Why weren't mRNA vaccines clinically tried earlier?

Why weren't mRNA vaccines clinically tried earlier?

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As 'researchers using conventional approaches have struggled to develop effective vaccines against a number of pathogens, particularly viruses, that cause both acute (Influenza, Ebola, Zika) and chronic (HIV-1, herpes simplex virus) infection', why weren't RNA vaccines earlier 'explored as a way to more rapidly and cheaply produce vaccines for these diseases, particularly in response to emerging outbreaks'? Why are clinical trials only now commencing to be 'carried out or are ongoing on mRNA vaccines for influenza, cytomegalovirus, HIV-1, rabies and Zika virus'?

Five things you need to know about: mRNA vaccines | Horizon: the EU Research & Innovation magazine | European Commission

1. They're a whole new type of vaccine

If an mRNA vaccine was approved for coronavirus, it would be the first of its type. 'It's a very unique way of making a vaccine and, so far, no (such) vaccine has been licenced for infectious disease,' said Prof. Bekeredjian-Ding.

In fact there are many RNA viruses and there is no reason they can't have a vaccine. In fact the flu we get every year is a good example. Influenzas are RNA viruses with a new vaccine coming out every year.

Vaccines sometimes don't even have the RNA/DNA of the organism you are trying to immunize against. (I'm just going to talk about viral vaccines - there are many other related topics). Immune response is typically targeted to proteins on the external surface of the virus. Antibodies to these proteins are not only effective in creating an immune reaction, but also are ideally protective; some antibodies will block the virus from infecting and help actively fighting the disease. That's a double win and a big reason why previously infected individuals might become immune to a disease: the antibodies in the blood are stopping the virus from acting on contact. There are no technical barriers to a vaccine.

So why don't we have a vaccine? There are literally millions of families of viruses and its not cheap to develop a vaccine and that money means nothing if the public don't accept vaccination. While SARS and MERS were a strong indicator that Coronaviruses would be a threat, in themselves they turned out to be easy enough to stop without bringing the global healthcare apparatus to bear.

Even if they did develop one, its not clear that a SARS or MERS vaccine would be effective against other cornona viruses. Even though the flu is from the same species of virus, we need a new one every year to react to how quickly it changes.

If there had been a corona vaccine available… lmk ask you a question… The MERS outbreak was 2012. The public, having lost awareness of the benefits of vaccines, are not big on seeing the value of paying even $10 for a shot and then not getting sick. You never knew it did you any good. Would you have taken one last fall? Every year for the past 5 years?

No, mRNA COVID-19 vaccines do NOT “hack the software of life”

Antivaxxers and COVID-19 conspiracy theorists were always going to spin conspiracies about COVID-19 vaccines. Unfortunately, some scientists have made it so much easier for them by having likened mRNA vaccines to “hacking the software of life” and being unclear on what gene therapy is.

If there’s one thing that I’ve learned over the years combatting science denial, quackery, and antivaccine propaganda and conspiracy theories, it’s that words matter and messaging is important. At no time in my life have I seen this more than now, in the middle of a pandemic, and I’d like to do something a little different from what I normally do here on SBM and discuss an example. It’s an example in which early messaging used years ago to promote and sell a promising new technology has been weaponized by antivaxxers and COVID-19 minimizers to demonize COVID-19 vaccines. You might recall a post of mine from two months ago, when I discussed how mRNA-based COVID-19 vaccines by Pfizer/BioNTech and Moderna are not “gene therapy”. Think of this as a follow-up looking at how that claim by antivaxxers came about, plus the idea that such vaccines “hack” your genes.

Actually, there are three highly related claims that antivaxxers have been using to sow fear, uncertainty, and doubt about mRNA-based vaccines:

  • mRNA-based vaccines “permanently alter your DNA.” (No, they don’t.)
  • mRNA-based vaccines are not vaccines, but “gene therapy.” (No, they are not. They are vaccines.)
  • mRNA-based vaccines are like a “software update” for your body or “hack” your genes, or biology, or the “software of life.” (A very bad analogy, as I will discuss below.)

As I discussed before, the claim that vaccines can “permanently alter your DNA” is not a new claim. Antivaxxers have been making this claim almost as long as I’ve been paying attention to the antivaccine movement and its disinformation. So it should come as no surprise that antivaxxers dusted off this hoary old disinformation chestnut to use on COVID-19 vaccines. There was no way that anyone could have stopped antivaxxers from making that claim. In contrast, the proliferation of disinformation that mRNA-based vaccines are “gene therapy” like “a software upgrade for your body” is largely a self-inflicted wound that derives from early hype over the new technology by Moderna. Don’t believe me? Take a look at this article by über-quack and “alternative health” entrepreneur Joe Mercola, entitled “COVID-19 Vaccines Likened to ‘Software Updates’ for Your Body“, where Mercola basically tells you where antivaxxers got these talking points from.

First, though, as an aside I can’t help but mention that, so prolific is Mercola’s empire of antivaccine and COVID-19 disinformation, that I could, if I so desired, devote my entire blog output, both here and at my not-so-super-secret other blog, to nothing other than countering Mercola’s misinformation, disinformation, distortions, and lies, and I would still not be able to keep up. The same could be said about antivaxxer Robert F. Kennedy, Jr.’s website Children’s Health Defense. Between the two of them, Mercola and RFK Jr. produce a veritable tsunami of antivax propaganda far beyond what science advocates can keep up with. That’s what we’re dealing with here, and they are far from alone.

