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What goes into a vaccine placebo, typically and in the specific case of Pfizer's SARS-CoV-2 vaccine trials?

What goes into a vaccine placebo, typically and in the specific case of Pfizer's SARS-CoV-2 vaccine trials?


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I am curious about what actually goes into a vaccine placebo formulation, given that there were apparently some reactions reported by trial subjects who received the Pfizer SARS-CoV-2 placebo.

From what I've been able to find out online, the actual vaccine contains as principle ingredients (simplified):

  • mRNA (active ingredient) to make the target antigen (spike protein)
  • lipids (to protect the mRNA and facilitate its delivery into cells)
  • salt(s) to adjust pH and match the salinity of blood
  • sugar to address issues which occur when the vaccine is frozen

An injectable placebo could be as simple as a saline solution… if so, how could reactions be explained? Is it entirely psychosomatic? Is the Pfizer SARS-CoV-2 trial placebo the complete formulation (or some subset of vaccine components) minus the active (mRNA) ingredient?

The lipids have been implicated in allergic reactions to the actual vaccine; would they have been present in the placebo and account for the placebo reactions?


Simple answer: This vaccine trial compared their trial vaccine against saline. See the original publication by Biontech and Pfizer in the New England Journal of Medicine linked below. The relevant information can be found in the methods section:

TRIAL PROCEDURES

With the use of an interactive Web-based system, participants in the trial were randomly assigned in a 1:1 ratio to receive 30 μg of BNT162b2 (0.3 ml volume per dose) or saline placebo. Participants received two injections, 21 days apart, of either BNT162b2 or placebo, delivered in the deltoid muscle. Site staff who were responsible for safety evaluation and were unaware of group assignments observed participants for 30 minutes after vaccination for any acute reactions.

As far as I followed up the case of the allergic reactions, two of these have been observed in England. Both people had an epipen injector for such cases by hand, making it possible that they have underlying problems with allergies (as this is not a medical device people usually have at hand), no such cases have been reported from the trial. Allergic reactions are always a small risk with vaccinations which is the reason why this is done in a controlled medical environment.

As for the vaccine reactions in the placebo group, this can be caused by the nocebo effect, where expecting negative effects leads to a more negative reaction. As @BryanKrause mentioned, all possible effects reported in such trials are recorded as possible side effects. This leads to a lot of things being recorded which happened at the same time as the vaccination but have no connection to it.

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine


Here’s what the different "phases" of vaccine production really mean

By Matthew Rozsa
Published October 25, 2020 8:00AM (EDT)

Healthcare professional in protective gloves & workwear holding & organizing a tray of COVID-19 vaccine vials (Getty Images)

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Articles about the ongoing effort to create a vaccine for the novel coronavirus often include talk of "phases," as if vaccine production were akin to the moon. For instance, CNN reported earlier this month that Johnson & Johnson's coronavirus vaccine was "fourth to begin Phase 3 trials in the United States." NBC News reported earlier this week that "AstraZeneca's phase 3 clinical trial was put on hold in early September after a study participant in the U.K. developed a spinal cord injury." A headline from Fierce Pharma proclaimed, "Moderna, now wrapped on phase 3 enrollment, touts diversity of vaccine trial participants."

For those who don't work in the pharmaceutical industry, understanding the different phases of a vaccine, and what that means, can be confusing. And any similarities to the moon's phases are superficial: vaccine candidates don't wax and wane, per se.

Yet given the urgency with which a vaccine will let our lives continue as normal, following the internecine twists and turns of vaccine production has suddenly become front-page news. What exactly they mean is crucial for understanding what's going on. Here's a brief primer on what vaccine "phases" mean, and why it's important.

The meaning of clinical trial "phases"

Before any vaccine candidate can be released to the public, it first has to go through several stages of study, which researchers organize into discrete phases. Typically, "phase" is capitalized. Before any phase begins, scientists work to develop a vaccine candidate. Once that candidate exists, they produce a small number of trial vaccines.

Then comes the first phase. In Phase I, a trial vaccine is administered to a small group of people for initial testing. (The phases are sometimes referred to with Roman numerals, and sometimes with numbers research institutions don't seem particularly consistent here.)

If Phase I goes well — meaning that "the vaccine appears safe and the people who get it mount a detectable immune response," according to Dr. Justin Lessler, an associate professor of epidemiology at Johns Hopkins Bloomberg School of Public Health — scientists can move on to Phase II. As Lessler added, however, "These trials are usually limited to healthy adult volunteers, but the exact composition will depend on the disease and who is at most risk."

"Generally, people that have the disease you are trying to prevent are not included," Dr. Georges Benjamin, executive director of the American Public Health Association, wrote to Salon. "Also, anyone that would be known to have a reaction to the vaccine or any of its components. For example, people with egg allergies are excluded from Influenza vaccine trials since the virus used is grown in eggs. Also, if it is a live virus that is used for the vaccine, you would exclude anyone that could get sick from this like a person on steroids or with an immune dysfunction. If they live with someone who might get sick from the live virus vaccine. Usually kids and pregnant women are excluded. [They] may also exclude by gender depending on the vaccines goal."

On to Phase II

Phase II expands that clinical study to include people from groups who are in particular need for a vaccine using, criteria such as age and health. According to Dr. Alfred Sommer, dean emeritus and professor of epidemiology at Johns Hopkins Bloomberg School of Public Health, these phases contain "larger number of healthy folks – to get better assessment (since now seemingly worth studying larger number) to better establish what was studied in smaller numbers" during the initial clinical trial phase.

"What would stop it there is the seeming lack of the responses you would like to see, or an abundance or severity of those you wouldn't," Sommer said. "If a trial of a therapy for disease you would hope to see some impact on small numbers of those involved who are infected. But for a vaccine – want to see good response but insufficient to have any idea whether it would be protective in real life."

