What to Know About the Recent Advisory Committee on Immunization Practices (CDC) Meeting

Part IV: Understanding Vaccine Safety

This is the last blog piece in this blog series, as I wrap up my coverage of the most recent ACIP meeting. It has become clear that many people, even some of the members of this committee do not understand vaccine safety, what it means when we say a vaccine is “safe,” and how we determine whether a vaccine is “safe.”

Before we begin, I have followed very closely what anti-vaccine (when I refer to anti-vaccine, I mean those who purposefully distort, twist, and misrepresent vaccine information with an agenda to serve their own ideological, political or financial interests through misleading and manipulating the public; I am not referring to vaccine skeptics, those who have been misled by anti-vaccine activists; and those who are just confused by all of this) doctors and others in positions of power or influence say and write to pick up common themes and strategies for confusing the public. Here are some warning signs that you may be reading and listening to anti-vaccine propaganda:

1. Statements about vaccines that are infused with inflammatory language, e.g., “crimes against humanity,” or violations of the “Nuremberg Code.” These statements are intended to conjure up images of the horrible, unethical treatment and experimentation on prisoners, especially twin children, by Dr. Josef Mengele in Nazi concentration camps, and wholly inappropriate to our current day clinical trials with human subject protections. Scientists have science to back us up; we do not have to resort to hyperbolic and inflammatory language.
2. Continued claims about vaccines as being experimental. Although, as you will see below, vaccines are experimental (i.e., under an investigational new drug (IND) designation following an application to the FDA) until the Phase I, II and III clinical trials are successfully concluded, once application is made to the FDA in a biologics license application (BLA) and the FDA experts and committees have completed their review and granted the vaccine a biologics license, they are no longer experimental. At this point all of the COVID-19 vaccines currently available in the U.S. are licensed and these vaccines are no longer investigational or experimental.
3. Claims that the mRNA vaccines are “gene therapy.” Gene therapy refers to treatments we can offer for some diseases that are caused by a single gene abnormality, e.g., sickle cell anemia and Huntington’s disease (just recently reported). That is completely different than an mRNA vaccine that couldn’t possibly alter your genes and anti-vaccine advocates use this phrase to try to make people think that their DNA is being altered if they receive the vaccine, which is absolutely untrue.
4. Statements that go something like this: “X vaccine has caused more deaths than the disease” it is intended to prevent. That is a sure-fire sign that the person is not serious. In recent history, the FDA has suspended or revoked licensure for vaccines that have caused less than a handful of serious adverse events or deaths (e.g., the J&J COVID-19 vaccine and the lxchiq chikungunya vaccine) that were dramatically less than the number of deaths caused by the diseases for which they were intended.
5. Inconsistencies. These are the result of some of the most common tactics that I see today, including this one that was offered by a member at the recent ACIP meeting. Statement A – “We shouldn’t recommend a vaccine until we have evidence that it is 100 percent safe.” Statement B – “We don’t need to wait until we have 100 percent evidence of effectiveness for (fill in the blank with ivermectin/hydroxychloroquine/a supplement they are selling/other).”

We often speak about safety in daily life and often make statements about things being safe. Usually when someone says that some activity is safe, it doesn’t mean that no one has ever been harmed by the activity or never could be in the future, but rather that the chances of harm are so low and/or the magnitude of the harm is low enough that the risk of harm is below the tolerance level for harm relative to the benefit of the activity to whoever is making the judgment that the activity is “safe.”

So, here is an example from my life. I have a friend who jumped off the side of a mountain cliff on a bungee cord and who went base jumping (i.e., jumped off a high bridge with a parachute), and filmed both events for me to see. He obviously is a thrill-seeker. No one has ever accused me of being a thrill-seeker. I do enjoy a good roller coaster ride, but, probably 30 years ago, with each of my daughters on either side of me, an amusement park lifted us up on a platform that we were lying down on as if we would fly like superman. We were to pull a cord when the lift stopped that would release us from the lift and allow us to free fall joined together and attached by a bungee cord. When we got as high as the lift was going to take us and they instructed us to pull the cord, I was paralyzed with fear and unable to pull the cord. One of my daughters did the deed for us. I have never done that again.

