccine because their immune responses to the normal dose of the flu shot are not as robust as younger people. We need to make sure that not only is this vaccine 90% protective in all of the participants, but it's going to have that same efficacy in older people who are more at risk of severe COVID.

Cardina: Absolutely. So that is one thing to watch when we do get access to the raw data. Is there anything else, safety or efficacy-wise that you are going to be looking for when we get the full results of this study?

Rasmussen: Yes. Of course, the safety profile is going to be really important and there haven't been any indications that this is potentially dangerous. There haven't been any really worrisome adverse effects reported, but we'll of course, have to wait for more than just the press release that Pfizer released on Monday. The big question that I have, in addition to how well does this work in these vulnerable people, is can these people still transmit the virus? This is protecting again against symptomatic COVID-19. It doesn't necessarily indicate that it prevents against infection with SARS-coronavirus-2, the virus that causes COVID-19. That has huge implications considering this vaccine is not going to be available to everybody for some months. If you get the vaccine and you're 90% protected against COVID, you might still be able to be infected with SARS-2 and shed that and transmit it to other people who have not been vaccinated. It's very much an important question that will need to be answered. In addition to that, if people can get infected while they're vaccinated and they don't develop severe disease, that's a huge public health benefit. I don't mean to discount that. We are getting more and more evidence that up to 25%, maybe even more people have what is starting to be called long COVID or so-called long haulers. Some of the people who have reported these persistent symptoms or symptoms of chronic disease had mild SARS-2 infection. They had mild COVID disease. So it's entirely possible that people might be having fewer symptoms, if they get the vaccine, but may still be susceptible to these longer-term effects of being infected. So there's a lot of really important questions that we need to address before we start celebrating and popping the champagne that the vaccine is here and we're all going to get it and the pandemic is going to be over.

Cardina: Yes, absolutely important to temper those expectations and dig into what the data really tells us. I would love to talk about the mechanism of this vaccine. An mRNA vaccine has never been approved and marketed before. Can you talk to us a little bit about how this kind of vaccine differs from a more traditional vaccine like the flu shot that we're all used to getting every year?

Rasmussen: Right. Yeah, absolutely. The flu shot is what is called an inactivated vaccine. Basically, it's pretty simple. You take a bunch of chicken eggs that have been fertilized, you inject them with your virus stock. You use those chicken eggs to grow up a bunch of virus because flu grows exceptionally well in chicken eggs. Then you inactivate that virus. You render it non-infectious usually by some chemical treatment. Then you give that vaccine to people. Your immune system will respond to what are called the antigen, they're proteins on the outside of the virus particle. That's how you develop immunity with that type of vaccine. An mRNA vaccine takes the mRNA or messenger RNA which is the instructions basically to yourselves, protein-making machinery to make the antigen. Rather than giving you an inactivated virus particle from SARS-coronavirus-2, they give you an mRNA that expresses the spike protein on the surface of SARS-coronavirus-2. So your immune system will still recognize that protein as being foreign and will respond to it. It circumvents the need to actually grow up a lot of virus. It makes yourselves basically do the work of expressing that antigen for your immune system to recognize for you. Both the Pfizer vaccine and the Moderna vaccine are mRNA vaccines that work this way. You're correct. They have never been approved for human use. They have had some clinical trials in Phase 1 for other viral infections. There is some precedent for testing them in people. But they have never been used on a wide scale, certainly not in circumstances like this.

Cardina: Great, thank you. What does this news mean for those drug developers that are going the traditional route? Do you think that 90% could be achievable for some of those companies doing the traditional inactivated virus approach or is that an out-of-reach milestone?