Now let’s get into the details.

A Virologist Explains: mRNA Coronavirus Vaccines And What Investors Should Know

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.

Ask a Caltech Expert: Professor Pamela Bjorkman on Vaccines

This article was reviewed by a member of Caltech's Faculty.

As part of Conversations on COVID-19, a webinar series hosted by the Caltech Science Exchange, Professor Pamela Bjorkman discussed COVID-19 vaccine development, the U.S. FDA-authorized COVID-19 vaccines produced by Pfizer-BioNTech and Moderna, and the biology of vaccines and immunity.

Bjorkman, a longtime leader in the study of how the human immune system detects and defends against harmful viruses, is Caltech's David Baltimore Professor of Biology and Bioengineering. Her research group turned its focus to SARS-CoV-2, the virus that causes COVID-19, in the earliest days of the pandemic. The group produced the first images of antibodies from plasmas latching onto a part of the virus and designed vaccine technology that could one day protect against many strains of coronaviruses.

Here, Bjorkman answers audience questions on the science behind COVID-19 vaccines.

Note on Vaccine Development Status

At the time of the January 2021 webinar, 63 vaccines were in clinical development—being tested in humans—and 172 in preclinical development, according to the World Health Organization. In the U.S., mRNA vaccines made by Pfizer-BioNTech and Moderna had proved more than 90 percent effective in clinical trials and received emergency use authorization. Large-scale trials were planned or in progress in the U.S. for vaccines made by AstraZeneca, Janssen (Johnson & Johnson), and Novavax that use methods other than the mRNA platform.

The questions and answers below have been edited for clarity and concision.

Two COVID-19 vaccines are currently FDA-authorized for emergency use. How do they work?

To understand a vaccine, all you need to know is that when a virus infects your cell, it turns on your immune responses. A vaccine turns on similar immune responses, but it does not contain an infectious virus. The vaccine mimics the virus enough so that your immune system recognizes it, but the vaccine doesn't cause you any sort of illness.

Both the Pfizer-BioNTech and Moderna vaccines are called mRNA (messenger RNA) vaccines. That means that what they do is deliver a genetic message to your cells that instructs them to make a part of the SARS-CoV-2 virus called the spike protein, which is normally on the outside of the virus. When it's attached to the virus, the spike protein allows the virus to bind to a cell and then infect it.

So the vaccines deliver the genetic message, and the cells take up that message and start making the spikes, and you make an immune response against the spikes. Part of your immune response is in the form of antibodies, which are circulating proteins in your blood that can go in and out of tissues and so on. Those are directed toward the spike. Now that you have the antibodies, your body can use them to prevent illness in the event you are exposed to the SARS-CoV-2 virus.

There are no components of the virus in the vaccine, so the vaccine can't infect you or give you the disease COVID-19.

How are the Pfizer-BioNTech and Moderna vaccines different from each other?

[Academic researchers outside of these companies] don't know how the two vaccines differ. The mRNA is made in a standard way that researchers in biology, bioengineering, and so on would know. After making it, the companies encapsulate it in what they call a lipid nanoparticle, which has components of membranes and cholesterol and other things. That nanoparticle allows it to go inside cells and might actually also stimulate your immune response. We know the sequence of the mRNA that's encapsulated, and we know pretty much what components are in the lipid nanoparticles.

Those nanoparticles probably differ a little bit between Moderna and Pfizer. People at those companies know exactly what is in the lipid nanoparticles, but we [academic researchers] don't, because that's proprietary. But you can guess based on earlier papers that tell what was in earlier formations of these lipid nanoparticles. People have been making formulations to package mRNAs for eight or 10 years. All of these things have been proven to be safe in animal models and humans.

Why are mRNA vaccines being used for the first time now against SARS-CoV-2?

Well, mRNA vaccines have been previously developed for humans, but the clinical trials weren't completed. For example, Moderna had an mRNA vaccine, I think, that went into humans in 2018 or 2019 against two forms of influenza. They got through the phase one clinical trials, but they haven't yet completed the phase two and phase three, which involve enrolling tens of thousands of people. Normally, the timeline for doing that is quite slow.

There was an emergency in this case. Once the pharmaceutical companies got the mRNA formulated into these lipid nanoparticles, they went very fast through phase one, phase two, and phase three but not skimping on any safety protocols whatsoever. It's just that they were allowed to do this at a much faster pace, and a lot of money was put into it. Normally, it would take a while to complete. The phase one would be, "Is there any horrible reaction?" Phase two would be, "Is there any horrible reaction? And, does it actually have protective immune responses?" Phase three would involve tens of thousands of people, enough people that you could look for rare adverse reactions. Companies combined phase one and phase two, and then combined phase two and phase three to get these out faster. No safety protocols were bypassed.

How quickly do coronaviruses mutate? Is it likely that the vaccines people are receiving now will protect against these mutated strains?

All viruses mutate because they make a huge number of progeny, and they don't have complete fidelity in copying their genomes. That's actually to their advantage, because some of the rare mutations might have properties that allow them to spread more. But the interesting thing is that when viruses mutate, they rarely mutate to become more virulent. Usually, they mutate to [cause milder illness]—because it's to the virus's advantage to infect more people and not, for example, kill them, because they'll spread more if they don't kill their host.

