COVID-19 vaccine development
SciLine reaches out to our network of scientific experts and poses commonly asked questions about newsworthy topics. Reporters can use these responses in news stories, with attribution to the expert.
What are Quotes from Experts?
February 3, 2021
How will scientists decide when to update vaccines in response to new SARS-CoV-2 variants?
“Scientists can draw blood from people who have received the vaccine and extract the serum (liquid) part of the blood that contains antibodies. They can then ask how well those antibodies work to prevent the virus from infecting cells in the lab. The good news, for the moment, is that the antibody responses to the virus by vaccinated people are strong. This means that even a 2-fold or 5-fold reduction in antibody recognition due to a particular variant would still be expected to be protective. As new variants of concern arise and spread, they can be tested in the lab against the blood of vaccine recipients using the same types of tests to determine the new variant’s susceptibility to vaccine-induced antibodies. There are efforts underway to create standardized ‘panels’ of antibodies from diverse groups of vaccine recipients so these experiments can be done by researchers from around the world against whatever viruses emerge in their own neighborhoods. The standard scientist caveat of ‘we need more data’ is true here too. Since we only have two months of ‘real world’ vaccine effectiveness data, and very limited data against the variants, these lab-based predictions will need to be validated in the real-world and could be wrong.” (Posted February 3, 2021)
“Updating vaccines for each emerging new strain is not practical. Since all first-generation vaccines are based on the spike gene of the ancestral strain from Wuhan, perhaps the first step should be testing serum antibodies in animals and humans immunized with these vaccines against the new variants. If a there is a significant (e.g., more than 50%) reduction in the ability of antibodies found in the blood of vaccinated people and animals to neutralize the virus, an update may be considered. However, it is unclear what the right threshold should be for such evaluation. A more stringent test would be a virus challenge in live animals susceptible to SARS-CoV-2 infection. If current vaccines fail to confer protection against new variants, they must be updated.” (Posted February 3, 2021)
How challenging is it to update different types of vaccines?
“It depends on the type of vaccine. One of the tantalizing features of the mRNA vaccines produced by Pfizer/BioNTech and Moderna is that making new vaccines with updated viral genetic coding should be very quick. I think that this technical simplicity could lull us into a false sense of complacency if we don’t also consider the underlying biology. What do I mean? When viral variants emerge in response to attacks from infected persons’ immune systems, that evolutionary pressure results in viruses that often are less effectively recognized by the immune system. For example, the B.1.351 variant (the “South African” variant) has a specific change called E484K in the spike gene. The ‘E’ here means that the original form of the virus encodes a glutamic acid amino acid residue in the 484th amino acid position of the virus spike protein, while the new B.1.351 variant viruses have a lysine amino acid (“K”) in this position. This change appears to reduce the ability of antibodies to recognize the spike protein.
“If a vaccine is updated to encode the lysine—so that the vaccine spike protein matches the new variant spike protein—there is no guarantee that the new vaccine will elicit antibodies that are as potent as those elicited against the original virus’s spike protein containing glutamic acid. Moreover, antibodies directed against variant viruses with lysine at this site in their spike protein may *continue* to exert selective pressure which will lead to the emergence of another variant that is even more poorly recognized by antibodies. There is already anecdotal data that the spike protein lysine found in the ‘South African’ B.1.351 variant can be replaced by another amino acid, alanine, that might be even harder for antibodies to recognize. So even if it is relatively easy to update the vaccines themselves, this doesn’t necessarily mean the updated vaccines will work as well.
“Taking a page out of the book on HIV, where the emergence of variants has bedeviled drug treatment for decades, the ‘right’ answer is to reduce the amount of virus replication globally to give the virus fewer opportunities to spawn new variants. Reducing the ‘global viral load’ is critically important. If we give the SARS-CoV-2 virus huge numbers of opportunities to evolve variants that are adapted to replicate in the face of immune responses, it will.” (Posted February 3, 2021)
“The time and effort required for updating a vaccine is determined by the underlying vaccine platform. In principle, it is easier to update nucleic acid vaccines, such as DNA, RNA, and viral vector-based vaccines, because scientists only need to incorporate the genetic information into these platforms. For protein-based vaccines, spike mutations can be readily made and tested, but it may take more time if a new family of cells that produce the spike protein for the vaccine has to be created and the manufacturing process has to be re-evaluated.” (Posted February 3, 2021)
If vaccines come on the market that are less effective than existing vaccines against new variants of SARS-COV-2, should people get them or wait until more effective vaccines are available?
“If your house is on fire, don’t wait until you have the perfect hose. People should get vaccinated with whatever effective vaccine they have access to because this will help protect themselves and their communities by impacting the global viral load. Continuing precautions like mask wearing and distancing even after you get vaccinated will have a much greater impact on how well the vaccine keeps you safe than which vaccine product you receive.