During Phase II, as Medical Xpress explains, "these studies are usually not large enough for us to confirm the vaccine actually does what it needs to do, and that is to protect people from the infection it's designed to provide protection from." They instead serve the purpose of being as sure as possible that a vaccine candidate is safe.

Phase III is where things get exciting (and safer)

Phase III involves an even further expansion of that group, usually involving thousands of patients.

"Ideally diversity is always wanted throughout but it is essential to get gender and diversity addressed here in order to not miss concerns or efficacy concerns," Benjamin wrote to Salon. "Anything can go wrong from serious health complication to it is not as effective as the earlier study suggested with a smaller pool. Generally, we are still only including generally health people, but you might include people with some chronic diseases at some point because you want to know if the vaccine is protective in people with certain chronic diseases. [It] depends on the protocol and the vaccine."

He added that "once you show it is safe to use you still must show it prevents the disease." Benjamin observed that this can be done in two ways: "Put them in the real world around people that could infect them and see who does and does not get infected. The other thing you can do is infect them on purpose. Very controversial approach and most ethicists say you can only do this if you have an effective treatment or cure for the disease you are trying to prevent with a vaccine. This would not be appropriate for COVID-19 since we don't have effective antiviral agents."

Dr. Russell Medford, Chairman of the Center for Global Health Innovation and Global Health Crisis Coordination Center, told Salon, reinforced that view.

"In Phase III, scientists are directly asking the question for the first time whether the vaccine protects people against SARS-CoV2 and whether or not there are serious side effects not yet detected in the smaller, earlier Phase 1 and Phase 2 trials," Medford wrote to Salon. "To do this, a large population (thousands) is studied that better reflects the diversity of people likely to receive the vaccine once it is approved. Further additional studies are often required to look at specific populations such as the immunocompromised, elderly and children."

He added, "In a typical Phase 3 study design, volunteers are randomized to receive either the vaccine or a placebo. Scientists then monitor all the volunteers over time (months) to see who becomes infected or develops potential side effects. Neither the volunteers nor the scientists conducting the study know which volunteer has received the vaccine or placebo. It is only at pre-specified times, such as at the end of the study, that 'the blind is broken' and the number of infections and potential side effects is compared between the vaccine and placebo groups." For a Phase III trial to be considered successful according to Food and Drug Administration (FDA) guidelines, "the vaccine group must demonstrate a statistically significant 50% or greater reduction in COVID-19 cases compared with the placebo group" and "the vaccine group must demonstrate no significant increase in serious, life-threatening side effects compared with the placebo group."

The final phase is Phase IV

Finally, if a vaccine is approved and licensed after Phase III, many companies will continue through Phase IV of testing to make sure a given drug is effective and safe. If a drug reaches Phase IV, that means it has been approved by the FDA. According to the National Comprehensive Cancer Network (NCCN), this means that "the drug is tested in several hundreds or thousands of patients," which "allows for better research on short-lived and long-lasting side effects and safety." This phase will often continue well after a vaccine is in widespread, common use.

I see stories about vaccine makers doing multiple phases at once. How does that work?

Yes, phases can also be blurred together.

"The phases are discreet — one, two and three — but sometimes companies can enter into approval with the Food and Drug Administration to combine elements of a safety study with an efficacy study," Medford told Salon. "That would be called a Phase I/II. And in Phase II/III, it's an agreement with the regulatory agency that will not only establish a dose finding, shall we say, but the study will be a sufficient size that efficacy results and safety results may be incorporated into a final package for a consideration for approval. It's not unusual to combine them."

What happens if you rush a vaccine without doing all these steps, as Russia and other countries appear to be doing?

"These steps reflect long years of experience and lessons learned by scientists, doctors, statisticians and government regulators in the US and the world in developing safe and effective vaccines against many of the world's most serious infectious diseases," Medford told Salon. "Today's extraordinarily rapid development and testing of COVID-19 vaccines in the US and Europe is based on new science, technologies and approaches that embrace and build upon these lessons. However, by ignoring these lessons, such as the approval of a vaccine without a large scale Phase 3 clinical trial to assess safety and efficacy, we run the risk of deploying a vaccine to millions of people that is neither protective against SARS-Cov-2 nor safe."

Dr. Lessler added, "The biggest risk is you get an ineffective, or even dangerous, vaccine. This can not only be dangerous in and of itself, but can make it harder to get a future vaccine approved or widely used by the population."

What are vaccines made of? How do they work?

A vaccine is a medical tool used to either prevent or therapeutically treat specific infectious diseases. Most vaccines work by containing agents that resemble microorganisms which normally cause diseases usually they are either weakened forms of the bacteria or virus that cause the disease, or else they contain the surface proteins and toxins associated with those microorganisms. The underlying goal is to help the body develop a proper immune response so that it will be able to protect itself from other diseases like it.

This is a painstaking process, one that requires repeated trial and error so that scientists can both guarantee that a given vaccine is effective and so that they will not accidentally give someone a drug that makes them sick, or perhaps even kills them. Rushing a vaccine can lead to "inflammatory reactions in the body when the body rushes to try to generate antibodies and T-cells against the 'antigens' or proteins in the vaccine formulation," Dr. Monica Gandhi, infectious disease doctor and professor of medicine at the University of California–San Francisco, told Salon last month.

For vaccines to work, however, a large number of people must actually use them. One of the major concerns held by scientists today is that anti-vaccine conspiracy theories will scare people off of getting a coronavirus vaccine if and when one is developed.