With the variant [first discovered in the UK] and other variants of concern, will the present vaccines work against them? I suspect they will. The data I've seen so far are supporting this. But I want to emphasize that when you make an immune response to any virus, your immune system makes antibodies against all the different places where the virus can bind. The virus is very unlikely to mutate against the whole range of antibodies your body creates.

It could happen that there are enough mutations that a lot of your immune response is diminished. The great thing about these mRNA vaccines is that [companies] estimate they could make a new one in six weeks that would encode a new variant. So, if that's necessary, they can do that. The [original vaccine] has already been in people, they know about how to formulate it, they know what safety procedures there are. They could probably get emergency use authorization quite quickly against new variants if that is necessary.

Do we know yet if people can still transmit COVID-19 after they are vaccinated?

No, we do not. That is a bit frightening. If we are so lucky as to do widespread vaccination all over the world, I think people should definitely continue with social distancing and wearing masks.

Some vaccines confer what's called sterilizing immunity, which means that you cannot get infected whatsoever. But other vaccines protect you against developing the disease that's caused by the virus. One of the polio virus vaccines is a good example. You can still be infected with polio virus, but the virus won't spread to your nervous system, so it won't cause paralysis.

Nobody has had enough time to really look at what's going on since the phase three trials. But people who have been vaccinated almost certainly can get infected. Now, can they transmit that? Nobody knows. Since it's not a vaccine that confers sterilizing immunity, I would think that vaccinated people should assume that you can transmit it and continue to wear masks and do other things to make sure they're not transmitting the virus.

We don't have long-term data from these vaccines yet. How should we think about the long-term potential side effects? What did we learn from previous vaccines?

I think the safety data from vaccines that we've all gotten—polio vaccine, measles vaccine, and so on—they're extremely good. In the long term, we have very few substantial side effects.

Some people have severe allergic responses to vaccines. I just looked up the data. In mid-December, they detected 21 cases of anaphylaxis after administering about 1.9 million doses of the Pfizer vaccine. Most of these occurred within 15 minutes of vaccination. A bit more than one person in 100,000 who's vaccinated will have a severe allergic response. But the interesting thing is, in the phase three clinical trial, they got allergic responses in 0.63 percent of the people given the vaccine, but 0.5 percent of the people who got the placebo also had allergic responses. There are going to be allergic responses. That's why, when you get these vaccines, my understanding is that you're supposed to wait for 15 minutes (or 30 minutes in the case of some previous allergic or anaphylactic reactions) and be observed to see if you're going to have one of these responses. If you do, you're given Benadryl or other things that will calm down your immune system.

Can you address misconceptions about the vaccines? Explain why it will not alter your DNA or cause fertility issues.

I honestly can't understand where the fertility issue came from. There was a very good piece by Katherine Wu in The New York Times in December that discussed this.

This is what I know scientifically: The spike protein on the coronavirus is there to fuse the membrane of the virus to the membrane of the host cell. Lots of viruses have these fusion proteins.

Somebody put out a blog that said [something like], "If you make antibodies against the viral spike protein, there's also a fusion protein that's in the placenta that plays a critical role in developing the placenta. Therefore, it will make you infertile." Well, actually, there is a fusion protein in the placenta. There are fusion proteins all over the place. They're involved in many biological functions in our body. The one in the placenta happened to have originally come from an ancient retrovirus that integrated into the host genome. It looks nothing like coronavirus fusion proteins, period.

The thing that's in common is the word fusion in a description of its function. Someone just read the word "fusion" and knew nothing about the biology behind viruses or the ordinary fusion events that happen all the time in our bodies.

Now, will the RNA get into your genome? RNA does not. They've done a lot of experiments on this using RNA vaccine studies over the years. The RNA remains in the cytoplasm of your cell. It will not go into your genome. There's no evidence for this.

A paper that had not gone through peer review said that under a very artificial situation in which you use cells and culture, you could turn on a natural enzyme that reverse transcribes RNA into DNA. In that case, you could get the SARS-CoV-2 mRNA into the genome. We have common cold coronaviruses all the time. They have basically the same machinery to copy their RNA. They do not go into the nucleus they just don't.

It's really too bad that this paper was out there because it was picked up by a lot of people in the news. Then the idea was, "OK, if we have a vaccine, and it's got RNA in it, the RNA is going to go into your genome and alter your genome," which is a really bizarre thought to have. It doesn't do that. Even if it did, your cell is going to die anyway. So it would make no difference. But anyway, that's not right.

Why do we have to get two doses of these vaccines?

In immune responses, you mount a stronger or more potent immune response the second time you see whatever it is that you're reacting to because of what's called immunological memory. Vaccines [have typically been tested for efficacy] for years in animals to see if second dose, a boost, is necessary. It's hard for me to know exactly how they came to the decision that the boost is needed in this case. A lot of people have been saying, "Let's just get one of these. Maybe you could spread them out more if you just give the prime," which is the first dose.

The FDA put out a statement on January 4 saying that there aren't enough data to know if the prime would be effective because they didn't have enough people in that arm of their clinical trial. Therefore, they don't want to go against what was done in the phase three trials. The short answer is that boosting helps your immune system. The second or third time you see a pathogen, you mount a much stronger immune response to it.

Inside a major Boston medical center’s secret stockpile of medical supplies

That was a big missed opportunity, according to Hotez and other vaccine scientists, who argue that SARS, and the Middle East respiratory syndrome, or MERS, of 2012, should have triggered major federal and global investments to develop vaccines in anticipation of future epidemics.