“As their part of the bargain, scientists and policymakers need to evaluate ways of improving the protection offered by vaccines that might have lower predicted efficacy. For example, the single dose Johnson and Johnson vaccine has several logistical advantages but has a lower clinical trial efficacy than the mRNA vaccines. Studies that look to pair a dose of the Johnson and Johnson vaccine with a later dose of an mRNA vaccine once supply isn’t as constrained should be started right away. This will let those who do get a less effective response initially to eventually be boosted to the same levels of protection as those who receive the most effective vaccines from the outset.” (Posted February 3, 2021)
“If the current vaccines become less effective against new variants but still reduce the symptoms of severe disease, that is a good enough reason to get vaccinated. However, if people who get vaccinated have a less effective immune response, that also increases the possibility of generating new and more evasive SARS-CoV-2 escape mutants.” (Posted February 3, 2021)
January 7, 2021
Why are the currently approved COVID-19 vaccines administered as two separate doses?
“The idea behind two separate doses is that the first dose ‘primes’ the immune response and the second dose acts as an amplifier, making the immune response against the virus stronger. Such a strategy is why vaccine manufacturers often design studies to have multiple doses. This doesn’t mean that one dose can’t be effective, but it is impossible to test every combination of doses, timings, routes, and vaccine compositions at once. The Moderna and Pfizer vaccine Phase 3 trials were designed to use each company’s ‘best guess’ strategy first. Fortunately, both of these were extraordinarily successful.” (Posted January 7, 2021)
“The first dose primes the immune system and generates memory cells, thus getting the body ready to respond quickly to an infection. Antibody and memory cell responses are induced after the first dose, but the level is usually lower and could wane quickly below thresholds needed for protection. The second dose, also called a booster, expands the number of immune cells that were primed by the first dose, resulting in a stronger antibody response that is generally more durable. Administering two doses of COVID-19 vaccines increases the likelihood of achieving maximum prevention of disease and increases the percentage of people vaccinated that develop protective levels of immunity, leading to more durable immunity.” (Posted January 7, 2021)
What data would be necessary to determine whether delaying or even eliminating a second dose to give more people first doses would be a net benefit?
“I believe that we could gather much of this data from real-world follow-up of existing programs. People will skip their second doses; some vaccine distributors won’t have the necessary number of doses at the specified interval. Hopefully state and federal governments are going to evaluate how many people receive the second dose at the specified interval and how many people skip their second dose entirely and make this information available publicly. It would also be a good idea to test a subset of individuals at the time they receive their first and second vaccines. Within the same community, a lower rate of SARS-CoV-2 in people getting their second vaccine relative to those who are receiving their first vaccine would suggest that the initial vaccine dose is protecting from infection.” (Posted January 7, 2021)
“Not all vaccines require two doses to achieve sufficient levels of immunity to provide protection. While a booster dose maximizes the response, in some cases a single shot may be able to induce sufficient immunity to provide protection. The data supporting this ‘dose sparing’ approach for the currently approved COVID-19 vaccines is evidence from phase 3 clinical trials showing there was a significant level of protective efficacy achieved within two weeks after only the first dose. However, since the second dose was administered within 3-4 weeks after the first dose, it’s not known how durable the immunity after a single dose will be and whether it will last long enough to provide persistent protection during the delay. Another concern is protection in the elderly. Due to aging of the immune system, the elderly will generally respond less well to vaccination. Even if a single dose provides sufficient immunity in younger people, the elderly may still require both doses.
“For most vaccines, spacing between doses can be stretched out without compromising the potency of the booster dose. In some cases, allowing a longer resting period of even up to 6 months between doses can generate stronger immunity after the second dose than a shorter, several week waiting period. The spacing of 3-4 weeks between doses is the minimum spacing needed to allow the first dose to effectively prime the immune system and was likely implemented with a view toward inducing maximum immunity in the shortest possible time.” (Posted January 7, 2021)
What are potential benefits and drawbacks of administering a second vaccine dose from a different brand than the first?
“The biggest drawback is that deviating from the specified interval used in the Phase 3 trial means that we can’t be confident that the vaccine will work as well in the real-world as it did in clinical trials. And this is a major drawback. At the same time, as a researcher who is not involved in vaccine implementation, vaccine delivery programs in the US seem chaotic at the moment. If this means that the carefully controlled conditions of the Phase 3 trials won’t be replicated anyway, it makes sense to me to administer as many first vaccine doses as quickly as possible even if that means that some people have their boosts deferred. It is still important to strive for two doses of the Pfizer and Moderna vaccines to maximize the likelihood of having protective immunity.” (Posted January 7, 2021)
“The primary benefit in being able to use different brands of vaccines interchangeably is better coverage in the population, especially if there is a shortage due to manufacturing or distribution. If there is a shortage of one brand, being able to use another brand for the second dose would allow vaccinations to stay on schedule. In support of this, there is evidence from previous studies with other types of vaccines that mixing different brands and types of vaccines is still effective and safe and may even be beneficial. The main drawback is we don’t yet know how the approved COVID-19 vaccines work when mixed, or if mixing them could generate new safety issues or increase the frequency of common reactions to the vaccines like fevers and swelling. Deviating from the regimen used in a Phase 3 clinical trial raises unknowns in both safety and efficacy. However, by approving and rolling out multiple COVID-19 vaccines, vaccine mixing is likely inevitable. Preclinical studies are now in progress to test vaccines in combination.