"We very clearly know that, if we don't get 70-something percent of the population covered, we will probably not get to herd immunity," Benjamin told Salon in May. "There are some people that think that, with this virus, we might be able to achieve it with 50 percent, so that's not 100 percent. But I'm thinking that 70-something percent is about where we need to be, and it's because I've looked at some of the data. We may achieve it with 50 percent, but the bottom line is we'd run the risk of not getting herd immunity with the vaccine."

What is herd immunity?

"Herd immunity, or community immunity as I like to call it, is the indirect protection we get because people around us are immune to the disease," Dr. Lessler wrote to Salon. "The basic idea is if there are fewer people around me who can get sick, then there will be fewer people around who can infect me, so I will be less likely to get infected even if I am not immune to the disease myself. Herd immunity is a more general concept, but when people use the term they often mean herd protection which is the point where there is so much immunity in the population that a community would not be able to start an epidemic if someone in that community got infected."

He added, "For SARS-CoV-2 it seems reasonable rough estimate of this amount of immunity needed to achieve this is 50-80% of people being immune."

Medford expressed a similar thought, writing to Salon that "herd immunity occurs when the spread of a disease, such as COVID-19, from person to person becomes unlikely because a high percentage of the community in which the person lives (approximately 70%) is immune to the SARS-CoV-2 virus, primarily through vaccination but also by contracting and surviving the COVID-19 disease itself. In this manner, herd immunity could help protect the rest of the community (up to 30% of the population) that is not immune to the SARS-CoV-2 virus."

Why has the novel coronavirus presented such a tough challenge?

The main problem, as Dr. H. Cody Meissner wrote for American Academy of Pediatrics News, is that the SARS-CoV-2 virus is very poorly understood. Vaccines take a long time to develop even when a disease has been around for a while, but because SARS-CoV-2 entered human beings less than a year ago, scientists have more work to do than would otherwise be the case.

This does not mean we should lose hope, however.

"It is encouraging to see so many players in the field, many using very different platforms (forms of vaccines)," Sommer told Salon by email last month. "This clearly increases the likelihood that at least one if not more of these vaccine candidates will prove safe and effective. Some are likely to prove more effective than others at reducing the risk of subsequent infection, and provide such protection for longer periods of time. The lessons we learn from each approach might well increase the likelihood, and the speed, at which even more effective vaccines are developed."

Which vaccine candidates are showing the most progress?

According to MarketWatch, there are only four major vaccine candidates right now that are currently in Phase III trials. These include one being developed by AstraZeneca in partnership with the University of Oxford, one being developed by BioNTech and Pfizer Inc., one being developed by Johnson & Johnson and one being developed by Moderna. AstraZeneca currently says they expect data by the end of the year, although they halted trials in the United States in early September due to an adverse event

Last week Pfizer CEO Albert Bourla announced that the pharmaceutical giant may apply for emergency federal approval of its coronavirus vaccine by as soon as late November. This marks the first time a drug company has offered a possible specific time for a vaccine to be ready for public use.

Matthew Rozsa

Matthew Rozsa is a staff writer for Salon. He holds an MA in History from Rutgers University-Newark and is ABD in his PhD program in History at Lehigh University. His work has appeared in Mic, Quartz and MSNBC.


Explaining vaccine clinical trial phases

Credit: CC0 Public Domain

Clinical trials are conducted in phases, each with slightly different objectives and increasing numbers of volunteers. This is primarily to ensure subject safety but also to make sure the process is as cost-effective as possible. The data from each phase is thoroughly reviewed and must show both safety as well as the desired effect before progressing from one phase to the next. While most vaccine studies are relatively long clinical trials, often around six to 12 months, safety and efficacy can often be established earlier than the end of the study. The later assessments are then used to demonstrate how long the protection from the vaccine is likely to last.

Before a vaccine is considered for human trials, it has to have robust data from laboratory and animal studies to make the investigators, as well as an independent ethics committee, confident it is very likely to be both safe, as well as effective. Once this is the case, it can move to phase 1 trials in humans.

Phase 1 trials are relatively small trials, usually around 100 volunteers, with the primary objective of confirming the safety already strongly expected from animal studies. Generally, blood tests are collected from the volunteers for testing of the vaccine's efficacy in the laboratory. This gives an indication of whether the vaccine has generated an immune response that is likely to be useful but doesn't guarantee it is going to work. Often multiple doses are used to try and find the ideal dose to take forward in later phase trials. Phase 1 trials are often conducted in a relatively narrow age range of healthy subjects with no comorbidities to reduce the prospect of confounders (something that would influence the result) and to ensure safety.

Phase 2 trials are still mostly focused on safety but now include a greater number of subjects, often in the order of 1000 to 2000. Laboratory studies of effectiveness are also conducted in phase 2 but actual protection from the pathogen in question starts to be looked at. A slightly more diverse population can sometimes be considered for enrolment, such as a broader age range, to begin to more closely resemble the actual target population. While giving the first look at actual protection, these studies are usually not large enough for us to confirm the vaccine actually does what it needs to do, and that is to protect people from the infection it's designed to provide protection from. This is where the phase 3 trials come in.

Phase 3 trials are the pivotal final trials before a vaccine is approved for widespread use. While safety remains a focus, these trials are primarily about showing that people that have received the vaccine have significantly lower rates of actual infection than those that have not. To show this typically requires large numbers of volunteers, in the order of 10's of thousands, depending however on many factors including how widespread the infection is that the vaccine is designed to protect from. While vaccines can fail to show sufficient effect and therefore fail to progress through any phase, it is the failure to provide sufficient protection in phase 3 studies where a number of potential vaccine candidates prove unsuccessful.

Once a vaccine is in widespread use, data collection on its safety, as well as how well it is working, continues to be collected in what is known as phase 4.