He invited me to go with him the next time he goes cliff or base jumping and I have politely declined. He considers both activities “safe,” but in his case, he gets a benefit out of it that for him outweighs the risks – a thrill, the sense that he has accomplished something that most other people have not, boasting rights, a sense of accomplishment and overcoming his fears, etc. So, he has a different lens for his risk-benefit analysis than I would. For me, the analysis goes like this-  On the benefit side: I have nothing to prove, I would be absolutely terrified rather than experiencing a thrill, I have plenty of other accomplishments, so in my estimation, the benefit of doing either of these activities is 0, in fact, probably a negative number in that the travel and time to do either of those activities means I would most likely give up a day of doing other things that to me would be more enjoyable or a productive use of my time. As for the risks, these are not well defined, because there is no registry, but there is one report that I found that the risk of death could be as high as 1 in every 2,317 jumps.

But let’s look at common every day risks that the majority of people still consider “safe activities.” Most people, including safety experts, consider commercial air travel “safe.” In the past 10 years, the number of deaths per year in the U.S. from commercial airline crashes in in single digits. Last year, it was zero. This year, it is unusually high surpassing 60 deaths. In the last survey I could find, 44 percent of Americans flew commercially just in 2022 and ninety percent of Americans reported having ever flown commercially. Obviously, the vast majority of Americans consider commercial air travel safe. Likely, they all have made the calculation that the benefit of travelling by air – whether allowing them to get somewhere that might be more difficult or impossible by other modes of transportation or by allowing for faster travel, made the risks of travel acceptable in their minds.

Many gun owners consider guns to be safe, even though they understand that there are significant risks with guns.

With all of these activities – base jumping, commercial air travel, and owning guns – what is “safe” is also different under different conditions and allows for mitigations or risk. For example, the risks of base jumping significantly increase when the weather is windy. Thus, the relative risks can be reduced by clear weather with low winds (however, I am still not going). With commercial air travel, risks are mitigated through regular maintenance of airplanes, safety inspections, coordination of flights by air traffic controllers, and intense safety training for pilots and flight attendants. Gun ownership risks can be mitigated with gun safety training and utilizing gun safes in homes with children.

Most of us don’t give significant thought about the risks of getting in the car to go to work, to visit friends and family or to go to other destinations (in 2022, there were 5,930,496 vehicle crashes that were significant enough that the police were called, or roughly 16,248 crashes per day). This is a case in which society agrees that your “freedom” to drive a car must be under some restrictions for the well-being of all of us. The states require all drivers to be of a certain minimum age that increases the likelihood we will be responsible and competent drivers. Each state requires licensure to drive and compliance with speed limits, stop signs or lights, and other restrictions on drivers, and every state restricts the freedom of drivers to be impaired in their driving from alcohol or drugs. Most drivers consider themselves to be “safe” and consider driving to be “safe” because it is a very convenient way for us to get to places we need to get to and we assume that because we are safe drivers and that other drivers will for the most part comply with traffic regulations, that we are unlikely to be in one of the 16,248 crashes that day.

In fact, it is hard to think of anything that is entirely, 100 percent safe. Some toys warn of the hazards of choking. Some packaging warns of the risks of suffocation if that packaging is put over a person’s head. People have drowned in their bath tubs. There are slightly less than 300 unlucky Americans that get struck by lightening every year.

So, too, when we say a medication or a vaccine is “safe,” we are not saying that nothing bad has ever happened or never will. Like all of the above, safe is a determination made after comparing the benefits against the risks. A common strategy of those who spread vaccine disinformation is to emphasize or exaggerate potential harms and, in some cases, to fabricate those harms, while dismissing or downplaying the benefits. Let me be clear here: misleading patients into believing that any medication or vaccine is perfectly safe is just as manipulative and improper as misleading patients into believing that a medication or vaccine that has been approved for use for a particular condition is all risk and no benefit for treatment or prevention of that condition.

Under the Public Health Services Act that sets the criteria for the FDA in determining whether medications and vaccines are safe, the word “safety” means “the relative freedom from harmful effects, direct or indirect, when a product is prudently administered, taking into consideration the character of the product in relation to the condition of the recipient at the time.” The word “relative” means relative, or in comparison, to the disease or condition that the medication is intended to treat or the vaccine is intended to prevent. Thus, if the FDA is asked to approve a medication that is miraculous and causes a self-limited (meaning that it will go away on its own and not get worse or cause complications) itchy rash overnight, but causes a fatal cancer in 5 percent of those who use the medicine, then that is not a safe medication because there is no chance of dying from the rash and no chance that the rash would cause a fatal complication, thus this is a case where the cure is worse than the disease.