“Historically, mixtures of vaccine types have been used on purpose. Two polio vaccines were eventually used, a live attenuated one and an inactivated one. For a time, they were actually used in combination, priming with the live attenuated vaccine and then boosting with the inactivated vaccine. In further support of mixing different types of vaccines, a phase 3 human clinical trial of an HIV vaccine—consisting of priming with a live attenuated Fowlpox viral vectored vaccine and boosting with recombinant protein vaccine—was safe and, to date, is the only HIV vaccine trial that exhibited some efficacy. The prime-boost regimen using different types of vaccines is an area of intense study and numerous other studies in the lab have shown that when you combine two different types of vaccines, you can get a better response with the combination than using either vaccine alone in a two-dose regimen. The reasons mixing can work are not entirely known, but the findings from these studies provide some confidence that mixing COVID-19 vaccines will not likely be a problem and may even be beneficial.” (Posted January 7, 2021)
December 10, 2020
NOTE: Quotes from December 10th, 2020 were given before the meeting of the FDA’s Vaccines and Related Biological Products Advisory Committee.
What does the FDA’s analysis of the Pfizer vaccine tell us?
“The FDA analysis provides more nuance than the previous press releases. Critically, the FDA analysis also provides an independent analysis. The take-home message is that the Pfizer vaccine offers spectacular protection from COVID-19 disease. Replicating this incredible outcome from the first 40,000 clinical trial participants in tens, or hundreds, or millions of people is going to be the next tall mountain to climb.” (Posted December 10, 2020)
“The FDA confirms earlier efficacy claims from the company and even some level of potential immunity a week after the first dose, although it remains imperative to get both doses in order to obtain truly high levels of virus-neutralizing antibodies. The outstanding questions that remain include the long-term durability of protection: weeks, months, years? Is manufacturing robust enough to get sufficient vaccine to the public, or will we need additional vaccines and technologies? Also, what’s the suitability for adolescents and children, and is there vaccine hesitancy for mRNA vaccines for children? This is important since we’ll need to reach adolescents and children to reach 60-80% population immunity. Finally, what’s the ability of vaccines to halt virus shedding and asymptomatic infection, essential for eliminating COVID-19?” (Posted December 10, 2020)
“It is important to note that the FDA performs its own independent analysis of the primary data for each of the COVID vaccines. In this case, the FDA as well as the company provides separate and independent briefings to be discussed and evaluated by the Vaccines and Related Biological Products Advisory Committee and later the Advisory Committee on Immunization Practices (ACIP). This will lead to the final decision of granting the emergency authorization and additional steps towards licensure.” (Posted December 10, 2020)
How does publication of AstraZeneca’s early results add to our understanding of that product?
“The AstraZeneca results underscore some of the challenges that arise when developing and testing vaccines with unprecedented speed. Issues with dose amounts and timing make it difficult to analyze all of the participants as a single, cohesive group. With that said, the vaccine clearly reduced symptomatic disease. Since the AstraZeneca vaccine, like Pfizer and Moderna, target the virus’s spike protein, this reinforces the message that this is an outstanding target for vaccine design.” (Posted December 10, 2020)
“The AstraZeneca/Oxford vaccine shows an important level of protection, not as high perhaps as mRNA vaccines but enough to keep the vaccine in play. Less clear is what FDA will require for emergency use authorization and licensure, including maintaining ongoing phase 3 study in US.” (Posted December 10, 2020)
“This publication provides initial evidence about the impact of using different vaccine formulations as well as results from different trial sites around the world. Additional data will be necessary to understand better the impact of these results.” (Posted December 10, 2020)
How does the efficacy of the AstraZeneca vaccine compare to that of the Pfizer and Moderna candidates?
“It is still premature to read too much into the bottom line numbers; it will be much more telling to look at performance over a longer interval, like one year. As recently as two months ago, scientists would have been elated with one vaccine that is 60% effective in preventing disease. Having three, with others on the horizon, is terrific. The more viable alternatives, the better.” (Posted December 10, 2020)
“Because they are very different platforms it is not easy to compare each vaccine. In addition, the methodologies used to evaluate the immunogenicity and efficacy may have been performed by different techniques and laboratories. The good news is that it seems both vaccines are safe, immunogenic and with efficacy above the threshold provided by the regulatory agencies.” (Posted December 10, 2020)
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November 16-17, 2020
What do we know about the similarities and differences between the Moderna and Pfizer/BioNTech vaccines?