Length of clinical trials

While typically clinical trials take many years, this is largely because of the cost of each step. Therefore, the time and money for each phase is not invested until the prior phase is complete and has demonstrated the desired safety and efficacy.

In the case of COVID-19, we have been fortunate to see sufficient investment that has enabled planning for all phases of clinical trials to take place at the beginning, allowing the next phase of clinical trials to commence quickly, so as soon as the data from the previous phase supports it. This has meant that we are seeing vaccine development happen at a rate much faster than ever before without compromising at all on any of the usual processes required to be certain about the vaccine's safety, as well as how well it is likely to work.


Related Articles

According to MarketWatch, there are only four major vaccine candidates right now that are currently in Phase III trials. These include one being developed by AstraZeneca in partnership with the University of Oxford, one being developed by BioNTech and Pfizer Inc., one being developed by Johnson & Johnson and one being developed by Moderna. AstraZeneca currently says they expect data by the end of the year, although they halted trials in the United States in early September due to an adverse event

Last week Pfizer CEO Albert Bourla announced that the pharmaceutical giant may apply for emergency federal approval of its coronavirus vaccine by as soon as late November. This marks the first time a drug company has offered a possible specific time for a vaccine to be ready for public use.


Who can take part in a COVID-19 vaccine trial?

Around the world, thousands of people are taking part in human trials to try to find a successful vaccine for the new coronavirus. According to Jansen, for stage one of the Phase 1/2 trial within Pfizer and BioNTech’s US clinical program, the aim is to enroll up to 360 healthy volunteers. “This may scale to more than 8,000 healthy participants by its conclusion,” she adds. The Inovio trial consists of 40 people in Phase 1 and “likely several thousand in Phase 2/3," Richardson says.  

Before taking part in a COVID-19 vaccine clinical trial, each participant has to go through a specific screening process. “Only people who have had no exposure to COVID-19 (established through antibody testing) will be allowed to participate,” Jansen says. “Volunteers will be pre-screened for the absence of antibodies against SARS-CoV-2 to show no history of past infection and no active infection within 24 hours of vaccination.”

Every trial has its own eligibility criteria, but across the board, younger, healthy adults are being immunized first. In the Pfizer/BioNTech&aposs US research program𠅌onducted by NYU Langone Health—older adults (age 65 to 85) will only be immunized with a vaccine candidate once testing in younger adults (age 18 to 55) has provided early evidence for safety and desired immune response.  

Being part of a COVID-19 vaccine clinical trial shouldn’t impact on someone’s life too much, but it’s important to continue to follow all public health guidance. Jansen warns that participants shouldn’t assume they’re protected and then engage in behavior that puts them at higher risk for infection. Researchers also check in with participants regularly, Richardson says. This is done both in person at the testing sites and electronically, over email and/or phone. 


False Polio Claim

As part of Baker’s specious argument that vaccines “don’t work,” he brings up the example of polio and falsely says the disease subsided because of sanitation, not vaccination.

“Obviously, polio went away because of sanitation because it’s a fecal-oral disease,” Baker says. “And if you start washing your hands and not drinking water in the streets, you’re probably not going to get polio.”

While better sanitation helps reduce the spread of poliovirus , which is passed along primarily through feces but can also be spread through infectious droplets from sneezes or coughs, it is vaccination that is credited with eliminating the virus in the U.S.

After all, sanitation was quite good in 1950s America, but polio was still a major threat to families every summer.

Perhaps counterintuitively, improved sanitation is thought to be why there was a surge in polio cases in the U.S. in the beginning of the early 20th century.

“Before 1910, polio was silently circulating,” explained Micaela Martinez , an infectious disease ecologist at Columbia University who has studied the history of the disease.

The virus was rampant, she said, but because virtually everyone would become infected as an infant when there is a low risk of getting severe disease and developing paralysis, it wasn’t particularly noticed.

As sanitation improved, however, children wouldn’t encounter the virus until they were older, when the risk of paralysis was greater. “So sanitation actually led to this first emergence of polio as being a widespread paralytic disease,” Martinez told us.

Polio epidemics became even worse after World War II with the baby boom, as more children were around to further spread the disease, she added. It wasn’t until vaccines arrived that cases began to fall — from more than 15,000 paralysis cases every year, according to the CDC, to fewer than 100 annually in the 1960s and fewer than 10 each year in the following decade.

The disease was eliminated in the U.S. in 1979, meaning there is no ongoing transmission of polio in the country, and no cases have originated in the U.S. since that time. Polio vaccination is still important, however, as the disease could be introduced at any time by travelers.


A Virologist’s Case For The COVID-19 Vaccine

Recent announcements from COVID-19 vaccine trials have sparked much interest and excitement. The first two vaccines announced from Pfizer/BioNTech and Moderna are mRNA vaccines, whereas the third potential candidate finishing up late-stage clinical trials is a viral vector vaccine from Oxford/AstraZeneca. Pfizer’s vaccine has been granted emergency approval in the UK and Canada, and it is very likely that it will gain this approval in the US today. Many other vaccines are in clinical trials and will likely be announcing results soon.

Although these ann o uncements have generated much excitement, there is a significant portion of the population that is hesitant to get excited about the possibility of a vaccine. Reasons for this hesitation range from concerns about the short time spent in clinical trials to concerns about what the vaccines contain.

I am a virologist. I also tend to lean fairly conservative (whatever that means anymore) when it comes to many political issues. Since the majority of vaccine concerns are being voiced by conservatives, I wanted to take a minute to explain my perspective on getting the COVID-19 vaccine and why I plan on getting it when it becomes available. Most of this article will focus on the new mRNA vaccines as they are the leading candidates at the moment, but I will reference other vaccine platforms when relevant.