On the other hand, if the FDA is asked to approve a medication for a rare cancer of children that eventually takes the lives of those children in 100 percent of cases and for which we have no current therapies, and this new medication cures 90 percent of the children, but can cause an incurable blood cancer in 5 percent of these cured children, the FDA would likely determine that this medication is safe (because safety is determined relative to the disease it is treating), even though this is a dangerous medication in that it itself can cause incurable cancer and obviously, you would not want to administer this medication to children who don’t have this rare cancer. In the same manner, a “safe” medication such as ivermectin (because it is highly effective in treating certain tropical parasitic diseases, with far milder health consequences than the untreated parasitic diseases for which it is therapeutic) would not be “safe” when used to treat certain viral illnesses because the accumulated scientific studies demonstrate a lack of effectiveness against these viruses (especially SARS-CoV-2) so the benefit is 0, while there is a percentage of people who will experience adverse effects from the medication.

How do we ensure Vaccine Safety?

The FDA Safety and Innovation Act (FDASIA) of 2012 requires vaccine manufacturers to submit a Pediatric Study Plan early in the development process for any vaccine that will be used in children. The initial plan must contain an outline of the study or studies that the sponsor plans to conduct that includes study objectives and design, age groups to be tested, relevant end points (end points are the measures to determine success – e.g., prevention of severe disease and death), and the statistical approach to be used.

The FDA’s Center for Biologics Evaluation and Research (CBER) regulatory staff consists of a multidisciplinary team of scientists, medical officers, and regulatory and public health professionals, including formal advisory committees, including experts in the fields of vaccinology, microbiology, infectious diseases, immunology, biostatistics, epidemiology, and clinical trial design.

Before a vaccine is ever approved, CBER will review the biochemistry, manufacturing, controls information, the manufacturing facility and equipment; preclinical and clinical data on the safety, efficacy, pharmacology, and toxicology; the suitability of the clinical trial design, and the analysis of the clinical data derived from the clinical trial(s). CBER scientists review research in the areas of statistical and epidemiologic analysis.

The sponsor (usually the manufacturer) must first obtain an investigational new drug (IND) designation for its candidate vaccine. Once the FDA staff have done the above reviews, determined that the regulatory requirements have been met and that the anticipated potential harms to subjects in the planned clinical trials are reasonable under the circumstances and to be fully disclosed by the plan sponsor, the vaccine candidate can receive the IND designation and the investigational phase may begin.

The investigational phase actually consists of three phases of trials. Phase I clinical trials are primarily aimed at providing the initial evaluation of safety and immunogenicity (the immune response resulting from the vaccine candidate). Phase I trials are typically conducted on a small number (usually 20 – 80 in a first attempt to identify common adverse events, which are those that occur at a rate of more than 1 per hundred subjects) closely monitored, healthy, non-pregnant adult volunteers. If the vaccine is intended for use in children, then the Pediatric Study Plan will most often call a series of these Phase I studies that progressively step down in age to the first age of life if no serious safety events occur and if the vaccine continues to be satisfactorily immunogenic in the older age groups.

Phase II clinical trials generally follow successful phase I trials with larger groups of subjects (often several hundred or more and now begin to identify some of the rare adverse effects, meaning those that occur at a rate of less than 1 per hundred subjects), usually in a randomized, controlled methodology. In addition to continuing to monitor for safety and assurance of adequate immunogenicity, the studies are often structured to test for the optimal dosage that allows for a reduction in dose so long as immunogenicity can be maintained. Phase II studies may or may not begin to also examine vaccine effectiveness against one or more endpoints (infection, symptomatic infection, severe illness, hospitalization, or death).

Phase III studies are begun after satisfactory results from Phase II trials and involve many more subjects (often thousands or tens of thousands) and more data is obtained regarding safety, immunogenicity, vaccine effectiveness, and at this point may begin to test for the safety and efficacy of the vaccine in combination with other vaccines that might be anticipated for coadministration (e.g., COVID-19 + influenza vaccines). Phase III trials would generally use our most rigorous study methodology – randomized, double-blind, well-controlled studies. Sometimes, investigators may also be able to explore the issue of immune correlates of protection, i.e., what level of immune response (generally antibody titers) are usually associated with protection from the end-point being measured.