“The Moderna and Pfizer/BioNTech vaccines are both mRNA vaccines and both cause the body to make a viral protein, called the spike protein, that SARS-CoV-2 uses to invade human cells. In that way, they are very similar. They both utilize a delivery and preservation technique to encase the RNA in the vaccine with lipid (fat) molecules, and these are likely somewhat different between the two vaccines. Both vaccines showed promise in creating an immune response in earlier trials and now both protect at a greater than 90% level in interim analyses. One difference that may become important is the temperature of storage, with the Pfizer product requiring -70 degree Celsius storage and Moderna reporting stability at -20 degrees Celsius, a more ‘normal’ freezer temperature. Recently, the company has stated that their vaccine is even stable for 30 days at refrigerator temperatures.” (Posted November 17, 2020)
“Both vaccine companies have evaluated the data at an interim timepoint, and both use an RNA platform. Each gave a glimpse of the data, but Moderna shared some demographics on the volunteers in the interim analysis. Moderna’s announcement also included some information on disease severity. Separately, Moderna announced that the vaccine can be stored at 2 to 8 degrees Celsius (36 to 46 degrees Fahrenheit) for 30 days, while the Pfizer vaccine has to be kept at minus 70 degrees Celsius (minus 94 degrees Fahrenheit) – the latter would be a huge challenge especially in underserved settings and/or for global use.” (Posted November 17, 2020)
“Both vaccines use an exciting new technology for making vaccines directly from the virus’s genetic sequence. Preliminary data from both vaccines are incredibly exciting. It is important to learn how long both vaccines protect against COVID-19—will it be months, years, or decades? The similar performance of both vaccines means that we now know that the region of the virus they target is good; this gives hope that other vaccines targeting the same fragment will work too. Having multiple options is great. For example, the Pfizer/BioNTech vaccine has more exacting cold-storage requirements and might be easier to administer successfully in cities where ultra-cold freezers are more widely available, while the Moderna vaccine might be easier to deliver to rural communities. As more data becomes available, we might learn that certain vaccines perform better in specific populations, for example, the elderly, children, and those with compromised immune systems. Having more options creates more choices for healthcare providers and their patients.” (Posted November 16, 2020)
“Both vaccines are superb, and that is an understatement. It appears that the requirements for refrigeration of the Pfizer/BioNTech vaccine are more cumbersome than those of the Moderna product.” (Posted November 16, 2020)
If two vaccines are authorized for emergency use by the end of the year, what does that mean for curbing the US spread of COVID-19 in 2021?
“It is very likely that both of these companies will submit an emergency use authorization application to the FDA as soon as they can, after meeting their goals for monitoring safety following the second dose of vaccine. If the FDA reviewers and outside experts who see the data agree that these are safe and effective beyond a reasonable doubt, then we are likely to have two authorized vaccines before the end of 2020 or very early in 2021. Given the urgency of combating the pandemic, this would be the best scenario we could hope for. The subjects will still be followed for a longer time if emergency use authorization is granted, so that longer-term safety data can be monitored. For the US population, it would mean access to vaccines from two manufacturers who have already geared up to produce tens of millions of doses before the end of the year, and who can produce many more doses in 2021. Although it will be complicated to distribute and coordinate, this is the type of challenge we were all hoping for, and ultimately should mean saving many lives. Widespread vaccine distribution and uptake will be required to slow and eventually stop the spread of the virus, and this level of uptake may not occur until the Spring or early Summer 2021. I have faith that our public health agencies will move this out as quickly as possible while not compromising safety.” (Posted November 17, 2020)
“Those decisions will depend on access to more data.” (Posted November 17, 2020)
“It is still going to be a very difficult winter. Distributing millions of vaccines will take months, so there will be a period where some people have natural immunity and others have vaccine immunity, while others remain vulnerable. Moreover, we don’t know how long vaccine immunity will last. While it would be great to get a vaccine on a Monday and celebrate your newfound immunity at a party on Tuesday, that’s not how it works. Those who are lucky to get a vaccine early in the process owe it to their communities to continue wearing masks and distancing until new cases and hospitalizations subside to near zero.” (Posted November 17, 2020)
“It’s really not clear. Assuming widespread uptake, which is not a given, I can hypothesize two ways in which an effective vaccine could decrease hospitalizations and deaths. First, by reducing the number of infections in the most vulnerable. Second, by making infections less lethal. I’d like to see trials directly demonstrate a reduced risk in either infection numbers or lethality of infections, but unfortunately the trials are not designed to evaluate either of these endpoints. Despite some protest, I see little sign the companies will adjust their plans at this point. Instead, the endpoint being studied in the trials is the risk of symptomatic COVID-19 of any severity, including mild infections, as FDA indicated it was willing to grant emergency use on that basis. The problem is that because mild COVID-19 is far more common than COVID-19 hospitalizations and deaths, and because the trials appear likely to deliver final results with less than 200 total cases amongst tens of thousands of participants, there may be very few—or even no—hospitalizations and deaths in the trial. I fear we will be left in a situation in which we are forced to make decisions without knowing if either of these candidate vaccines are effective against severe forms of COVID-19. And as for prevention of infection, many do not expect, even theoretically, that vaccines delivered into the muscle would prevent a respiratory infection like SARS-CoV-2. This is one of the reasons why some are pursuing a nasal spray vaccine. So we may not learn the answers to key questions by the time the vaccines are authorized. And once authorized, it is quite possible that those given the placebo will be offered the vaccine, in which case it will become impossible to know what would have happened in the absence of the vaccine. SARS-CoV-2 may very well have seasonal cycles and if hospitalizations and deaths come down, how will we know it was the vaccine and not just a seasonal effect or some other intervention? All we will have is our guesses. I think we deserve better evidence than that.” (Posted November 16, 2020)
“Roll them out, roll them out, roll them out! They will make all the difference!” (Posted November 16, 2020)
November 9, 2020
Based on past experience with initial clinical trial data, how certain is Pfizer/BioNTech’s initial 90% efficacy figure?