Instead, the SARS vaccine that Hotez's team created in collaboration with scientists at the University of Texas Medical Branch at Galveston is sitting in a freezer, no closer to commercial production than it was four years ago.

"We could have had this ready to go and been testing the vaccine's efficacy at the start of this new outbreak in China," said Hotez, who believes the vaccine could provide cross-protection against the new coronavirus, which causes a respiratory disease known as COVID-19. "There is a problem with the ecosystem in vaccine development, and we've got to fix this."

Hotez took that message to Congress on Thursday while testifying before the House Committee on Science, Space and Technology. He argued that the new coronavirus should trigger changes in the way the government funds vaccine development.

"It's tragic that we won't have a vaccine ready for this epidemic," Hotez wrote in prepared remarks. "Practically speaking, we'll be fighting these outbreaks with one hand tied behind our backs."

As of Sunday, there had been well over 100,000 confirmed coronavirus cases globally and at least 3,700 deaths. Public health officials are concerned that the virus, which can lead to respiratory failure brought on by pneumonia, will spread widely in the U.S. and last beyond this year — much like the seasonal flu, but more severe and potentially deadlier.

In response, pharmaceutical companies, university researchers and the federal government have been rushing to develop a vaccine. In addition to the official government effort led by the National Institutes of Health, several drugmakers are also scrambling to develop a vaccine that can be tested in humans in the coming months. But even under the rosiest of projections, one won't be ready for more than a year, government officials say.

"I'm cautiously optimistic that we will get a vaccine," Dr. Anthony Fauci, the National Institutes of Health's director for infectious diseases, said in an interview this week. "The thing that's sobering is that it's not a vaccine we're going to have next month, so we're going to have to tough it out through this evolution."

After 40 years of AIDS, here’s why we still don’t have an HIV vaccine

The early days of the HIV pandemic in the United States were fraught with controversy as some people saw AIDS as a disease that affected only the gay community. In July 1983, people marched in Washington, D.C., to demand the funds to fight HIV/AIDS.

Mark Reinstein/Alamy Stock Photo

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Forty years ago, researchers described the mysterious cases of five gay men who had fallen ill with a pneumonia caused by the fungus Pneumocystis carinii. Two of the five men had already died.

That type of pneumonia usually affects only individuals who are severely immunocompromised, researchers wrote in the June 5, 1981 Morbidity and Mortality Weekly Report. Scientists would soon discover that a disease that would come to be known as AIDS was devastating the men’s immune systems.

Three years later, scientists pinned the blame for AIDS on a virus dubbed HIV, or human immunodeficiency virus. Margaret Heckler, the then-U.S. Secretary of Health and Human Services, said in an April 1984 news conference that a vaccine to build protection against the virus would be ready to test within two years, holding out promise that protection was on its way.

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Meanwhile, the HIV pandemic, which probably got its start in Congo in the 1920s, has led to devastating loss. More than 75 million people have been infected around the world as of the end of 2019. Approximately 32.7 million people have died.

That toll would undoubtedly be much higher if it weren’t for advances in antiviral treatments that can prevent infected people from dying from HIV and from transmitting the virus to others (SN: 3/4/20 SN: 11/15/19). To date, only three people have beaten an HIV infection (SN: 8/26/20). For most, it lasts a lifetime.

That long-lasting infection is just one reason why no vaccine against HIV exists yet. It’s also a tricky virus to pin down, with many variants and an uncanny ability to evade the immune system.

And money is an issue too. The lack of an effective HIV vaccine stands in stark contrast to COVID-19 vaccines that took less than a year to develop (SN: 11/9/20). For COVID-19 vaccine development, “the money poured in, which was the right thing to do,” says Susan Zolla-Pazner, an immunologist at the Icahn School of Medicine at Mount Sinai in New York City. Funding for HIV vaccine research comes in five-year installments, making it difficult to allocate the money in an efficient way to get a vaccine off the ground. Still, that funding stream has allowed for advances in HIV research, which partly enabled the rapid success of multiple COVID-19 vaccines.

The technology behind Johnson & Johnson’s COVID-19 jab, for instance, was first developed as a strategy to tackle HIV because it triggers a strong immune response (SN: 2/27/21). The shot uses a common cold virus that has been altered so that it no longer causes disease. That carrier delivers instructions to cells to make the viral proteins needed to train the immune system to recognize the invader. Johnson & Johnson’s COVID-19 vaccine uses a virus called adenovirus 26 the first HIV vaccine candidates used adenovirus 5.

Unfortunately, a clinical trial to test the HIV vaccine showed that participants who had already been naturally infected with adenovirus 5 were more likely to become infected with HIV. Researchers halted the trial. They speculated that those participants were more susceptible to HIV because they already had immunity to adenovirus 5 and that dampened HIV-protective responses from the vaccine.

A pharmacist brings shots for the first participants in an HIV vaccine clinical trial called HVTN702 in KwaZulu-Natal, South Africa, in November 2016. The trial was halted in February 2020 after an interim analysis found that the vaccine was not effective at preventing HIV infection. Gallo Images/The Times/Jackie Clausen

The absence of a good HIV vaccine is not for lack of trying, says Mark Feinberg, a viral immunologist who is president and CEO of the International AIDS Vaccine Initiative in New York City. “The work that’s gone into HIV vaccine development has been by far the most sophisticated and creative.”

Complexities of HIV

Much of the difficulty in making a vaccine comes from the complex biology of the virus itself.