Rasmussen: I don't think so. For a lot of these different vaccine strategies, and there are inactivated vaccines in development. A company in China has actually made an inactivated vaccine, and I believe are vaccinating people with it. That's certainly a valid approach. The other approaches that are in Phase 3 trials right now are what are called viral vector vaccines that use a different kind of virus to basically do the same thing as the mRNA vaccines. They clone the spike protein into an adenovirus. That adenovirus infects you and then expresses that spike proteins to your immune system. Thinks you are being infected with SARS-coronavirus-2. That's a different strategy. Those vaccines have been approved only very recently. There are also subunit vaccines where they basically make the protein, the spike protein, in a bioreactor and vaccinate you with that. So there's all these different vaccine strategies. There's actually also live attenuated vaccine in development, at least one. That's where they basically take SARS-2 virus, they make it less virulence and they give it to you, that's similar to the oral polio vaccine or the measles vaccine which are live attenuated vaccines. All of these strategies have been used before. They're all good. Really, we don't know how they're going to perform in people until we do the Phase 3 clinical trials. One thing that's important to note is that all of these vaccines, should they get FDA approval, will continue to be studied post-market or so-called Phase 4 trials, which is basically just seeing what happens when you start vaccinating a lot of people with it. We may find that in the larger population, this isn't 90% effective. Or maybe it doesn't prevent infection, but one of these other vaccine candidates further behind in the pipeline might prevent infection. So you might see a situation where we actually switch from one vaccine to the other. This is definitely not without precedent. When the polio vaccine was developed by Jonas Salk in the '50s, people in the U.S. were vaccinated with it en masse. That's a very effective vaccine and it's what we still use today, it's an inactivated vaccine but it requires multiple doses, which the Pfizer vaccine does and many of the vaccine candidates do. In fact, there were so many people immunized with the Salk vaccine in the U.S., that Albert Sabin, who developed the live-attenuated vaccine had to conduct clinical trials in Russia. But then, when we got the results of those trials, it turned out that with one dose, the Sabin vaccine was actually more protective and provided lifetime protection, so we switched to using the Sabin vaccine for general childhood vaccinations, only recently did we switch back to the Salk vaccine because we're hoping to eradicate polio, we don't want live attenuated vaccine viruses floating around. It has gone back and forth between different vaccine platforms for many of the vaccine-preventable diseases, I think it's completely possible that one of these vaccines that's a little further behind the Pfizer and Moderna, AstraZeneca (NASDAQ:AZN) and Johnson & Johnson (NYSE:JNJ) vaccines may be more effective, may be more protective, and we may, in the future, end up switching to one of those different vaccines.

Cardina: Absolutely. The bottom line is really this is not a winner-take-all market, the company that gets the first FDA authorization is certainly not going to be the only vaccine maker for a lot of different reasons including manufacturing constraints, distribution constraints, and everything that you just mentioned. Does that sound right?

Rasmussen: Yeah. That sounds really right, and I think that while the company that is first-to-market will definitely have a financial advantage. That will be a big windfall for them because there will be extremely high demand. I think that right now we are in a situation where frankly, it's really frightening for everybody, especially for public health people; we are on a very steep upward trajectory of cases, so the more vaccines right now that can be approved and made available, the better. Secretary Alex Azar said yesterday that Pfizer expects to have 20 million doses available by the end of the year, and that's not enough to vaccinate all of the vulnerable people who are going to be first in line to get it, all the healthcare workers, etc. If we can have more than one vaccine, since they've all been manufacturing vaccines pre-emptively due to operation work speed, then we will be in a much better position to vaccinate more people, more quickly, and then the challenge will become convincing people to actually get vaccinated.

Cardina: Absolutely. Of course, it's important to remember that 20 million vaccine doses, if people require two doses, that's really only enough for 10 million people to take the vaccine, so the dosing will play into that as well.

Rasmussen: Absolutely.

Cardina: Let's talk about timelines. You mentioned, of course, there are certain demographics and people who are in high-risk frontline jobs who are going to be first in line to get the vaccine. Do you have any thoughts? Of course, this is the big question, everyone wants to know about when a vaccine will be open to the general public.

Rasmussen: I think that's a really tricky question because it partly depends on how many vaccines get some type of FDA approval, whether that's full licensure or whether that's an emergency use authorization. I think that a conservative estimate would be by the end of next year, I think of, probably, a more realistic estimate is sometime next summer. I know that, again, Secretary Azar is extremely optimistic about the timelines and said that everybody should have access to it by March or April of 2021. I think that that, again, is extremely optimistic and especially if we only have one vaccine that actually has approval. As you pointed out, the Pfizer vaccine does require two shots, as do many of these candidates that are in Phase 3 trials. The Pfizer vaccine also has one real challenge and that's going to be distribution. These mRNA vaccines, mRNA itself is a very unstable molecule, so it has to be kept in an ultra-cold freezer, that is minus 80 degrees Celsius or below. Many places do not have these ultra-cold freezers and they're expensive and out of reach of many community places where people normally get vaccine, like say your local neighborhood drugstore, your local primary care physician's office. It's going to be very difficult for all of them to invest in these ultra colds freezers to make distribution much easier. So there's going to be a real challenge getting those, especially, to places that are not near a major medical center, major hospital which is where these ultra cold freezers are usually located. I think that just these logistical issues are going to delay that timeline, they're going to make it very challenging for people to roll out. It's not just the number of doses that we've manufactured by now because for an mRNA vaccine, the good news is that they're actually fairly straightforward to manufacture. They're not difficult, they don't require inoculating a bunch of chicken eggs, they can be synthesized fairly easily. But again, the challenge is making sure that they can get to all the people who are going to need them.