If you have concerns about whether or not you should get the vaccine, I hope these thoughts will help you as you think through that decision.

The vaccine is effective

I plan on getting the vaccine because the clinical trial data shows that they will protect against the virus.

Perhaps some of the most anticipated and exciting news about the COVID-19 vaccines in development is that they appear to be highly effective. This is the case for the two leading mRNA vaccines, at least. Pfizer announced that their vaccine was 95% effective against COVID-19 in their phase III clinical trials. The graph (figure 13 on page 58 of the report submitted to the FDA) showing cumulative COVID-19 cases in the vaccine and placebo groups, respectively, is about as clean and clear as you can get in a phase III clinical trial, showing a stark and definitive protective effect in the vaccine group.

Similarly, Moderna announced that their vaccine is 94.1% effective. These are very promising numbers. AstraZeneca was the third company to announce an effective vaccine, with one dosing regimen showing 62% effectiveness and another regimen showing 90% effectiveness. For comparison, the seasonal flu vaccine is typically 40–60% effective each year (this is in part due to the nature of the influenza virus compared to coronaviruses).

To be fair, these efficacy numbers are specific to the clinical trials environment. In the real world, vaccine effectiveness might be lower. However, these data showing very high vaccine effectiveness suggests that these vaccines work well and will protect a significant number of people. I would guess that efficacy rates in the wild will be quite similar to those reported above, if just slightly lower.

The vaccine is safe

I plan on getting the vaccine because all signs point to the vaccine being safe.

The two leading vaccines from Pfizer and Moderna are mRNA-based. mRNA is a natural molecule in our own cells, taking instructions coded in our DNA and presenting that information to proteins called ribosomes, which build proteins from the mRNA instruction. Coronavirus mRNA vaccines contain instructions that tell your cells how to make a Sars-CoV-2 (the virus that causes COVID-19) protein that is typically found on the outside of the virus. Your cells then take these instructions and make the protein, which they then present to your immune cells to recognize and make antibodies towards (this is an over-simplified explanation, but it serves our purposes).

This is actually what would happen in a normal infection, except in a normal infection, the virus would introduce instructions for your cells to make all the viral proteins instead of just the one that the vaccine has. There is therefore no possibility of infection from mRNA vaccines, because there are no instructions to make all the necessary virus components. Further, mRNA is an inherently unstable molecule, meaning that it will degrade rather quickly (and thus not stay in our cells for very long), and it cannot change our cell’s DNA. This rationale is why mRNA vaccines are considered very safe.

But do we really know that these vaccines are safe? They’ve only been in trials for a few months, and vaccines normally spend years in clinical trials, right?

From years of vaccine research, we have a good understanding of vaccines and how they work in the body, so we have a good idea of what to be looking out for as far as adverse events or side effects, both severe and non-severe. For example, typical non-severe or minor adverse events often include pain, redness, and swelling at the injection site, fever, fatigue, and headache. These symptoms have been noted in the COVID-19 vaccine trials, and although they may be uncomfortable, they usually resolve within a few days. Severe adverse events that have been seen with other vaccines include seizures, anaphylaxis, and Guillian-Barré Syndrome (note that GBS, the adverse effect with the most potential to have long lasting effects, has a prevalence of between 6 and 40 cases per 1 million people in the US, and being sick with diarrhea, lung, or sinus issues poses a greater risk for developing GBS than vaccines). We also know that typically these symptoms develop within days to months, not years down the road.

While this is the first mRNA vaccine to be approved, there are several reasons to be confident in the safety of these vaccines. As explained above, the theoretical basis for mRNA vaccines gives every indication that they will be safe and not cause serious adverse effects. Further, mRNA vaccines have been in development for several years for other infectious diseases, such as influenza, and clinical trials had already begun.

COVID-19 vaccine trials are also under intense scrutiny, as the whole world is watching for obvious reasons (for example, Oxford’s vaccine trial results have generated questions and concerns from the scientific community). Independent review boards are being used to review the results to eliminate as much bias as possible.

Moderna has enrolled 30,000 participants and Pfizer nearly 44,000, and to date, there have been no severe adverse events following immunization. The AstraZeneca vaccine trial, which also enrolled around 30,000 participants, saw one participant develop spinal cord inflammation. The trial was immediately halted until review occured, and it was determined the patient developed multiple sclerosis and there was no evidence that this was related to the COVID vaccine.

To question the speed of development and approval of these vaccines is a legitimate concern. The development of a COVID-19 has proceeded at an unprecedented pace. This is especially true for mRNA vaccines, as the mRNA vaccine platform has yet to be approved for any disease. However, this rapid development does not mean that bad science is being done. It is indeed impossible to know all the downstream effects of these new vaccines. However, there has been no evidence to warrant any fear that these vaccines will be anything other than safe. Compare that with the known detrimental effects (both short term and long term) that COVID-19 can have on the body and I believe that the risk-benefit analysis weighs heavily on the side of the vaccine.

The vaccine will allow us to reclaim our social lives

I plan on getting the vaccine because I want us all to be able to spend quality time with our friends and families again.

This year has been difficult for most of us, not only because of the pandemic but perhaps even more so because of what the pandemic has taken away from us: our social lives. I truly believe the short- and long-term mental health effects from social distancing and isolation are underappreciated as of yet. An effective vaccine holds the potential to allow us to reclaim our social lives without the fear of spreading the virus to those we love.

Although there are some concerns that a vaccine will not fully allow us to get back to normal, I believe these concerns are overstated. An effective vaccine that is widely accepted by the public will severely limit the number of people that the coronavirus can infect, which in turn will drive down viral transmission. In the best-case scenario, there will not be enough people that the virus can infect to keep it in circulation.

