It’s a common, misleading refrain in anti-vaccine circles: Childhood vaccines may be unsafe because few if any have been tested in placebo-controlled trials before being approved. But that claim misunderstands the vaccine safety testing process and takes advantage of a narrow definition of a placebo, scientists told us.
“Not a single childhood vaccine on the schedule has ever been through a double-blind placebo-based trial prior to licensure,” Del Bigtree, a prominent activist with ties to Health and Human Services Secretary Robert F. Kennedy Jr., said at a March 9 conference that billed itself as being about a “massive epidemic” of vaccine harm. “It is now a known fact they were never done. No placebo trial anywhere in sight,” Bigtree went on to say.
Kennedy has been making similar claims for years. He previously led Children’s Health Defense, a group that says its “mission is ending childhood health epidemics by eliminating toxic exposures” and writes frequently about alleged harms from vaccines, and hired Bigtree as his communications director during his 2024 presidential run. Kennedy has generally refrained from speaking about vaccines in recent months, but in a congressional hearing on April 21, he repeated the claim when stating that he’s “never been anti-vax.”
“I don’t believe all vaccines are bad. I’ve never said that. What I’ve said is they should be safety tested,” Kennedy said, noting that the government is funding the development of a universal flu vaccine and cancer vaccines. (In a 2023 podcast, he said that “no vaccine” is safe and effective, and later denied making those remarks.)
“With one exception, none of the 92 doses of 18 vaccines now given to our kids has ever gone through a randomized, controlled placebo trial,” he continued. “And all I’m saying is we should know a risk profile so that we can inform parents.”
Kennedy made the same basic appeal about placebo-controlled trials on at least three occasions in January.
“Today’s children get between 80 and 92 vaccines and the only ones that have been safety tested in a randomized placebo-controlled trial is the COVID vaccine. None of the other ones have,” Kennedy said in an interview with USA Today on Jan. 16. (As we have written before, this number of routinely recommended vaccines was only ever possible when counting each dose, including annual flu and COVID-19 shots through age 18 and separating out combination vaccines.) “So we do not know whether those vaccines are causing downstream effects,” such as chronic diseases.
And in similar remarks at a Jan. 21 rally in Pennsylvania, he said that without such trials, “we don’t know what the risk profile is.”
On the surface, it seems to be a compelling argument. Most Americans have enough familiarity with science to know that testing a medical product against a placebo control is the most rigorous way to determine if the product works. Such trials can also reveal common side effects.
All approved vaccines have been tested for safety, experts say, but that does not always involve a saline-only placebo, as Kennedy and others often contend must be used. There are scientific and ethical reasons to choose other controls, such as another vaccine or a solution with inactive ingredients, as Johns Hopkins’ International Vaccine Access Center explains.
Moreover, while the trial process ensures a certain level of safety, trials are unlikely to be large enough to rule out side effects that are rare, the center says. That information can only come from vaccine safety surveillance systems and population-level studies with tens of thousands or millions of people.
“Safety is not determined by any one study,” John Grabenstein, a vaccinologist and director for scientific communications for the nonprofit Immunize.org, told us. “It’s determined by the collection of all of the studies.”
Kennedy’s statement that the “risk profile” of childhood vaccines is unknown without placebo-controlled trials is “clearly false,” Jeffrey S. Morris, director of the division of biostatistics at the University of Pennsylvania’s Perelman School of Medicine, told us, because it “dismisses all of the other studies and data that are present.”
“Many of these vaccines have been given for a long, long time,” Dr. Kathryn Edwards, a now-retired Vanderbilt University vaccinologist, told us. “Their safety profiles have been confirmed with observational studies involving millions of children.”
With Kennedy at the helm of HHS, the focus on narrowly defined placebo-controlled trials for vaccines has begun to shape messaging and policy. In May, as we wrote, an HHS spokesperson said “very little” is known about “the actual risk profiles” of vaccines because of a lack of testing against an “inert placebo,” and suggested that regulators would require placebo testing for all “new” vaccines. A few weeks later, the Food and Drug Administration indicated it would now require new placebo-controlled trials to approve updated COVID-19 vaccines for lower-risk populations.