Cardina: Yeah, that's a great point. Another big question mark is the length of immunity. I think mutation possibly plays into that; if the virus can mutate, people may need a vaccine yearly. We don't know that this is going to confer lifetime immunity. Do you have any thoughts on the length of immunity and/or possible mutation?

Rasmussen: Yeah. Those are really two different issues. Durability is, of course, very important. Unfortunately, the only way for us to determine durability is to actually wait and see. We can't really speed that process up experimentally. We just need to continue looking at people who have participated, not only in the Phase 3 trials but in the Phase 1, 2 trials and see how long they have detectable antibody titers, which is what is being used predominantly to measure vaccine immunogenicity, or the ability to elicit an immune response. But neutralizing antibodies or antibodies that can render the virus non-infectious are thought to be a really important correlate of protection. One thing that's going to be really critical post-market is to follow people after they've been vaccinated and see how long they have detectable levels of either IgG, which are the antibodies that are more likely to be neutralizing or actually neutralizing antibodies, because there are assays that can look directly at neutralization. So that's going to be really important. The other thing that you mentioned, mutation is something that we definitely have to follow. That's going to be through surveillance testing and that's going to be monitoring people in the community, seeing who has SARS-coronavirus-2, and sequencing the viruses that they are infected with to determine whether or not they have acquired mutations that could allow them to escape the vaccine. People have been very alarmed about mutation, I think just because in the popular minds mutation is usually associated with something bad or radical change. But RNA viruses like coronaviruses do mutate, it's a normal function of those viruses. If they weren't mutating, that would actually be really unusual. We already know that this virus is acquiring mutations, the good news though, is that it has a much lower mutation rate than influenza virus, for example, so it's going to be slower to develop those types of mutations that would allow it to escape or evade a vaccine. So far, there's not really any hard evidence that any of the mutations that have been acquired allow it to escape neutralization by antibodies, so the mutation that has been best characterized to the spike protein is called D614G, and it has been attributed with making the virus more transmissible, which is still not settled science. But that mutation is not in a part of the spike protein that is important for antibodies to bind to it. That mutation so far, even though it is in spike, is not thought to change vaccine efficacy or the way that antibodies work at all, compared to the original virus that emerged from China and that all the vaccines are designed against. Right now, we don't have any evidence that there are mutations that would render these vaccines less effective. But that is something that could happen in the future, which is why it is really important to do that surveillance testing and genomic analysis to make sure that the vaccines don't need to be adjusted.

Cardina: Absolutely. That's such a great explainer of these topics. I think that everyone is so excited about the big news from Pfizer. We've touched on this a little bit, specifically the difference between being infected and actually developing COVID-19 is a really big topic that people need to understand. Are there any other big misconceptions about the coronavirus vaccine development that you think should be corrected?

Rasmussen: The biggest misconception is actually just what people's expectations are. There are really two camps. There are people who think that the vaccine is going to get approved and like "bam", the sun is going to come out, pandemic's over, everything can go back to normal. There's also another subset of people who think that because of some of the messaging around vaccines and especially some of the statements that President Trump himself has made about vaccine approval, that these vaccines are going through an evaluation process that is not as rigorous as normal, that will potentially allow a vaccine to get FDA approval that's not safe, that's not effective, and they don't want to take it. Both of those ideas about this process are incorrect. There's a couple of reasons why. Operation Warp Speed, despite the name implying that corners are being cut, is primarily designed to manufacture and distribute vaccines. It really doesn't have that much to do with how the vaccines are being evaluated in clinical trials. While we won't be able to evaluate durability based on these clinical trials because they're being performed in such a compressed timeline, we should be able to pretty effectively evaluate safety and efficacy at least in the short-term with these vaccines, and that would be a huge win. But that said, there's going to be a real challenge in getting people to not only take the vaccines, they are skeptical of this process. But these vaccines as you pointed out, many of them require two doses. Those doses are spaced over 21 to 28 days, so three to four weeks. Then you may not have full protective immunity until at least a week after your second dose. So it's going to take time to actually get these vaccines to people who have access to them. It's going to take time for those vaccines to actually induce protective immunity. Then it's really important to point out that this is still a marathon. When we have a vaccine approved, it's going to be the beginning of the end. But the vaccine alone is just one thing that we need to keep in mind as we try to end and contain this pandemic. That means that we have to do other things as well as the vaccine. There are a number of countries: Singapore, Vietnam, Taiwan, South Korea, New Zealand that have effectively controlled this virus within their borders without a vaccine. So we're going to need to continue to take some of the measures that allow that. We're going to need to continue to avoid crowds, to wear masks, to physically distance, to ventilate if possible, to practice good hand hygiene, to take all of these measures that are intended to reduce and control community transmission as the vaccines are being rolled out, especially if there are a significant number of people that myself, my colleagues, and other people who are advocates for vaccines won't be able to convince to actually get a vaccine. Again, it's really encouraging news from Pfizer. I think that we are on the verge of having at least one vaccine available, but it's going to take months to really get that out there and then we may not even be able to do that. So we shouldn't be relying just on a vaccine to end this protracted national and actually global nightmare that we've been going through since the beginning of this year.