One major challenge is the immense genetic diversity among HIV viruses infecting people around the world. Much like the coronavirus, which has variants that are more transmissible or able to evade parts of the immune system (SN: 1/27/21), HIV has variants too. But “it’s a completely different world for HIV,” says Morgane Rolland, a virologist with the Military HIV Research Program at the Walter Reed Army Institute of Research in Silver Spring, Md.

That’s because the virus makes new copies of its genetic blueprint at a dizzyingly fast rate, generating tens of thousands of new copies every day in a single person, Rolland says. Each of those new copies carries on average at least one unique mutation. Over the course of years, a single person can carry myriad variants in their body, though only a select few variants can be transmitted to others.

The main problem these variants pose for vaccines is that some mutations are in parts of the virus that the immune system tends to attack. Such changes can essentially help the virus go incognito. Good vaccines must spark an immune response capable of handling that vast diversity to provide broad protection against infection.

What’s more, the virus deploys multiple tactics to hide from the immune system. One tactic the virus uses is to cover parts of its surface in a dense layer of sugar molecules. Many of those surfaces would be the prime targets of immune proteins called antibodies that latch onto viral particles.

The complex biology of the human immunodeficiency virus (shown) has so far stymied efforts to design a vaccine effective at preventing infection with the virus. But researchers are developing creative solutions to tackle the problem. NIAID/Flickr (CC BY 2.0)

The body recognizes these sugars as “self,” says Barton Haynes, an immunologist at Duke University School of Medicine’s Human Vaccine Institute. “Basically, what the virus is saying to our immune system is ‘Sure, you can make a protective immune response, go for it.’” But if the antibodies attack, they’re seen as turncoats and are eliminated. That means the body can’t fight the virus as effectively.

Perhaps the biggest hurdle, however, is the lifelong nature of the infection. Many viruses disappear from the body after the immune system fights them off. But HIV has the ability to insert its genetic blueprint into host DNA, establishing a hidden reservoir in immune cells called T cells, which normally fight infections (SN: 10/24/13). That reservoir makes the virus invisible to the immune system. Once the virus inhabits its new hideout, the immune system can’t eradicate it, nor can drug treatments.

That means “you’ve got to have protective immunity there the day, the moment of transmission,” Haynes says. “If [the immune system] doesn’t get rid of the virus within 24 hours, the virus has won.”

Most vaccines don’t generate this type of sterilizing immunity that stops the infection from ever happening in most people who get the vaccine. Instead, shots are more likely to prevent people from becoming severely ill. Many COVID-19 vaccines, for instance, are highly effective at preventing people from developing symptoms, particularly severe ones. But some vaccinated people might still get infected with the coronavirus (SN: 5/4/21).

That’s not an option with HIV since it never leaves the body, Zolla-Pazner says. “It’s a very different bar that we have to jump over for an HIV vaccine.”

Testing HIV vaccine candidates

To date, there have been only a handful of clinical trials to test the efficacy of potential HIV vaccines in people. Of the six trials that scientists saw to completion, only one vaccine candidate proved effective at preventing infection.

That lone successful trial, known as RV144, used a “prime-boost” strategy in which participants received a total of six shots. The four “prime” jabs contained a canarypox virus that is incapable of replicating in cells and carries the genetic instructions for select HIV proteins. The participants’ cells make those viral proteins and develop an immune response against them.

Then participants also received two “boosts,” an injection of an HIV protein fragment that is essential for the virus to enter cells. The hope was that participants would develop a strong, wide-ranging immune response, giving those people broad protection against a variety of HIV subtypes.

Ultimately, that vaccine strategy lowered the risk of infection by 31.2 percent in vaccinated participants compared with the unvaccinated group. Although the shot showed only modest efficacy, those results changed the field by homing in on what type of immune response people needed to prevent infection, Zolla-Pazner says.

“Up until then, there was this raging debate about whether T cells or antibodies were most important in terms of protection,” Zolla-Pazner says. The results from RV144, first published in December 2009 in the New England Journal of Medicine, suggested specific antibodies were the crucial factor in reducing the risk of infection. “That’s not to say that T cells are not important — they are. But I think it established the primacy of antibodies,” she notes. If researchers could push people to make protective HIV antibodies, then perhaps a vaccine was within reach.

More recently, however, the canarypox/protein strategy has produced some less-promising results. In February 2020 — as COVID-19 was spreading around the globe — researchers stopped a follow-up trial being conducted in South Africa that used the same vaccine platform with the goal of improving on the RV144 finding (SN: 2/3/20). The results from the trial didn’t lower the risk of HIV infection in vaccinated people, researchers reported March 25 in the New England Journal of Medicine.

This is where more money for HIV vaccine research could have helped, Zolla-Pazner says. “If you had the money up front and you use it as needed… [scientists] would be doing science more efficiently and therefore getting the answers more quickly.” That investment is especially crucial for early animal testing. Instead of spending decades testing approaches on a handful of animals at a time to see if something works, an influx of money could support more robust experiments. And that could speed promising approaches into the arms of clinical trial volunteers.

Making the right immune response

There are now hopeful signs that vaccine developers working on a variety of platforms might be on the right track to make an effective shot that provides sterilizing immunity. Still, “I don’t think at this point we should be taking any approach off the table,” says Zolla-Pazner.

