COVID-19 vaccine developments
SciLine reaches out to our network of scientific experts and poses commonly asked questions about newsworthy topics. Reporters can use the video clips, audio, and comments below in news stories, with attribution to the scientist who made them.
What are Quotes from Experts?
August 18, 2021
What does the evidence say about COVID-19 booster shots for everyone? What research questions about booster shots remain unanswered?
Dr. Jesse Goodman
“Right now, what’s driving this consideration of booster shots is two things: One, is we’re seeing the levels of antibody that vaccinated patients have decline over time, which can sometimes signal a loss in protection. But number two, more important, we’re seeing that the protection against overall infections is also declining. What we’re not seeing yet, and remain in question, is whether this has an effect on the outcomes we’re really trying to prevent, which is hospitalization, severe disease, death. And so far vaccine protection against those more severe manifestations is holding up well.”
(Posted August 18, 2021 | Download Video)
Dr. Dorry Segev
“Eventually all of us will need booster shots for our COVID vaccines because the immune response we get to that vaccine decreases over time. This is called the durability of the immune response. We don’t know exactly how long the immune response will last, but we expect that at about eight months or so is when we’ll need that additional booster. Ongoing research will tell us better what that magic window is.”
(Posted August 18, 2021 | Download Video)
“The limited data sets shared by the vaccine manufacturers show that indeed a third shot substantially increases neutralizing serum antibody levels so the body can more effectively fight off the virus. However, these samples were collected within a month after that third shot, which would be the time antibody production is highest after a booster shot. Two main questions remain: First, how sustained is the increase in antibody levels? Ideally it would last six months or more. Second, would that third shot impact the spread of highly infectious variants, such as delta?” (Posted August 18, 2021)
“The term ‘booster’ shot implies that the primary vaccine series was effective at making a strong protective immune response, which has waned, and now needs to be revitalized.
“Evidence generally shows that the vaccines currently used in the United States remain strongly protective from severe illness, hospitalization and death, but that the mRNA vaccines may not be quite as effective as they were when first administered, especially for the delta variant. We’re seeing this in real-world data from the Pfizer and Moderna vaccine in New York, for example, as well as with the Pfizer vaccine in Israel. And although antibodies are not the only important part of immune protection, we are seeing decreasing antibody levels after full vaccination and less effectiveness of those antibodies against the delta variant. Data show that a booster dose will elevate immune responses significantly and should offer a substantially higher level of protection from infection and illness. These findings are most significant for those in the highest risk groups, including the elderly and those with high exposure, like health care workers and those in long-term care facilities. If boosters are recommended by the FDA and CDC, it is likely these groups will be targeted first.
“Data that are still coming out include comparable information for the Johnson & Johnson vaccine. We also would like to understand better how well previously vaccinated individuals are protected by their immune system’s ‘memory’ and T cell responses, which may kick in to provide protection from illness even if antibody levels have dropped.
“Finally, it is important to remember that this is highly dynamic, and decisions are being made with the best intentions to prevent as much illness as possible, even if complete and perfect data is not yet available. We have new information emerging continuously, paired with the current serious COVID-19 situation in United States and future changes in the virus that we cannot totally predict.”
Toward the goal of ending the pandemic, what does the evidence show about boosting immunity for those already vaccinated versus prioritizing vaccine access worldwide?
Dr. Jesse Goodman
“The most serious impacts of this pandemic are severe illness, hospitalization, stress on health systems, and all those consequences for patients and their families. To address that, we really need to focus first on vaccinating the unvaccinated, both here in the U.S. and globally. Booster shots may help protect some people, particularly our most vulnerable individuals, but are far less likely to impact the overall curve of the pandemic.”
(Posted August 18, 2021 | Download Video)
Dr. Dorry Segev
“The only way to really deal with this virus is for every single person to be vaccinated effectively against the virus. Vaccinating effectively means boosters for people whose vaccine immunity has decreased, and it means first vaccinations all across the world. Balancing these is challenging but it’s important for us to focus on getting both of these goals accomplished.”
(Posted August 18, 2021 | Download Video)
“The virus flourishes in communities where vaccination rates are very low—that is where variants emerge.” (Posted August 18, 2021)
“Worldwide equity in vaccine access is arguably the most important challenge we are facing in this pandemic. In addition to the enormous humanitarian issues in regions without vaccine access, the lack of vaccinations will permit the emergence of other new variants and will impede the global control of this pandemic. This makes booster shots in the United States a very challenging decision. We must protect our own citizens, and at the same time show a similarly aggressive and steadfast commitment to get these vaccines to all populations throughout the globe.”