If the results of Phase I, II and III investigational clinical trials are favorable, the vaccine may progress to the licensing phase after the sponsor or manufacturer submits a biologics license application (BLA). CBER’s multidisciplinary team of experts will review all the materials submitted, review the investigational clinical trials design and the results. In addition, the manufacturing facility will be inspected. CBER will often then convene its advisory committee, the Vaccines and Related Biological Products Advisory Committee (VRBPAC) to review the data and offer recommendations as to the information that will eventually go into the package insert if the vaccine is granted a biologics license.

If approved by the FDA, the matter is then, most often, taken up by the CDC’s experts to study the vaccine’ approval, safety and immunogenicity and then convene its committee of outside experts, the Advisory Committee on Immunization Practices (ACIP), to make recommendations regarding the ages, timing, and frequency of administration of the approved vaccine that become effective if and when the CDC Director signs off on them.

At this point, the vaccines will generally have coverage by Medicare, the Children’s Health Insurance Program (CHIP), small and individual market plans and the Vaccines for Children Program (VCP) that reflects the recommendations signed off by the CDC Director.

At this point, post-licensure and post-marketing adverse event monitoring will begin. There is a sophisticated interrelated system of vaccine safety monitoring in the U.S. Before I explain this system, let’s get a few concepts down.

Side effect – these are commonly occurring, time-limited, and usually local reactions that generally occur within minutes to hours following the vaccination. Common examples are redness at the injection site, soreness at the injection site, and swelling at the injection site. Other examples that are not local reactions include fever, muscle aches, and fatigue, most often improving, if not resolving, by the second day.

Adverse events – these unexpected reactions that can range from minor to life-threatening, and that oftentimes require medical attention and evaluation.

Background rates of conditions – An effective tool to help us sort our safety signals from coincidence, especially with new vaccines.

Vaccine Adverse Event Reporting System (VAERS) 

The Vaccine Adverse Event Reporting System (VAERS) is administered and operated by the FDA and CDC jointly. “Its primary function is to detect early warning signals and generate hypotheses about possible new vaccine adverse events or changes in frequency of known ones.” https://pubmed.ncbi.nlm.nih.gov/15071280/. VAERS, however, is highly misused and misrepresented by anti-vaccine advocates. They pull reported data from VAERS and try to make claims about numbers of deaths or any number of other adverse events that they attribute to vaccines; however, incidence rates and relative risks of specific adverse events cannot be calculated from the data in VAERS. That is because anyone can report to this database, but the public’s view of data only portrays data that has not been verified (it comes from raw data).

Those who misuse and abuse the raw data from VAERS in an attempt to discourage or scare others from getting vaccinated generally take every report at face value without questioning the self-reported diagnosis and with the assumption that every death reported is a vaccine death instead of accounting for background rates of mortality and whatever other reported conditions they wish to exploit. Let me explain.

Let’s look at the month of April in 2021. Recall that the mRNA vaccines (Pfizer and Moderna) were given emergency authorization in the fall of 2020 and were rolled out starting in late December, primarily to health care providers. In early 2021, eligibility was gradually expanded as vaccines increasingly became available, and in the first few months of that year, priority was generally given to the elderly (>65 years old). In early April 2021, around the time most states expanded vaccine eligibility to include all adults, more than two million people were receiving their first vaccine each day. https://www.usatoday.com/in-depth/graphics/2021/01/14/covid-vaccine-distribution-by-state-how-many-covid-vaccines-have-been-given-in-us-how-many-people/6599531002/. Let’s assume then a rate of roughly 2 million people receiving the COVID-19 vaccines. I am going to use 2019 data as to the average number of daily deaths in the U.S. so as not to reflect any deaths from COVID-19. In 2019, just short of 8 thousand people died per day. https://www.consumershield.com/articles/how-many-deaths-every-day-us. Now the 2 million people getting vaccinated per day is not evenly distributed across all age groups, because none of the vaccines were being administered to children and adolescents at that time, and of course, deaths are not evenly distributed across all age groups, as we know a person’s risk of dying increases significantly after age 65. Further, 8 thousand deaths per day, is simply the background rate of mortality among Americans; obviously, with a pandemic that was causing many deaths, especially among those over age 65, one would reasonably expect the number of deaths to be higher. But, those who wanted to create alarm and vaccine distrust, attributed every death reported in VAERS as caused by the vaccines without accounting for the fact that roughly 8,000 people in the age groups being vaccinated were expected to die daily, not even adjusting for the death rates in these age groups from COVID-19 infection itself.