“As usual it is hard to draw conclusions from a company press release. From this statement, it is not clear if the events have shown whether the vaccine protects against both severe and mild illness. We also don’t know anything about durability of protection or the ability of the vaccine to stop virus shedding and therefore transmission. That said, if the data supports the statements and we understand better what population this will be for and what type of protection was achieved, it would be great to see something initially rolled out during this winter and into next year. Even if this vaccine isn’t the best one, those who qualify can get it in the immediate term and we can worry later about getting their immunity boosted, if necessary.” (Posted November 9, 2020)
“This figure comes from review by a data safety and monitoring board. This group has access to the data and is composed of experts outside of Pfizer. Given that they evaluated 94 confirmed cases, with plans for 164 confirmed cases to make a final analysis of efficacy, they are well over halfway to the case endpoint. Ninety percent efficacy is very high, so this is extremely encouraging. The experts who designed the trial outlined the final endpoint of 164 cases, so we should still wait to get the entire dataset analyzed when this endpoint is reached. However, this is encouraging news, as the percent efficacy was entirely unknown prior to this trial. We can hope that this positive result indicates not only that the Pfizer vaccine will work, but that other vaccines based on generating responses against the spike protein of SARS-CoV-2 will also have positive results. This may be the first of several positive reports in coming weeks and months.” (Posted November 9, 2020)
“The number could hold up or it may not. There’s of course going to be a margin of error that hasn’t been stated, and the analysis took place looking only at those with no evidence of past SARS-CoV-2 infections, which Pfizer estimated would be 80% of all enrollees. So it is possible that around 20% of people in the study may have been excluded from the analysis, meaning that the real-world numbers would be less exciting. Time will tell and independent scrutiny of the data will be vital.
“The main issue is: 90% efficacy against what, and in what kinds of people? In a deadly pandemic, we want to see efficacy data demonstrating of a reduction in severe disease—hospitalizations, ICU use, deaths, and long-term consequences of the disease. Efficacy against a transient, mild illness in relatively healthy people is far less important than protecting the most vulnerable, but if I had to guess, this is likely all Pfizer’s results show at this point in time – a reduction in mild disease. So it’s still unclear what effect this vaccine has against severe disease, against COVID’s complications, against hospitalizations and deaths. We also don’t know anything about the prevention of infection. This is all because none of the studies, including Pfizer’s, are set up to answer the most important questions. The trials are instead all focused on a far less compelling target of proving a reduction in disease of virtually any severity, including the most mild disease. So we have to see these results in that context.” (Posted November 9, 2020)*
* Links included in quotes were supplied by the expert.
What does the Pfizer/BioNTech vaccine announcement mean for curbing the spread of COVID-19 in the near term?