Should we expect regular or annual COVID-19 booster shots?
Dr. Jesse Goodman
“We really don’t know yet how often we might need repeat COVID shots. Even though the antibody levels have been waning, suggesting we may need boosters periodically, we don’t know that they correlate perfectly with protection from infection. Also, we can’t predict what new variants COVID may throw at us and whether that may necessitate periodic changes and revaccination. So right now, anyone who tells you they can answer that question really can’t do so.”
(Posted August 18, 2021 | Download Video)
Dr. Dorry Segev
“I have little doubt that at least once a year we’re going to be getting boosters for this virus, either in the form of new vaccines that cover new variants or boosters that take our decreased immune response and help it regain some protection.”
(Posted August 18, 2021 | Download Video)
“That will largely depend on how the situation with the variants evolves. So far, I do not see a reason for a regular or annual shot.” (Posted August 18, 2021)
Might COVID-19 booster shot formulations change as the SARS-CoV-2 virus evolves?
Dr. Jesse Goodman
“The COVID virus has proved to be pretty tricky, and it sort of changes its coat constantly. And as we’re seeing now with delta sometimes these new variants may to some degree resist our vaccines. So I do think going forward we’re probably going to need to continually adapt our vaccines to changes in the virus, perhaps very much like we’re doing with influenza.”
(Posted August 18, 2021 | Download Video)
Dr. Dorry Segev
“Right now in terms of boosters what we have are the same vaccine over again. So if our immune system has decreased to the vaccine we got, we can give more vaccine and our immune response increases. Ultimately I think what will happen is the variants will change to the point where we need new formulations of the vaccine. And I expect that that will happen every one to two years where the booster will actually be a new vaccine formulation.”
(Posted August 18, 2021 | Download Video)
“Yes, this is a likely possibility. It will depend on how infectious new variants are and if the current vaccine can still prime our immune system to recognize them.” (Posted August 18, 2021)
“Yes, this is certainly possible. Vaccine companies test whether antibodies made in the body following the original vaccine formulation will still work to neutralize new viral variants. If they do, the formulations will not change. If not, then we can expect vaccine formulations to be modified to optimize effectiveness.”
August 13, 2021
What does the research show about the benefits of a COVID-19 vaccine booster for different groups of people?
“With the standard two-dose regimen of the mRNA vaccines, half of transplant patients don’t produce any detectable antibody response, and even those who do show some antibody response have, in general, lower levels of antibodies than the general population. In addition, clinical protection for vaccinated transplant patients is much lower: A fully vaccinated transplant patient has an 82-fold higher risk of getting a breakthrough infection, and a 485-fold higher risk of getting a breakthrough infection associated with hospitalization or death, than the general fully vaccinated public.
“Other immunosuppressed populations also have decreased responses to the vaccines, although the amount of the decrease varies by the medications they take and the condition they have.” (Posted August 13, 2021)
“The proactive approach that the FDA is taking by authorizing booster vaccinations for the immune compromised is very welcome news. So far there have been somewhat limited data about booster shots—meaning an extra dose of the same or a different vaccine beyond the currently authorized vaccination schedule—but emerging evidence seems to suggest that they can strengthen or achieve immunity in patients who are immune suppressed and who generally have a lesser chance of mounting an immune response. This includes patients after a solid organ transplant, certain types of cancers, especially blood cancers, and certain types of cancer treatments that impair the immune system. The limited data in patients with solid organ transplants or certain cancer types, for example, might suggest that the booster shot converts 20-40% of patients from an antibody negative test to a positive one—meaning the patients have at least some detectable level of immunity by a lab test after their booster shot. In addition, booster shots in these studies have been overall just as safe as vaccinations otherwise. Questions remain about whether booster shots work for all patients or if some patients have such a low chance to respond to the additional shots that they need other methods of protection, as well as whether a mix and match strategy might work better—meaning getting a different type of a booster vaccine than the original series.” (Posted August 13, 2021)
“Our study shows that in organ transplant recipients, a third dose of the Moderna mRNA vaccine was significantly better than a placebo for improving patients’ immune response. Organ transplant patients have a very poor response to the standard two dose regimen of COVID-19 vaccines. With a third dose, as compared to placebo, patients in our study had increased antibodies against the spike protein, as well as neutralizing antibodies, which serve to prevent viral infection, and T-cell responses, which limit severity of infection. Ours is the first study to include a placebo group for comparison with the group receiving a booster shot, which is very important to demonstrate the efficacy of an intervention. Based on the results of this study, we believe that a third dose should be recommended for organ transplant patients. The results may also be applicable to other groups of immunocompromised patients such as cancer chemotherapy or bone marrow transplant recipients, but we encourage further studies in those groups.” (Posted August 13, 2021)
How do policymakers decide who is eligible to receive a COVID-19 booster shot?