One approach is tapping into the idea that some infected people naturally make antibodies capable of attacking a wide assortment of HIV variants and stopping those viruses from infecting cells (SN: 7/20/17). These antibodies take a long time to develop. Sometimes they don’t develop until years after an HIV infection has taken hold, Haynes says. HIV vaccine-makers want to speed up the process.

There are several ways to do that. One, being tested now in a clinical trial led by Johnson & Johnson, is to spark a broad immune response using an HIV protein composed of a mosaic of different HIV strains circulating around the world. Another way is to teach the immune system to make broadly neutralizing antibodies.

To do that, researchers identify broadly neutralizing antibodies in people infected with HIV. Then they can analyze the steps the body took to create those immune proteins. The goal is to craft a vaccine that tells vaccinated people to make similar antibodies when exposed to specific viral fragments, says Kevin Saunders, a vaccinologist at the Duke Human Vaccine Institute.

In a December 2019 Science study, Saunders, Haynes and their colleagues showed that in vaccinated mice and rhesus macaques, they could spur the first steps of HIV antibodies that might eventually become broadly neutralizing. A separate effort by Feinberg and his colleagues recently showed that 97 percent of human participants in an early-stage clinical trial made those same rare immune cells when exposed to a piece of HIV engineered to specifically generate the cells.

Other groups are focusing on T cells to fight infection. Louis Picker and Klaus Früh, for instance, developed a vaccine that causes specialized T cells to kill other T cells infected with HIV, rather than relying on antibodies to prevent infection entirely, the team reported in March in Science Immunology.

The team had previously shown that around half of monkeys given the vaccine were protected. The animals became infected with SIV — the primate equivalent of HIV — but the virus couldn’t replicate very well and over time the infection went away, says Picker, an immunologist at Oregon Health & Science University in Portland.

The next step is to move the vaccine into people. “Whatever we see in the clinical trial, it’s breaking new ground,” says Früh, a viral immunologist also at Oregon Health & Science University. “It’s the first time this has ever been done so we’re very excited about that.”

After nearly four decades of trying, there is some light at the end of the tunnel. “I do believe we’ll get a vaccine, I really do,” Zolla-Pazner says. “But I don’t know how long that’s gonna take.”

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Editor's Note:

This story was updated June 7, 2021, to correct the description of Pneumocystis carinii. It's a fungus, not a bacteria.


M.S. Gottlieb et al. Pneumocystis pneumonia — Los Angeles. Morbidity and Mortality Weekly Report. Vol. 21, June 5, 1981, p. 1.

S. Rerks-Ngarm et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. The New England Journal of Medicine. Vol. 361, December 3, 2009, p. 2209. doi: 10.1056/NEJMoa0908492.

National Institute of Allergy and Infectious Diseases. Experimental HIV vaccine regimen ineffective in preventing HIV. Press release, February 3, 2020.

Toothpaste and shampoo

Pfizer’s and Moderna’s clinical trials of the vaccines, which involved tens of thousands of people, did not find serious adverse events caused by the vaccine. But both studies excluded people with a history of allergies to components of the COVID-19 vaccines Pfizer also excluded those who previously had a severe adverse reaction from any vaccine. People with previous allergic reactions to food or drugs were not excluded, but may have been underrepresented.

The two vaccines both contain mRNA wrapped in lipid nanoparticles (LNPs) that help carry it to human cells but also act as an adjuvant, a vaccine ingredient that bolsters the immune response. The LNPs are “PEGylated”—chemically attached to PEG molecules that cover the outside of the particles and increase their stability and life span.

PEGs are also used in everyday products such as toothpaste and shampoo as thickeners, solvents, softeners, and moisture carriers, and they’ve been used as a laxative for decades. An increasing number of biopharmaceuticals include PEGylated compounds as well.

PEGs were long thought to be biologically inert, but a growing body of evidence suggests they are not. As much as 72% of people have at least some antibodies against PEGs, according to a 2016 study led by Samuel Lai, a pharmaco-engineer at the University of North Carolina, Chapel Hill, presumably as a result of exposure to cosmetics and pharmaceuticals. About 7% have a level that may be high enough to predispose them to anaphylactic reactions, he found. Other studies have also found antibodies against PEG, but at lower levels.

“Some companies have dropped PEGylated products from their pipeline as a result,” Lai says. But he notes that the safety record of many PEGylated drugs has persuaded others that “concerns about anti-PEG antibodies are overstated.”

Szebeni says the mechanism behind PEG-conjugated anaphylaxis is relatively unknown because it does not involve immunoglobulin E (IgE), the antibody type that causes classical allergic reactions. (That’s why he prefers to call them “anaphylactoid” reactions.) Instead, PEG triggers two other classes of antibodies, immunoglobulin M (IgM) and immunoglobulin G (IgG), involved in a branch of the body’s innate immunity called the complement system, which Szebeni has spent decades studying in a pig model he developed.

In 1999, while working at the Walter Reed Army Institute of Research, Szebeni described a new type of drug-induced reaction he dubbed complement activation-related pseudoallergy (CARPA), a nonspecific immune response to nanoparticle-based medicines, often PEGylated, that are mistakenly recognized by the immune system as viruses.