“This news is an important achievement since it may be the first result coming from those vaccines in advanced phase 3 clinical trials. However, remember these Phase 3 trials will not say anything about levels of efficacy needed to achieve what we really need in the long run- herd immunity or protection in large numbers of the global population.” (Posted November 9, 2020)
“We will still need to reach the efficacy endpoint of 164 cases that was outlined at the outset of the vaccine trial. However, this strong result promotes optimism that the company could pursue an emergency use authorization soon after reaching this final endpoint. If an emergency use authorization is approved, then we would expect Pfizer to begin preparations to provide the vaccine for critical populations as outlined by CDC. I think we can expect that initial supplies will be limited so that distribution in early months following the emergency use authorization will be phased, with critical/high-risk populations given initial priority. It will take longer to have enough supply to provide equitable access across the entire population to curb virus spread.” (Posted November 9, 2020)
“The problem here is the medium, not the message. A press release is not the way to do science. All we have is a headline right now and that is a terrible vehicle for communicating scientific findings. Nobody can look at the data and understand what this means. We know close to nothing about the safety data from this trial. Did it demonstrate a reduction in severe COVID-19 cases, or so-called ‘long-haul COVID’, or was the reduction limited to just mild, transient illness, like a sore throat or cough with lab-positive test? If it was just in mild cases, was that mild COVID in generally healthier people, or were there sufficient numbers of older and frail adults to say anything about how the vaccine works in that population? We don’t know, and I suspect the numbers – just 94 total cases amongst over tens of thousands of participants – means we likely have no statistical certainty about those important questions. Pfizer says it will have the data it needs to seek regulatory authorization in two weeks—they could have waited two weeks and then shared a full report. I think we need to be clear that for COVID-19 products to be accepted or promoted as ‘based on science’, there needs to be complete transparency of all the data.” (Posted November 9, 2020)*
* Links included in quotes were supplied by the expert.
October 21, 2020
Do we know enough about SARS-CoV-2 to conduct human challenge vaccine trials?
“There have been discussions about the ethics of conducting human challenge studies or Controlled Human Infection Models (CHIMs) for SARS-CoV-2. Establishing a controlled human infection model for SARS-CoV-2 is risky. Some have called for this as a means of speeding up COVID-19 vaccine evaluation. In this scenario, you would vaccinate subjects with a candidate COVID vaccine, and then at a later timepoint intentionally expose them to SARS-CoV-2 and see if they clear the virus rapidly and don’t get sick. The main risk is that we know the virus can cause serious illness or death, and that even though this mostly affects higher-risk groups, this is not entirely predictable. So you would be risking serious illness or death by challenging vaccine recipients with live SARS-CoV-2, and doing so without a drug that could reliably treat the illness once it begins. You could propose to develop a weakened (attenuated) strain of SARS-CoV-2 that is not lethal, but this would likely take many months to years to complete and evaluate safely. The bottom line is that efficacy trials are proceeding now and will be able to provide some answers in coming months, making the risky idea of a COVID-19 controlled human infection model into a moot point. I would stay away from this approach.” (Posted October 21, 2020)
“I argue that we do not know enough about the spectrum of illness, short term and long term, to expose individuals to SARS-CoV2 in a human challenge model. In my mind, these models are not yet ethically defensible. Neurologic and cardiac events, for example, have occurred in otherwise healthy persons, as well as persistent (“long-hauler”) symptoms. There is clear disagreement on this point in the field.” (Posted October 21, 2020)
How might human challenge trials change the timeline to vaccine approval?
“At this point, for the vaccine candidates that are already being tested in humans, a challenge model would not speed up anything. Conceivably a challenge virus strain could be developed to help evaluate future vaccine candidates. We also hope to have better drugs to fight the virus in the future, so the challenge could potentially be done when better drugs exist with less risk to subjects. However, I think this is an idea that will not need to be pursued for the COVID-19 pandemic. We do use controlled human infection models to help evaluate other vaccine candidates, after the model has been shown to be safe. Examples include malaria, Shigella, and influenza.” (Posted October 21, 2020)
“It is not clear that these studies would change the timeline to the approval of the first vaccines, but they could significantly contribute to useful knowledge that helps us understand how to use COVID-19 vaccines, how to compare them to each other, and how to understand how they impact transmission of viruses.
“These studies are unlikely to completely replace phase III trials, but they would give an early read as to a vaccine’s efficacy in a much smaller number of people. Use of a robust SARS-CoV-2 challenge model would allow the testing of multiple vaccines in a short period of time, direct comparison of one vaccine vs. another, and aid in eliminating vaccines that are not sufficiently efficacious. In addition, these studies could help answer very important questions that are hard to answer in large Phase III trials. These questions include topics around transmission—following vaccination, even if an individual is themselves protected from getting sick upon exposure to SARS-CoV2, does the vaccine also prevent the individual from shedding virus and transmitting infection—and immunologic responses—measuring markers in the blood, such as a specific level of antibodies, that could demonstrate that a vaccinated individual is now protected from getting sick.” (Posted October 21, 2020)
October 2, 2020
How does the COVID-19 vaccine development process deviate from normal vaccine development?