“With the phrasing of the FDA authorization, it seems that this will be an individual decision between a patient and their medical team, balancing the risk of the third dose, such as risk of rejection in organ transplant patients, versus the benefits. It is also possible to use antibody levels as a surrogate for how much immune protection the patient had, and to include the results of these tests as part of the clinical decision-making.” (Posted August 13, 2021)
“There is evidence emerging that immunity after vaccinations might wane slightly over time and also that some patient groups might just not develop immunity from the usual vaccine doses. Because of this, there is a lot of interest in boosters for both certain patient cohorts, such as immune suppressed patients with an organ transplant or on cancer therapy, as well as the larger community—in particular, more vulnerable members, such as the very elderly. Next there will be discussions about boosters for health care workers because they have the highest risk of exposures working at front lines and then, finally, the general population. All these decisions should keep in mind health equity issues among populations within the U.S. as well as globally, as some countries have had very little access to vaccines, let alone boosters. Accordingly, our first consideration needs to be identifying populations at the highest risk from COVID-19 who might not be protected by the standard vaccinations—immune suppressed patients and possibly the elderly in the next wave.” (Posted August 13, 2021)
“They generally review available evidence and decide. We have shared our data with the FDA and other regulatory authorities. The best type of evidence is usually considered a randomized controlled trial.” (Posted August 13, 2021)
How do doctors decide which patients need a COVID-19 booster shot?
“Doctors will need to follow FDA and CDC guidance and then discuss with their patients the pros and cons of booster vaccinations dependent on each patient’s overall risk/benefit assessment as to their underlying disease and ongoing therapy with regards to immune suppression. Booster shots will likely be an excellent suggestion for a patient following an organ transplant who is on chronic immune suppression, but it is less clear if booster shots are helpful for a patient with a remote history of cancer without any ongoing therapy that could lead to immune suppression.” (Posted August 13, 2021)
July 28, 2021
What is the likelihood of breakthrough COVID infections after people are fully vaccinated?
“All vaccines are designed to protect from symptoms of disease, not necessarily against infection. That means breakthrough infections can happen and are expected. With the emergence of the more transmissible Delta variant, we will likely see an increase in breakthrough infections where vaccinated people test positive for COVID-19 but feel just fine.” (Posted July 28, 2021)
“The likelihood of a severe breakthrough infection as tracked by the CDC after vaccination remains rare. Among 161 million Americans vaccinated, 4072 hospitalizations occurred due to COVID after vaccination (0.0025%) and 849 deaths occurred due to COVID after vaccination (0.0005%.)” (Posted July 28, 2021)
How serious might COVID infections be for fully vaccinated people?
“As of now, the vaccines continue to offer outstanding protection from severe COVID-19 disease. This may change in the future as the virus evolves and the immunity conferred by vaccines wanes. We need to view this as a long battle between the virus and the countermeasures developed to fight it. Policies will need to change as new information comes to light. For example, the high amount of virus observed in some breakthrough infections with the Delta variant means that people who are vaccinated may need to be tested more frequently than previously thought if they develop symptoms, and they may need to wear masks more frequently to avoid spreading the virus to others who are susceptible.” (Posted July 28, 2021)
“If a vaccinated person gets infected with SARS-CoV-2, the virus will have a battle on its hands, since the vaccine has primed the vaccinated person with robust immune defenses that can shut down the virus before it has a chance to get very far. Even with the variants, the vaccines still have high efficacy in protecting people from severe disease and hospitalization. A vaccinated person may still get infected with COVID-19 but will likely experience no symptoms or only mild symptoms and will certainly recover more quickly than if they hadn’t been vaccinated. Vaccinated individuals who are immune compromised or have underlying conditions are vulnerable to getting the disease, but again, they are more likely to recover than someone with the same conditions who has not been vaccinated. In fact, for immune compromised people, getting vaccinated or not can make the difference between life and death.” (Posted July 28, 2021)
“The serious infections are quantified above. However, there are more mild breakthrough infections among vaccinated people due to the Delta variant, likely because of higher circulating virus and higher viral loads with this variant.” (Posted July 28, 2021)
How should vaccinated people protect themselves and others from breakthrough infections?