But even if vaccination rates are much more modest, any proportion of the population that is immune to the virus should decrease viral transmission. Not to mention the fact that especially vulnerable populations, such as the elderly and those with risk factors, will have an option for a line of protection even if the general public is less than enthusiastic about the vaccine. We cannot let perfect be the enemy of good enough.

Two common objections

These are the main reasons I am planning on getting the COVID-19 vaccine. Honestly, for many people, getting the vaccine just seems like common sense. Why wouldn’t you get the vaccine?

Yet, there are quite a few people who are hesitant to get the vaccine. And a growing number are voicing outright opposition to the vaccine. Hesitancy that spawns from uncertainty about the safety of a new vaccine is reasonable, though there is good reason to believe that the vaccine will be both safe and effective. However, there are a couple of claims that are making their rounds that are misleading people about the vaccine, causing unwarranted fear and opposition to the vaccine. This article would not be complete if I didn’t address these concerns.

The vaccine does not contain poisons

You might come across some claims that the new COVID vaccines that they are making contain different chemical poisons. Statements like these are designed to frighten and intimidate, often using unfamiliar chemical names to frighten people. What statements like these are trying to imply is that there are chemicals in the vaccine that are toxic to our bodies.

However, this misunderstands (or deliberately ignores) the definition of poison. Poison is a vague term, and it is determined by the dose. It is true that a lot of vaccines contain small amounts of different chemicals (with long, frightening names) that are used at various stages of the production process, but the amount of these chemicals in the final vaccine products is minuscule. For example, the amount of formaldehyde, a common chemical named as one of the ‘poisons’, in a vaccine is less than the amount of formaldehyde that our own cells produce as a natural by-product of metabolism (for more information about vaccine safety, see my article, “Your Flu Questions Answered”). So, to call that poison is to misuse the concept of poison.

The COVID vaccines are going through rigorous safety trials, and the only ones that will get FDA approval will be those that can show that they are both safe and effective. And as stated above, the safety data for the mRNA vaccines is looking very good. It is true that we cannot know for certain the long-term safety profile of these new vaccines, but this is also true of any novel medicine or medical device. The vaccines will continue to be closely monitored for safety even after they pass through Phase III clinical trials. However, there is no reason at the moment, from theory or clinical trials, to believe that these vaccines will be anything but safe. On the other hand, we can be quite sure that COVID-19 will continue to harm and kill people in the absence of a vaccine.

The vaccine does not contain aborted fetal tissue

Statements asserting that the COVID vaccine contains or is made with aborted fetal tissue are increasingly becoming a common refrain in some circles opposing the vaccine. These statements are not new among those who have opposed vaccination for years, but rather have been recycled for various vaccines.

What is new, however, is that I am starting to hear this line of reasoning in the more mainstream conservative community in reference to the COVID vaccine. The reason for this is fairly obvious. Abortion is being used as a trigger word to rally conservatives that would not normally fall into to the far-right community, but already have some concerns about the COVID-19 vaccine. And it is an effective persuasion tool. However, this statement is at best a half-truth designed to mislead, and at worst an outright lie.

To begin, I want to make one thing abundantly clear: none of the vaccines currently in development contain aborted fetal tissue. The two leading mRNA vaccines contain lipids and mRNA, and the next contender (Janssen) is based on a recombinant protein encoded in a viral vector. More traditional vaccine approaches use a weakened or killed form of the virus that causes COVID-19. Any statement that asserts the new COVID-19 vaccine contains aborted fetal tissue is simply incorrect.

Now that that is out of the way, we can look into where statements about aborted fetal tissue originate. As far as I can tell, claims such as these are based on the fact that research groups and companies often use a particular cell line, named HEK-293 cells, during their vaccine development stage. It is true that the HEK293 cell line was derived from an aborted fetus in 1973 in the Netherlands. However, there are several important points that need to be discussed before we use this as a reason to oppose vaccines.

First, the reason for the abortion is unknown. The scientist who derived the cell line from the fetus could not recall the circumstances in which he obtained the fetus. What is certain, however, is that reason for the abortion had nothing to do with the scientist making the cell line with the tissue (it could have even been a spontaneous abortion — we just don’t know). There is little moral ground for blaming the scientist in this situation. As a parallel, if an organ donor is murdered, we wouldn’t say it is morally reprehensible to use his/her organs to save a life on the basis that the murder itself was immoral.

Second, the HEK293 cell line is a very popular cell line in biological/medical research (probably second only to HeLa cells, another cell line with a controversial origin story) and is used in practically every major lab and biotech company that exists today. They are widely used to study various aspects of infection, vaccine, and drug effects. They work very well in genetic assays, often playing a vital role in genetic research.

So, if research with this cell line provides grounds to not get the COVID vaccine, then it also provides grounds not to get any vaccines (which certain groups would likely agree with) or medications at all, as practically every lab that has produced modern therapeutic agents has used this cell line at some point, from cancer labs to infectious disease groups to basic biology researchers.

Finally, and relating to the original point, whereas HEK293 cells have likely been used at some point in researching a vaccine, they are not used to produce the vaccine. The cells are used in the testing process, not the development of the actual vaccine.

Actually, if you support the claims that vaccines contain trace amounts of the cells they are grown in, you should be for the new mRNA platform of vaccination. All components of mRNA vaccines can be made completely free from any animal-based products. They are not grown in human cells at all, much less the HEK293 cell line.

But even the traditional approaches to the COVID-19 vaccine would not use HEK293 cells to grow the virus. These cells simply do not work well to produce large amounts of virus. Rather, another cell line, called Vero cells (derived from African green monkey kidney cells) has proven to be the best at producing large amounts of the coronavirus, and it is likely that this would be the cell line of choice for the COVID-19 vaccine.