“The current process differs from previous vaccine development primarily in its urgency and speed. The COVID-19 pandemic presents a true emergent need for a vaccine. We should keep in mind that this pandemic is causing disease and death on a scale that has not been seen since the great influenza pandemic of 1918, and of course it is disrupting our national and global economy as well. Vaccine manufacturers and government officials are addressing this by accelerating the process of vaccine design, manufacturing, funding, and potentially approvals. The basic steps in vaccine development and approval remain in place, but are moving at a vastly accelerated pace.” (Posted October 2, 2020)
“Under normal circumstances you don’t have one hundred companies across the world trying to make a vaccine. You don’t have about one hundred and eighty different vaccines moving forward, either at the research or clinical level. You don’t have tens of billions of dollars being put forward by the World Health Organization and the United States government to serve as a pull mechanism for a vaccine. You don’t have the government paying for things like phase three trials and mass production, thus taking the risk out of COVID-19 vaccine development for pharmaceutical companies. So this is an unprecedented moment in time.” (Posted October 2, 2020)
“The United States has developed a robust system to ensure vaccines are safe and effective. The system that we utilize assures us that vaccines are more adequately tested and validated than that for any other medicine we prescribe. COVID vaccine development has been accelerated; however, the process retains the key safeguards that are necessary. What is important now is that we complete the Phase 3 trials and that the results of the trials are transparently shared before the vaccine is licensed and implemented. My scientific colleagues are committed to ensuring we get to the finish line by meticulously sticking to the standards we know. Without the trust that the standards are followed, we may have a vaccine, but we will not have an immunized population.” (Posted October 2, 2020)
What are signs that a vaccine trial is too rushed?
“For the trials that I have been directly or indirectly involved in, there has been as expected some occasional difficulties that arise in moving at ‘warp speed.’ These are mostly logistical issues that come up with implementing large trials in many sites in a rapid fashion. However, we have not seen serious issues with protocol design or the conduct of the trials themselves. You can argue that a rush to develop a safe and effective vaccine is appropriate given the public health emergency.” (Posted October 2, 2020)
“By taking the risk out of COVID-19 vaccine development for pharmaceutical companies, the government moved development along very quickly, which is fine as long as the phase three trials are allowed to continue until there’s clear, statistically significant evidence that the vaccine works and is safe. As long as that happens, the fact that development has been so fast really won’t matter.” (Posted October 2, 2020)
How will researchers know when the phase three trial for a given vaccine is complete and that the vaccine is adequately safe for widespread distribution?
“Actual completion of the trials as designed would occur following more than 2 years of follow-up for all the subjects. However, it seems unlikely that distribution will have to wait for completion of the trials and the usual practice of manufacturers filing a biologics license application (licensure). The FDA has outlined the possibility that an Emergency Use Authorization (EUA) could be issued for one or more vaccines, if there are appropriate efficacy and safety data available in coming months. The exact amount of data required and timing is not known with certainty, but will likely depend upon meeting a pre-defined number of key events, usually stated as subjects developing COVID-19 disease, that occur in vaccine and placebo recipients in the trial. Efficacy of the vaccine would have to be shown to be statistically significant, meaning that there would be very high likelihood that the vaccine is protecting subjects from disease. If this is found, then the manufacturer(s) in negotiation with the FDA could file an EUA application. The evidence behind this would be reviewed by experts within the FDA and by outside experts prior to issuing an EUA. If found to be safe and effective, then the formal EUA would lead to initiation of vaccine distribution outside of the trial subjects. Distribution to the public is likely to start with high risk groups prior to being widely available, until supplies and delivery systems are adequate to support widespread vaccination.” (Posted October 2, 2020)
“Our rotavirus vaccine took four years to complete a phase three trial. The HPV vaccine took seven years to complete a phase three trial. So it really depends on the number of study sites and the instances of disease. That’s HPV compared to rotovirus, and the length of phase three trials depends on whether you get enough sick people in the placebo group to say that something is effective. It’s possible that within a year, by early next year the data safety monitoring board will be able to report, ‘look, we have one hundred fifty patients who are sick in the placebo group, we only have three who are sick in the vaccine group.’ That’s a statistically significant finding. And it makes us confident that this COVID-19 vaccine candidate is an effective vaccine. And at that point it’s been given to fifteen thousand people safely. So I think it’s possible to stop the phase three trial early, as long as there’s statistical evidence that you can stop it early.
“Or they’ll keep going, give the vaccine candidate to thirty thousand people, and finish the phase three trial off and still not have clear evidence that the vaccine works. That’s another possibility. Then the trial has to keep extending, which is what happened with our rotavirus vaccine. During the original trial for the rotavirus vaccine we were trying to rule out a rare adverse effect called intussusception, and we were originally going to do a forty thousand person trial, but there weren’t enough people with this adverse effect in the placebo group to say that our vaccine did or did not cause intussusception. So we had to move on to fifty thousand, then sixty thousand, then seventy thousand. The upside, if you will, of a country with a lot of disease—assuming the vaccine candidate can be tested in areas where the infectivity rate is about five percent—is that researchers should be able to get enough patients in the placebo group who are sick to answer that question.” (Posted October 2, 2020)
“Clinical trials for vaccines, or for any medication, just take time. Several very large trials are underway, and we just have to wait until enough unfortunate people become infected to know if the vaccine in question prevents infection in some percentage of people. I think most people believe that the first vaccine, if shown to work, will not be perfect and will not protect 100% of people. I think the key will be if a successful vaccine protects 80% or 50% of vaccinated people. Even if we get a vaccine that protects 50% of people, that will be a first step that can be improved upon. For the most part, I expect the initial vaccines in testing to largely be safe for the vast majority of people, because they are designed to be safe. Sometimes there is a compromise between safety and efficacy. Will these vaccines be efficacious enough? Only time will tell.” (Posted October 2, 2020)
“Getting COVID-19 vaccines into the general population as fast as possible is of the utmost importance. We don’t need a COVID-19 vaccine which is 100% effective. Even a less than perfect vaccine administered to those who need protection against SARS-CoV-2 infections is highly desirable!