“The combination of vaccination and masking—especially in crowded or indoor areas with higher COVID-19 transmission—likely provides the best defense from breakthrough infections. In addition, if you receive the Pfizer or Moderna mRNA vaccine, make sure you get both doses and between doses, mask up. With only the first dose of mRNA vaccines, efficacy against the Delta variant is much lower than against previous variants, and you really need that second dose to reach the levels of immunity that will provide you with sustained protection.” (Posted July 28, 2021)
“In areas of high community transmission, vaccinated people should mask indoors to protect themselves from even mild breakthrough infections (substantial or high transmission as defined by the CDC table.)” (Posted July 28, 2021)
June 15, 2021
How is the Novavax vaccine technology different from that of vaccines previously authorized in the US?
“The Novavax vaccine is a protein subunit-based vaccine. The protein in the vaccine is a modified form of the COVID-19 virus’s spike protein. The spike protein gene is inserted into an insect virus that infects moth cells and causes them to produce COVID-19 spike proteins. The spike protein is then purified from the moth cells and packaged into nanoparticles—composed of ingredients to protect the spike proteins and boost the immune system response—which are then injected into people as a vaccine.” (Posted June 15, 2021)
“The Novavax vaccine is based on a COVID-19 virus spike protein produced in insect cells. Once produced, the protein then self-assembles into a particle. The coronavirus spike protein particle is then formulated with an adjuvant to increase the immune system response, combined with cholesterol and fat molecules that form a protective barrier around the COVID-19 protein.” (Posted June 15, 2021)
How does the Novavax COVID-19 vaccine fit into the US and the global strategy to combat disease?
“In the US, we already have several other types of vaccines under Emergency Use Authorization, which are now widely available, so the Novavax vaccine may not play a major role in the US strategy to combat COVID-19. However, for the global strategy, the Novavax vaccine could still make important contributions. It doesn’t need the ultra-cold temperatures for storage that the mRNA-based vaccines require, and it’s not based on live-virus vector technology, which has safety concerns. So the production, global distribution, and administration of the Novavax vaccine will be simpler, which is important for countries in most need of COVID-19 vaccines.” (Posted June 15, 2021)
“Novavax has entered into an agreement with the Serum Institute of India for scale-up production, but the company is also entering into agreements with additional manufacturers. In general, protein-based vaccines offer enormous promise for filling the COVID-19 vaccine access gaps, especially for the world’s lower- and middle-income countries in Africa, Latin America, and Southeast Asia.” (Posted June 15, 2021)
“The Novavax vaccine will hopefully become available in the US later in 2021, following either an Emergency Use Authorization or full licensure. Given the availability of other vaccines, it is unclear what the market will look like within the US at that time. Some individuals may prefer a protein subunit vaccine over an mRNA vaccine or the J&J adenovirus vaccine. Expanding our options is always advantageous, particularly because the Novavax vaccine has simpler storage requirements and because we are not sure about the long-term durability of mRNA or adenovirus vaccines. In the US, the Novavax vaccine could have a role as a booster if these are needed. Globally, there remains an enormous need for more vaccines. The Novavax vaccine can help protect high-risk individuals across the world, many of whom are still unvaccinated.” (Posted June 15, 2021)
Are there any particular benefits or drawbacks of the Novavax vaccine compared to other COVID vaccines?
“In addition to vaccine storage benefits, the major advantage of the Novavax vaccine is its safety. Protein-subunit vaccines are considered the safest form of vaccines, based on a widely used technology. The hepatitis B vaccine is an example of a recombinant protein subunit vaccine. If one reason for someone’s hesitation to get a COVID-19 vaccine is safety, then the Novavax vaccine may be a good alternative. The drawback is that it may not be as effective as the mRNA vaccines against the new variants. Developing new versions of protein-based vaccines against the variants will take more time and effort than altering mRNA vaccines.” (Posted June 15, 2021)
“The vaccine induces high levels of virus neutralizing antibodies and protective immunity shown in multiple clinical trials and also has an excellent safety profile.” (Posted June 15, 2021)
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April 14, 2021
What do we know about how the Johnson & Johnson vaccine is connected to cases of blood clots?