Cardina: Absolutely. The vaccine will be a very powerful tool, but we really need the whole toolbox to get this under control.

Rasmussen: Exactly.

Cardina: Dr. Angela, I know that you're a doctor of course, but us, The Motley Fool, we are investors. So I'm going to put you on the spot and ask, what would you say to any investors who are considering buying stock of one or more companies that are working on COVID-19 vaccines?

Rasmussen: That is definitely out of my wheelhouse because I'm not any kind of financial advisor or investment advisor. Certainly, Pfizer is a good bet, probably looking forward. Buying stock in any of these companies is probably advisable especially if they have promising trial results like Pfizer has had. There's room in the market for all of these vaccines and, in my opinion, the more, the better, the more people we can get vaccinated. Maybe as we get more data, some of these vaccines may work better for certain groups than others. Perhaps the Pfizer vaccine works well in elderly people but the Moderna vaccine does not. That's not fact, that's just a hypothetical situation. But let's say that one vaccine works better for some people than for others, that means that there's really room in the market for everybody. I think that investing in any of these companies that have late-stage vaccine candidates is probably a smart move financially. It's what I would do if I were buying stocks in pharmaceutical companies, which I'm not because of conflicts of interest.

Cardina: Absolutely.

Rasmussen: But I think that any of these companies that have a later-stage vaccine candidate would be a wise investment.

Cardina: Absolutely. So maybe taking a basket approach and purchasing a couple of different stocks. Of course, not putting your entire portfolio into this part of the market, but definitely a lot of intriguing stocks there. We've gotten a couple of questions from Slido. One, I'm just going to answer really quickly by posting a link into the chat. David Applebee asked, "What is the category of COVID-19 vaccine that GlaxoSmithKline (NYSE:GSK) and Sanofi (NASDAQ:SNY) are developing?" I love this tracker that I'm putting in the chat. It's by BioPharmaDive. It goes through all of the candidates in late-stage trials, tells you exactly what mechanism they are taking, so give that a look. I believe it says that GlaxoSmithKline is using the protein. Let me just search here. Dr. Angela, are you familiar with the GlaxoSmithKline candidate?

Rasmussen: There are so many of them that I'm looking at the tracker right now to remind myself because I don't want to say the wrong thing.

Cardina: No problem. It's protein-based. It says, "coronavirus-derived protein produced in insect cell lines." Like what Dr. Angela was talking about with the chicken eggs, this uses insect cells extracted and delivered alongside an adjuvant. So take a look at that.

Rasmussen: I can tell you based on that description what it is. It's what's called a subunit vaccine. It's a little different than the influenza vaccine. This doesn't actually require them to grow up the virus either. This is using an insect cell expression system. Novavax (NASDAQ:NVAX) is another example of a vaccine that is being produced in this way; to grow up what I'm sure is probably the spike protein and possibly one or two other proteins, I'm not sure. Coronavirus-derived protein usually means spike, but it can also mean nucleic acid and envelope proteins as well. But in any case, they're growing up protein antigen in these insect cells, and then they're giving you that protein antigen with an additional adjuvant which is something that stimulates the immune system further because proteins alone often are not very immunogenic or capable of eliciting robust immune responses. So these types of vaccines are also usually given with some type of adjuvant. Another example of a vaccine like this would be the hepatitis B vaccine which is also a subunit vaccine. I don't believe it has an adjuvant but they usually give three doses of that vaccine to make up for the fact that it does not.

Cardina: Very helpful. Thank you. Well, folks, that is 11:30. Thank you so much Dr. Angela for coming on Fool Live. I think we've learned so much from you today and we will have to keep in touch. Good luck with all your hard work.

Rasmussen: Thank you so much. It was my pleasure to be here.

This article represents the opinion of the writer, who may disagree with the “official” recommendation position of a Motley Fool premium advisory service. We’re motley! Questioning an investing thesis -- even one of our own -- helps us all think critically about investing and make decisions that help us become smarter, happier, and richer.