“Clearly, safety is the number one consideration, but even a less than totally effective vaccine would be a major breakthrough. If a less effective COVID-19 vaccine would reduce the symptoms experienced by a 75-year-old patient to those of a 45-year-old patient, I believe this would already be a major success. Or, if a patient with other health complications (e.g. diabetes) would have a more benign course of COVID-19 following vaccination, this would also be a success.
“If our experience with vaccines against the influenza virus, another respiratory virus, is of any guidance, COVID-19 vaccines should be safe and be effective in reducing severe disease and death.” (Posted October 2, 2020)
What else do you think the American public should know about COVID-19 vaccine development?
“There’s nothing magical about it. When we have a vaccine, let’s say it works great, let’s say it is seventy five percent effective against moderate to severe disease, which I think could happen. That means that one out of every four people who got the vaccine is still not going to be protected. And since you don’t know whether you’re that person, everybody should continue wearing a mask until we get control of this virus. I think what worries me is that people say, ‘I’ve got a vaccine, I’m good,’ as if we just sprinkled some magic powder across the land that means they don’t need to wear a mask and can engage in high risk activity, which would set us back. Mask wearing is the most important.” (Posted October 2, 2020)
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Maria Elena Bottazzi, PhD, Associate Dean, National School of Tropical Medicine and Professor, Pediatrics & Molecular Virology & Microbiology, Baylor College of Medicine and Texas Children’s Hospital
Dr. Bottazzi is a vaccinologist who is developing several vaccines for neglected and emerging diseases including vaccines against SARS, MERS and COVID-19. No funding for these activities is received from for-profit entities.
Peter Doshi, PhD, Associate Professor of Pharmaceutical Health Services, University of Maryland School of Pharmacy
Peter Doshi has been pursuing the public release of COVID-19 vaccine trial protocols and access to raw data for all COVID-19 products.
Deborah Fuller, PhD, Professor of Microbiology, University of Washington School of Medicine
Peter Hotez, MD, PhD, Dean, National School of Tropical Medicine and Professor, Departments of Pediatrics, Molecular Virology & Microbiology, Baylor College of Medicine
We’re also developing a recombinant protein COVID19 vaccine now being tested across India: https://www.bcm.edu/news/biological-e-limited-and-baylor-covid-19-vaccine-begins-clinical-trial-in-india
Mary Anne Jackson, MD, FAAP, FPIDS, FIDSA, Professor of Pediatrics and Dean, University of Missouri-Kansas City School of Medicine
Bertram Jacobs, PhD, Professor, School of Life Sciences and Member, Biodesign Center for Immunotherapy, Vaccines, and Virotherapy, Arizona State University
Beth Kirkpatrick, MD, Professor, Department of Microbiology and Molecular Genetics, University of Vermont Larner College of Medicine
Dave O’Connor, PhD, University of Wisconsin Medical Foundation Professor of Pathology and Laboratory Medicine, University of Wisconsin-Madison
I am not directly involved in any of the COVID-19 vaccine trials, however, I have received grant funding from Bristol Myers Squibb and Amgen and have done collaborative genetics work with many pharmaceutical companies including Pfizer. I am a participant in the AstraZeneca phase III vaccine trial.
Paul Offit, MD, Professor of Vaccinology and Pediatrics, Perelman School of Medicine at the University of Pennsylvania, director of the Vaccine Education Center at Children’s Hospital of Philadelphia (CHOP)
Peter Palese, PhD, Professor of Microbiology and Medicine, Icahn School of Medicine at Mount Sinai
Paul Spearman, MD, Professor and Director of Infectious Diseases, Cincinnati Children’s Hospital
I hold NIH grants (NIH is involved in many current vaccine efforts). I am a member of the Leadership Group of the Infectious Diseases Clinical Research Consortium, which evaluates some COVID-related proposals. My division is conducting trials with the Pfizer and AstraZeneca COVID19 vaccines. I am a member of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) of the FDA. My views are my own and do not represent those of the FDA.
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