“These events have only been seen in the U.S. following the Johnson & Johnson vaccines, not following either the Pfizer or Moderna vaccines. This appears to be associated with antibodies in the blood that are directed against platelets and cause both low platelets, which is associated with bleeding, and blood clotting.” (Posted April 14, 2021)
“There is an observation of rare coagulopathy (abnormal clotting) events that include low platelet levels following vaccination with the Johnson & Johnson AD26 vaccine. This situation appears to be similar to that observed with the AstraZeneca ChAdOx vaccine. The incidence rate, which appears to be between 1/250,000 to 1/1,000,000 seems to be comparable between both vaccines. Perhaps not surprisingly, given the low rate of occurrence, this has not been noted until millions of people have received these vaccines.” (Posted April 14, 2021)
If someone already got the Johnson & Johnson vaccine, should they be worried? Are there symptoms they should watch for?
“Given how rare the blood clotting event is, right now thought to be less than one in a million, individuals who received the Johnson & Johnson vaccine should be aware but recognize it is extremely unlikely they will be affected. In the first one to four days after vaccination, vaccinated persons should anticipate the known side effects from this vaccine—including the low-grade fever, chills, aches, mild headache, injection site soreness. These are expected and not the symptoms associated with these rare clotting events. Symptoms of concern occur anywhere from five days to three weeks after vaccination, and include severe headache with or without vomiting, any new neurologic or stroke-like symptoms, or other new symptoms including easy bruising, red dot-like rash, severe abdominal pain, and trouble breathing.” (Posted April 14, 2021)
How might pausing the Johnson & Johnson vaccine alter vaccine rollout in the U.S.?
“There are two linked concerns. First, pausing the rollout reduces the number of shots in arms. In a race against variants that is unrelenting, any slowdown in vaccination is a cause for concern. On the one hand, we should be extraordinarily grateful that there are three options available in the US currently. On the other hand, our ability to reduce the risk of severe disease is critically dependent on getting people of all ages vaccinated as quickly as possible.
“The second concern is that people who are on the fence about getting vaccinated and are skittish about side effects might be more reluctant to be vaccinated with any of the vaccines. Some communities with a high level of vaccine enthusiasm are well on their way to having most people vaccinated. In Dane County, Wisconsin where I live, for example, more than 50% of people will have received at least one vaccine dose by the end of the week. Among those with high enthusiasm, this news is unlikely to deter many from getting vaccinated. Other counties in Wisconsin have just over 20% with one vaccine dose. In communities with a lot of hesitancy towards vaccines already, this pause is likely going to make the hard job of convincing people to get vaccinated even harder. Already, misinformation about vaccines (such as vaccines causing infertility) is rampant on social media. When news of this pause is weaponized into misinformation, it will likely create new barriers to vaccination.” (Posted April 14, 2021)
“If this is a short term pause of only a few days, it should not significantly alter the roll out.” (Posted April 14, 2021)
“It will certainly impede the speed of the vaccine rollout in the US, but the availability of mRNA vaccines from Pfizer and Moderna will still allow reasonable progress to be made. Based on projected numbers, the delay in the Johnson & Johnson rollout may reduce the available number of vaccines in the US by one third to one half in the near term. But perhaps the impact will be more substantial in other countries where access to mRNA vaccines is much lower. Vaccination is required globally, and until sufficient levels of vaccination are achieved worldwide, there will still be substantial impacts due to SARS-CoV-2. This is why other vaccines that have positive data need to be made available as soon as possible – the vaccine from Novavax for example—and why it was so important to pursue multiple vaccines right from the start of the pandemic.” (Posted April 14, 2021)
Two major adenoviral-vectored vaccines—Johnson & Johnson and AstraZeneca—have been paused because of blood clots. Is there a connection?