In sum, the vaccine itself does not contain (or use) aborted fetal tissue however, the research process that led to the vaccine likely at some point used that cell line. Just like the research that led to most modern medicines that save countless lives today.

If you are struggling over whether or not you should get the vaccine when it becomes available, I hope this helps you think through the decision. I know that it can be a tough choice due to the different uncertainties and concerns that you may have, or might have heard about from close friends and family. However, I think the theory and data for the new vaccines are solid, showing them to be both safe and effective.

I plan on getting the COVID-19 vaccine when it becomes available. I hope you will too.


How to Calculate the Values of N_min and N_vUT for a Desired Power Level

In equations 2A and 2B, the term P(N_v ≤ N_vUT) is simply the sum of the probabilities of N_v=k, where k=0,1,2,3,…,N_vUT. Let’s write this statement out as a an equation:

Applying Bayes’ rule to the probability inside the summation:

We can use the fact that N_t = N_c + N_v to rewrite the clause: (N_t=N_min) as (N_c=N_min-k):

Recollect that N_c, N_v and N_t are Poisson distributed random variables with mean incidence rates of λ_c, λ_v and λ_t respectively such that λ_t = λ_c + λ_v. We’ll put these recollections to excellent use.

Let’s use the Poisson Probability Mass Function to express all three probabilities in Eq (5):

Plugging these probabilities into eq (5), and after performing some simplifications, we get the following:

Recollect Eq (1) in which we expressed Vaccine Efficiency in terms of mean disease incidence rates. Let’s reproduce it below for reference and also plug it into Eq (6) so as to express (6) in terms of Vaccine Efficacy:

If you have a paper and pen handy, I will encourage you to work out the math and verify that these substitutions actually work to yield equations (6) and (7).

Let’s keep in mind the transformation shown in the red box. It’s a very useful equation that we’ll get to in a bit.

Meanwhile, if the R.H.S. of Eq (7) reminds you of something, you wouldn’t be alone! It’s the Probability Distribution Function (more accurately, the Probability Mass Function) of a Binomially distributed random variable. So, we can re-write Eq (7) like this:

Where Bin(N_min, k, θ) is the probability of seeing k events of interest in N_min trials given that the probability of a single occurrence is θ. But using the Binomial PMF in this manner isn’t going to work out for us unless θ, the probability parameter, is shown to vary smoothly from 0.0 to 1.0. Let’s verify that is indeed the case.

Let’s first look at the endpoints of the scale. VE can take on any value from -∞ to 1.0. In the extreme scenario where everyone from the vaccine group catches the disease and no one from the control group does so, Relative Risk RR → ∞ and VE=1 — RR → -∞. Conversely, if no one from the vaccinated group catches the disease, while everyone from the control group does so, RR = 0.0 and VE is 1.0.

A plot of θ versus VE shows how θ varies smoothly in the open-close interval (1.0, 0], as VE varies smoothly in the open-close interval (-∞, 1]:

In fact, this is exactly the transform function used by the folks at Pfizer in their vaccine protocol document (see page 111).

Let’s plug in Eq (8) into Eq (3):

Finally, let’s plug in the (True VE =VE_assumed) and (True VE = VE_LT) clauses which we had omitted for brevity:

Notice that the R.H.S of 10A and 10B is the Cumulative Distribution Function of the Binomial distribution. We can rewrite Eq(10A) in a concise form as follows:

Where, F(.) is the CDF of the Binomial distribution. Ditto for Eq (10B).

We need to fix certain parameters so that we can calculate the values of N_vUT and N_min for the desired power at a certain significance level α and a lower bound VE_LT on the efficacy.

We’ll use the parameters used by Moderna, Pfizer and AstraZeneca in their respective protocol documents.

All three companies are aiming for a 90% desired power level for their test at a significance level of 0.05 (i.e. 95% confidence level) to conclude that the null hypothesis (VE >= 30%) can be rejected, under the assumption that the true VE is 60%.

So, we will set the following parameter values:

(1-β) = 0.9 , VE_assumed = 60% , θ_assumed = (1–0.6)/(2–0.6) = 0.28571

α=0.05, VE_LT = 30%, θ_0 = (1–0.3)/(2–0.3) = 0.41176

To calculate N_vUT and N_min that will yield the above power under the specified True VE assumption, we will vary N_min from 0 to some arbitrary value (say, 200) in steps of 1. For each value of N_min, we’ll vary N_vUT from 0 to the current value of N_vUT in steps of 1, and we’ll use Equation (10A) to calculate the power. If the calculated power is greater or equal to 0.9, we plug in the combination (N_vUT, N_min) into Equation (10B) to calculate the p-value — the probability of observing the earlier power level under the assumption that in fact the vaccine is not even minimally effective. In other words H0 is true and True VE≤0.3. If this p_value is ≤ the significance level α=0.05, we note down this combination of (N_vUT, N_min) as a tuple of interest.

The above procedure can be easily executed using a simple Python script which I have embedded at the bottom of the article.

When we plot all such selected combinations (N_vUT, N_min), we get the plot shown below (I’ll explain the red marker on the plot in a bit). Meanwhile, notice that we have also varied VE_assumed from 0.3 to 0.9 in steps of 0.1.

We do not see any plots for True_VE=0.3, 0.4 and 0.5 because our procedure was not able to find any (N_vUT, N_min) combinations at these assumed true VE values that would satisfy our desired power level of ≥ 90% at a significance level of 0.05.

One can see that for any given value of observed N_min, desired power level and significance criterion, the max number of infections that one should expect to see in the vaccine group (N_vUT) decreases as the assumed True VE increases.