Szebeni believes CARPA explains the severe anaphylactoid reactions some PEGylated drugs are occasionally known to cause, including cancer blockbuster Doxil. A team assembled by Bruce Sullenger, a surgeon at Duke University, experienced similar issues with an experimental anticoagulant containing PEGylated RNA. The team had to halt a phase III trial in 2014 after about 0.6% of 1600 people who received the drug had severe allergic responses and one participant died. “That stopped the trial,” Sullenger says. The team found that every participant with an anaphylaxis had high levels of anti-PEG IgG. But some with no adverse reaction had high levels as well, Sullenger adds. “So, it is not sufficient to just have these antibodies.”

Until we know there is truly a PEG [polyethylene glycol] story, we need to be very careful in talking about that as a done deal.

Alkis Togias, National Institute of Allergy and Infectious Diseases

At the NIAID meeting, several attendees stressed that PEGylated nanoparticles may cause problems through a mechanism other than CARPA. Just last month, Phillips and scientists at FDA and other institutions published a paper showing patients who suffered an anaphylactic reaction to PEGylated drugs did have IgE antibodies to PEG after all, suggesting those may be involved, rather than IgG and IgM.

Other scientists, meanwhile, are not convinced PEG is involved at all. “There is a lot of exaggeration when it comes to the risk of PEGs and CARPA,” says Moein Moghimi, a nanomedicine researcher at Newcastle University who suspects a more conventional mechanism is causing the reactions. “You are technically delivering an adjuvant at the injection site to excite the local immune system. It happens that some people get too much excitement, because they have a relatively high number of local immune cells.”

Others note the amount of PEG in the mRNA vaccines is orders of magnitude lower than in most PEGylated drugs. And whereas those drugs are often given intravenously, the two COVID-19 vaccines are injected into a muscle, which leads to a delayed exposure and a much lower level of PEG in the blood, where most anti-PEG antibodies are.

Nevertheless, the companies were aware of the risk. In a stock market prospectus filed on 6 December 2018, Moderna acknowledged the possibility of “reactions to the PEG from some lipids or PEG otherwise associated with the LNP.” And in a September paper, BioNTech researchers proposed an alternative to PEG for therapeutic mRNA delivery, noting: “The PEGylation of nanoparticles can also have substantial disadvantages concerning activity and safety.’”

Katalin Karikó, a senior vice president at BioNTech who co-invented the mRNA technology underlying both vaccines, says she discussed with Szebeni whether PEG in the vaccine could be an issue. (The two know each other well both are Hungarian and in the 1980s, Karikó taught Szebeni how to make liposomes in her lab.) They agreed that given the low amount of lipid and the intramuscular administration, the risk was negligible.

Karikó emphasizes that based on what we know so far, the risk is still low. “All vaccines carry some risk. But the benefit of the vaccine outweighs the risk,” she says.

Szebeni agrees, but says he hopes that’s also true in the long run. He notes that both mRNA vaccines require two shots, and he worries anti-PEG antibodies triggered by the first shot could increase the risk of an allergic reaction to the second or to PEGylated drugs.

It begins, as is often the case, on Twitter

I first recall seeing the antivaccine narrative, claiming that lipid nanoparticles from COVID-19 vaccines accumulate in the ovaries and other tissues, showing up on Twitter from “Nurse Erin”:

There is evidence to suggest that the Covid mRNA-LNP (lipid nanoparticles) are adhering themselves to human organs (i.e. female ovaries). No long-term studies. You can never get unvaccinated. Leaked confidential study from Pfizer. #knowledgeispower

&mdash NurseErin (@erin_bsn) May 30, 2021

Conspiracy theorists being conspiracy theorists, “Nurse Erin” says that the claim that lipid nanoparticles from the Pfizer vaccine “adhere” to the ovaries is based on a “leaked confidential” study from Pfizer (of course). It turns out that “Nurse Erin” is an antivaccine nurse named Erin Marie Olszewski, who caused a minor ruckus last summer after having worked as a traveling nurse during the first surge of the pandemic last spring. She wrote a book about it, Undercover Epicenter Nurse: How Fraud, Negligence, and Greed Led to Unnecessary Deaths at Elmhurst Hospital . (That longtime antivaccine activist J.B. Handley, who has more recently—and not unexpectedly—joined the COVID-19 conspiracy theory antimask grift train, wrote the foreword should tell you all you need to know about this book, as should the endorsement by Joe Mercola.) In it, Ms. Olszewski claimed that people who had tested negative for COVID-19 were being diagnosed as having COVID-19 anyway, put on ventilators, and “drugged up with sedatives”. In the process, besides spinning conspiracy theories, she also appears to have engaged in what sounds like a massive violation of HIPAA by videotaping medical records, and including them in a conspiracy video with minimal redaction. Unsurprisingly, doctors and nurses at Elmhurst understandably felt betrayed and took pains to debunk “Nurse Erin’s” disinformation.

In any event “Nurse Erin” appears to have gotten her “information” from here:

To be clear this is a Japanese study that was acquired from a group of doctors including Dr. Byram Bridle from the Japanese government.

The EMA report is public knowledge that was released in February of 2021 confirming accumulation in organs.

&mdash fly (@dankdly111) May 30, 2021

So as a summary, my research has now revealed to me:
1) They absolutely accumulate in organs
2) They are highly inflammatory
3) Safety studies are suggesting the cause of side effects are primarily from the lipid nanoparticles
4) There is no long term analysis on what happens

&mdash fly (@dankdly111) May 30, 2021

Amusingly, fly tried to appear “reasonable”:

Please chill out with the sterilization claims. We don't know for sure. The study points to no known effect of toxicity on ovaries.