“This is the million (or billion) dollar question. It is tempting to link these events since both vaccines are based on similar platforms, but more data will be needed to know for sure. I think it is essential to remember that some serious, rare side effects are often linked to large-scale vaccine efforts. The Yellow fever vaccine, one of the most successful in history, causes roughly one-in-a-million adverse neurological outcomes. So two things can be true at once: the Johnson & Johnson and AstraZeneca vaccines offer lifesaving potential for ending the pandemic and should continue to be used aggressively throughout the world, while a very small number of people who receive them could be adversely impacted. Figuring out how to identify those at risk of serious complications and how to manage their care is what I hope comes out of a (hopefully brief) safety pause.” (Posted April 14, 2021)
“Based on what we know today, these two vaccines appear to be associated with this phenomenon, which appears thus far to be an autoimmune phenomenon related to antibodies directed against a component of the blood that helps to normally clot the blood (platelets). Exactly how and why this is happening, and if any individual is predisposed, is not yet understood. The Russian vaccine, Sputnik, is another adenovirus-vectored vaccine. Less is known about the Sputnik vaccine.” (Posted April 14, 2021)
“A very small number of people who have received adenovirus-based vaccines appear to have a coagulation disorder that is comparable to a rare clotting syndrome observed as a reaction to treatment with heparin. This has not been observed with other vaccine platforms as of yet, which may suggest that this is not being caused by the SARS-CoV-2 spike antigen and is in fact due to the adenovirus vector; however, it is important to note that this is a very small number of people and a causal relationship has not been established. There are other adenovirus-vectored vaccines, including the Sputnik V vaccine from Russia and the CanSino vaccine from China. I have not seen reports of blood clots with these vaccines, but am unsure how many have been vaccinated with these platforms, and you need to vaccinate 4 million people or so be able to detect rare events at the frequencies observed with the Johnson & Johnson or AstraZeneca adenovirus platforms.” (Posted April 14, 2021)
How does today’s news on the Johnson & Johnson vaccine from FDA and CDC reflect on the safety of COVID vaccines generally?
“The ‘large scale’ clinical trials that led to EUA approval and its international equivalent relied on data from tens of thousands of people. It is virtually inevitable that vaccinating orders of magnitude more people will lead to identification of suspicious events that could be linked to the vaccine. An extreme example—some number of people likely got into car accidents on their way home from getting vaccinated, but the vaccines didn’t cause car accidents. The FDA and CDC’s rapid action should be taken as an example of how seriously they are taking potentially worrisome side effects and should engender more confidence in the vaccine enterprise, not less.” (Posted April 14, 2021)
“COVID vaccines remain generally very safe overall. The move to pause vaccination is a transparent and conservative decision in the setting of rare events—in the middle of a pandemic—and demonstrates the dedication of the CDC and FDA to the safety of all vaccine recipients.” (Posted April 14, 2021)
“Everyone wants safe vaccines and the pause to further investigate is evidence that the reporting system for adverse outcomes is working. Rare events will only be noted once millions of people are vaccinated and so the investigation that is currently ongoing is timely, prudent, and appropriate. There is always a risk/reward balance that has to be considered and we are seeing really quick and adaptive decisions being made as data is available.” (Posted April 14, 2021)
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)
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)
The text and video on this page are licensed as Creative Commons CC BY-SA 4.0. Journalists are free to use any text or video on this page with or without attribution to SciLine.
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.
Natalie Dean, PhD, Assistant Professor of Biostatistics, University of Florida
Nothing to disclose.
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.
Ali Ellebedy, Ph.D., associate professor, pathology & immunology, Washington University School of Medicine in St. Louis
Darryl Falzarano, PhD, Research Scientist, Vaccine and Infectious Disease Organization (VIDO), University of Saskatchewan
No direct conflict. We have received financial support from the Government of Canada through CIHR, WD and MSI that has led to the develop a subunit vaccine that is currently in phase I clinical trials.
Deborah Fuller, PhD, Professor of Microbiology, University of Washington School of Medicine
Monica Gandhi, MD, MPH, Infectious Diseases doctor and Professor of Medicine, University of California, San Francisco
Jesse L. Goodman, M.D., M.P.H., professor of medicine, Georgetown University
Dr. Goodman is an infectious diseases clinician and also conducts research and policy work on emerging infectious diseases. He was previously FDA chief scientist, and before that director of FDA’s Center for Biologics Evaluation and Research (CBER). He reports serving as a board member for GSK and for Intellia Therapeutics (for which he receives compensation), and as a board member for the US Pharmacopeia, and on the scientific advisory board for the International AIDS Vaccine Initiative (IAVI) (both volunteer positions).
Balazs Halmos, M.D., Professor of Medicine, Montefiore Medical Center/Albert Einstein College 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
Atul Humar, M.D., Director of Transplantation, University Health Network, Toronto
No relevant disclosures to this work. Specifically, the study received no funding or involvement from Moderna.
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, M.D., 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
Lee W. Riley, MD, Professor and Head, Division of Infectious Disease and Vaccinology, School of Public Health, University of California, Berkeley
Dorry Segev, M.D. Ph.D., professor of surgery and epidemiology, director, Epidemiology Research Group in Organ Transplantation, Johns Hopkins University
I am the PI of an NIH-funded trial of booster doses in transplant patients that just launched this week.
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.