The Special Sauce That Makes Some Vaccines Work

Potential COVID-19 vaccines are kept in a tray at Novavax labs in Maryland on March 20. The Novavax vaccine requires an immune-boosting ingredient called an adjuvant to be effective. Andrew Caballero-Reynolds/AFP via Getty Images hide caption

Potential COVID-19 vaccines are kept in a tray at Novavax labs in Maryland on March 20. The Novavax vaccine requires an immune-boosting ingredient called an adjuvant to be effective.

Andrew Caballero-Reynolds/AFP via Getty Images

There are many approaches to making a vaccine against COVID-19. Some use genetic material from the coronavirus, some use synthetic proteins that mimic viral proteins and some use disabled versions of the virus itself.

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But before any of these approaches can generate the antibodies to the coronavirus that scientists say are essential to protecting people from getting sick, the immune system has to be primed to make those antibodies.

That's the job of something called an adjuvant.

"The definition of [an] adjuvant is something you add to enhance, in the case of immunity, the immune response," says Gregory Glenn, president of research and development at Novavax, one of the companies that has received money from Operation Warp Speed.

Vaccines essentially trick the body into making an immune response to a specific virus or bacterium, so if something dangerous comes along, the immune system will be prepared.

But before it can prompt a response to a specific virus, the immune system has to be made ready.

"When you inject a vaccine, the first immune cell that's of importance is a dendritic cell," Glenn says.

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Dendritic cells are part of what's called the innate immune response. These cells will respond to anything foreign that enters the body, the coronavirus included.

"If they see something — they see a virus or bacteria — they become highly activated, and then they create a whole cascade of events," Glenn says.

That cascade leads to the production of antibodies, and it's the antibodies that will recognize the specific virus of interest.

Novavax's testing shows an adjuvant is critical to its vaccine working well. That's the case for many vaccines.

But the strange thing is that there aren't a lot of adjuvants out there.

"We only think about adjuvants when there's a dire need, such as this pandemic, for example," says Bali Pulendran, a vaccine developer at Stanford University. "Now everyone is interested in faster response and a better response and a longer-lasting response."

Pulendran says for almost a century, scientists relied on a compound called alum to act as an adjuvant. It was only in the 1990s that new adjuvants started appearing on the scene. Now there are several more options, but Pulendran says more choices are needed.

"This is a topic that needs, deserves better attention," he says.

That's a sentiment Corey Casper totally agrees with. He's the CEO of the Infectious Disease Research Institute and a proselytizer for adjuvant research. Casper says to consider what happened when the pharmaceutical company GlaxoSmithKline added a powerful adjuvant to a shingles vaccine.

"It took a vaccine that had previously existed which was about 50% effective, and it made it 97% effective," Casper says. "Not just in all people but in the hardest-to-protect people, which are the elderly, who typically make poor immune responses."

Casper says the vaccine community has underestimated the importance of adjuvants. He even has data suggesting that adjuvants alone might be capable of preventing infectious disease. That has enormous implications.

"Every time a new infection pops up, there's a race to develop a new vaccine for it," Casper says. "But what if you could give the adjuvant alone and you didn't have to develop a vaccine? That adjuvant could be stockpiled, it could be made at millions of doses, placed on the shelf, sitting there waiting for the next pandemic."

Sallie Permar, a vaccine researcher at Duke University, says there may be some validity to what Casper is proposing. She says scientists now have a better idea of how adjuvants work and how they might be able to prevent disease all by themselves.

But Permar says you have to be careful with adjuvants.

"There are some downsides to having such a strong adjuvant affect," she says

In the process of activating immune cells, adjuvants can also bring on some of the symptoms of disease, such as fever, malaise or inflammation. The GlaxoSmithKline shingles vaccine works well because of its adjuvant, but many people complain about unpleasant side effects.

One problem facing vaccine developers is the fact that many companies are reluctant to share their adjuvant technology.

"Adjuvants end up being very proprietary," says Barney Graham, deputy director at the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases. "It's kind of the secret sauce of how to make your protein vaccine work."

Academic researchers are hoping the urgency of finding a successful vaccine against COVID-19 might make companies more willing to share.

"There is a whole science awaiting us in vaccines that lies in adjuvants," Permar says.

With so much attention being paid to vaccines now, that science may not be far off.


How Can You Protect Yourself From the Vaccine or Exposure to Those That Were Vaccinated?

Indeed, that is the question of the day. We talked about shedding from the vaccine. Obviously, the vaccine does not classically shed virus particles but it can easily cause people to shed spike proteins, and it is these spike proteins that may cause just as much damage as the virus.

While Seneff’s paper didn’t delve deeply into solutions, it provides a major clue, which is that your body has the capacity to address many of these problems through a process called autophagy. This is the process of removal of damaged proteins in your body.

One effective strategy that will upregulate autophagy is periodic fasting or time-restricted eating. Most people eat more than 12 hours a day. Gradually lowering that to a six- to eight-hour window will radically improve your metabolic flexibility and decrease insulin resistance.

Another beneficial practice is sauna therapy, which upregulates heat shock proteins. I have discussed this extensively in previous articles. Heat shock proteins work by refolding proteins that are misfolded. They also tag damaged proteins and target them for removal.

Another vital strategy is to eliminate all processed vegetable oils (seed oils), which means eliminating virtually all processed foods as they are loaded with them. Seed oils will radically impair mitochondrial energy production, increase oxidative stress and damage your immune system.

Seed oils also are likely to contain glyphosate, as it is heavily used on the crops that produce them. Obviously, it is important to avoid glyphosate contamination in all your food, which you can minimize by buying only certified organic foods.

Finally, you want to optimize your innate immune system and one of the best ways to do that is to get enough sun exposure, wearing in your bathing suit, to have your vitamin level reach 60 to 80 ng/ml (100 to 150 nmol/l).