My question is, lipid nanoparticles are highly inflammatory. So are we sure? How do we know for certain? I'm scared of the answer though.

&mdash fly (@dankdly111) May 30, 2021

But antivaxxers were having none of it:

Nix fertility (ie infertility issues). Any critically thinking person could be reasonably concerned about this specter of vaccine driven infertility given this information. Definitely don’t think people should freak out, but let me ask you. Knowing this, and assuming a person…

&mdash David McMillan (@DavidMc16001975) May 30, 2021

Huiveringwekkende studie #mRNAvaccin nanodeeltjes

Japans onderzoek over #LipidNanoParticles (#LNPs) die de #mRNAcode bevatten, en na #vaccinatie op grote schaal door 't lichaam circuleren en hersenen, milt, dikke darm, hart, lever, longen etc. bereiken

&mdash ▪Doorn▪ (@top_grafisch) June 3, 2021

Which brings me to Byram Bridle, who, if the above Tweets are to be believed, is the person who “discovered” this “confidential” Japanese study. Before that, he had been spreading misinformation about the “deadly spike protein” produced by COVID-19 vaccines:

Dr Byram Bridle, Professor of Viral Immunolog: The spike protein in the covid vaccines is a very dangerous toxin. This 7 minute video can save your life, your childrens’ lives and your grandchildren’s lives.

&mdash Ossi Tiihonen (@OssiTiihonen) June 1, 2021

I’ll just refer you to my extensive discussion from two weeks ago of the studies being misrepresented by antivaxxers.

After clinical trials, the vaccine goes to the FDA

After a clinical trial has compiled data that prove effectiveness and safety, this research is presented to the FDA for approval to be used for the general public it&aposs the safety stamp given to everything from medication to food additives. In the case of the COVID-19 vaccines, however, the FDA didn&apost give the typical kind of approval. Instead, all three were granted emergency use authorization (EUA) from the FDA: Pfizer on December 11, 2020, Moderna on December 18, and Johnson & Johnson on February 27, 2021.

The FDA defines EUA as "a mechanism to facilitate the availability and use of medical countermeasures, including vaccines, during public health emergencies, such as the current COVID-19 pandemic." As Dr. Gayle explains, emergency approval is granted faster than traditional approval, which was necessary as deaths and severe illnesses rose. "Emergency use says you weigh the risks of the moment—the COVID crisis𠅊gainst the minimal increase in knowledge you might gain by following the trials longer. It does not mean approval without normal safeguards in place," explains Dr. Gayle.

After receiving an EUA, it&aposs expected that manufacturers will continue clinical trials to collect data that they can use when they apply for full FDA approval.  Volunteers who participated in the trials (like Kedl) continue to be monitored to track their antibody levels and any related reactions. According to Reuters, Moderna and Pfizer will track all of its Phase 3 participants for two years to assess long-term protection and safety.

What are your closing thoughts and best-case scenario for public health control of SARS-CoV-2?

G.A.: We need to understand the nature of reinfection. Natural correlates of exposure could significantly change the game and give us insights to drive vaccine development and, more importantly, to prioritize particular vaccines for those that are most vulnerable to disease. In the meantime, social distancing will be a reality for the foreseeable future. This should be emphasized. We will not be out of masks for a long while. The economy continues to suffer, and we need creative solutions to help our population and world heal. This will not be the last pathogen, and if we learn only one lesson, let us continue to make diagnostics and vaccines a priority, so we can stop emerging infections in their tracks and prevent a pandemic from paralyzing our globe again.

K.B.: The best-case scenario for public health control of SARS-CoV-2 is that we find a cheap, stable sterilizing vaccine. Assuming that doesn’t happen (immediately), the next best case is we have multiple vaccines for different at-risk populations, which are disease modifying, lessen the severity of the infection, and (together with effective therapeutics) reduce mortality from COVID-19. I am optimistic this will happen.

However, we have to recognize that we are likely to face future evolution of the biology of the SARS-CoV-2 virus and also of future viruses. So this means we need to improve our global public health preparedness, where vaccines are just one piece of the pie.

J.D.: My best-case scenario for public health control of SARS-CoV-2 is not scientific. Instead, it is social: a return to truth-based conversations. Politicians must acknowledge and appreciate the value of objective scientific evidence. Until we return to these norms, SARS-CoV-2 will remain a social and political issue and, as a result, scientific and public health solutions to COVID-19 will be encumbered.

In the United States, scientific and medical professionals must continue to highlight the need for everyone to wear masks. I am in awe of our frontline medical workers, many of whom have spent time away from family, gotten sick, or died. Frontline medical professionals are willing to make the ultimate sacrifice for us, and yet many of us will not make the small sacrifice of wearing a mask for them.

J.M.: My best-case scenario is that several vaccines are proven to be safe and effective and can be very widely used throughout 2021. Combined with better therapies, and also with more traditional methods (masks, social distancing, lockdowns), vaccines could end the pandemic next year.

Company executives at vaccine manufacturers (and politicians) really need to pay much more attention to the need to boost public confidence in their products. Vaccine hesitancy is a real thing, and it’s becoming worse during the ultrapoliticized COVID-19 pandemic. Creating a vaccine that is effective but not widely used because it’s not trusted would be a very expensive Pyrrhic victory …. In other words, some companies may need to rein in their ambitions to be first, as they will need the support of the vaccine science and public health communities. If the latter believe or suspect that shortcuts have been taken with safety, that support may not be a given.