The way that VAERS is intended to work and how the CDC and FDA evaluate its data is to look for safety signals – adverse events are being reported that are unexpected and in a higher number of people than would be expected based on the background prevalence of that condition or disorder, when CDC and FDA are alerted by the reports of the adverse event examine multiple vaccine monitoring sources. If a safety signal is identified, the CDC and FDA will then conduct a hypothesis testing study to examine the incidence of the adverse event risk after vaccination. Many times, the safety signal is not verified or validated after an investigation of the reported cases is undertaken. On occasion, and this happened with one of the non-mRNA vaccines, a safety signal was verified, and even though its occurrence was so uncommon that it would not have shown up until millions of people were vaccinated, the severity was such that its use was paused and then physicians were notified not to offer the vaccine except in those cases where the patient wanted to be vaccinated, but could not or would not take one of the mRNA vaccines, and was advised of the risk. Once we had another authorized vaccine that could serve as an alternative, the non-mRNA vaccine at issue was pulled from the market.

When a safety signal is verified, teams of researchers begin work to identify the biologic mechanisms of the adverse event and look for strategies to prevent the adverse event.

The CDC’s Immunization Safety Office monitors vaccine safety through other monitoring systems in addition to VAERS. These include VSD, CISA, and V-safe.

VSD is the Vaccine Safety Datalink. It is a collaborative model for high-quality vaccine safety data, unlike VAERS. VSD is provided data from 13 integrated healthcare systems covering more than 15.5 million people per year including sites on both coasts and in middle and midwestern states. Active monitoring and chart reviews for vaccine adverse events are based only on health care professional input in the medical records of patients. Rapid monitoring occurs for pre-specified events as well as for unexpected adverse events. This system allows for quick detection and assessment of safety signals. The VSD provides CDC and FDA experts with much richer data and information than is available through VAERS only, including links to vaccination records, individual patient characteristics and health care visits, whether these occur in clinic settings, emergency rooms or in-hospital. VSD allows for weekly sequential monitoring of possible adverse events with rapid cycle analysis surveillance. Whereas VAERS will potentially alert us to a safety signal, VSD is designed to detect statistically significant safety signals. VSD allows analysts to compare adverse events among vaccinees in the same age group, gender, race/ethnicity and geographic location. It also allows for comparison of a detected potential adverse event in the first 21 days following vaccination (the time interval in which most adverse events occur) to a comparator group of other vaccinees up to 63 days post-vaccination. VSD detected a safety signal for ischemic stroke following the Pfizer bivalent booster in patients age 65 and older in October of 2022. Monitoring in other vaccine safety systems did not reveal an ischemic stroke signal, and with investigation and further monitoring, the evidence became clear that this safety signal was not verified.

The CDC’s Clinical Immunization Safety Assessment (CISA) Project, established in 2001, is a national network of vaccine safety experts from the CDC, eight medical research centers and other partners that can provide consultation to public health and healthcare providers about complex vaccine safety questions relating to individual patients (these consultations are offered free of charge), and who can conduct clinical research studies to better understand vaccine safety and find preventive strategies for adverse events following immunization. The clinical experts include the disciplines of infectious diseases, neurology, allergy, immunology, pediatrics, hematology, and obstetrics/gynecology.

V-safe is a program that has enrolled more than 10 million participants and sends them periodic check-ins via test or email to monitor how they feel following vaccination, even if the person is experiencing no signs or symptoms.

Together, these four vaccine safety monitoring systems give the CDC and FDA a lot of information from various perspectives from people of all ages and across all parts of the country. These systems have surprised me in their ability to alert CDC and FDA staff when only a hand-full of serious adverse events have triggered a safety signal with vaccines.