In December, the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices, which Kennedy had remade earlier in the year, hosted Aaron Siri, a vaccine injury lawyer, who emphasized the lack of pre-licensure placebo-controlled trials for routine injected childhood vaccines in a more than 90-minute presentation.
And when the CDC unilaterally cut the number of universally recommended childhood vaccines in January, officials noted a lack of placebo-controlled trials for some shots. (On March 16, a judge temporarily blocked that policy and all others made by the current ACIP, preliminarily finding that the government likely had not followed proper procedures when making vaccine schedule changes and appointing committee members. HHS has since issued a new charter for ACIP, altering the rules to permit other experts, including those specializing in “recovery from serious vaccine injuries.”)
While we’ve addressed the vaccine-placebo claim several times before, it remains a persistent misconception. Here, we discuss it in detail, explaining why certain childhood vaccines were not tested against saline placebos — and why scientists say that’s not a reason for concern.
Narrowly Defined Placebos
As we’ve explained before, those making these claims are very strict in their definition of a placebo. They accept saltwater, or saline, as a placebo control, or another substance they say would be “inert” — but often don’t count similar controls that contain inactive ingredients to match aspects of the vaccine’s formulation but lack the antigen, which is the key part of the vaccine that the immune system responds to in order to generate protection.
These inactive ingredients can include surfactants to keep the vaccine well-mixed; stabilizers, preservatives or buffers to keep the vaccines safe and long-lasting; as well as trace ingredients leftover from the vaccine manufacturing process.
“Even though it’s not a saline placebo, it is considered a valid placebo,” Morris said.
In fact, perhaps the most famous placebo-controlled vaccine trial — the massive 1954 Salk polio vaccine trial — used a reddish liquid virtually identical to the one in the vaccine, but without killed polio virus, as a placebo. As the pediatrician Dr. Vincent Iannelli explains on his Vaxopedia blog, this was done to help keep participants and the people running the trial unaware of who got a placebo versus a real vaccine, or what’s known as blinding.
The varicella, or chickenpox, vaccine, was also tested against a placebo that contained a stabilizer and a trace amount of the antibiotic neomycin. The vaccine contains trace neomycin because it is made by growing weakened virus in cells and the antibiotic is used to prevent contamination. While most of the neomycin is removed in purification, a residual amount remains.
There is no evidence that this trace antibiotic causes any problems, except for rare individuals who are allergic, the University of Oxford’s Vaccine Knowledge Project explains. Even for those who are allergic, the risk is theoretical, the Children’s Hospital of Philadelphia notes, as minute amounts of antibiotics in vaccines “have never been clearly found to cause severe allergic reactions.”
“Studies involving approximately 11,000 children and adults followed for periods ranging from 2 to 12 years showed the vaccine to be safe and effective,” two FDA scientists wrote in the Journal of Pediatrics, explaining the agency’s decision to approve the chickenpox vaccine in 1995. “No severe side effects attributable to vaccination were reported in healthy recipients,” they added.
Continued safety monitoring — including a review of 22 years of postmarketing safety data — has borne out the overall safety of the chickenpox vaccine.
The two available rotavirus vaccines, which are given orally, also used solutions with various inactive ingredients as placebo controls when they were evaluated in randomized controlled trials.
Other Controls
Activists opposed to the childhood vaccination schedule also don’t accept controls that include adjuvants, which are ingredients that help the immune system respond to a vaccine and create a more protective response, sometimes lowering the number of needed doses or the amount of antigen. Adjuvants often cause temporary, local reactions, such as redness and swelling at an injection site, and therefore can be useful when a trial is blinded.
One of the issues with a saline placebo is that there usually isn’t any kind of typical, mild vaccine reaction, which could tip someone off that they received a placebo. If people know they received a placebo, they might alter their behavior, which could change their risk for the disease in question, or change their perception of any side effects.
Trials that use adjuvant controls isolate the effect of the vaccine’s active ingredient, or antigen, and determine if it is responsible for additional side effects, Johns Hopkins and the Children’s Hospital of Philadelphia explain. One commonly used adjuvant is aluminum, which groups such as Children’s Health Defense have long claimed is problematic. But the available scientific evidence does not indicate it is dangerous in the small amounts present in vaccines, as we’ve explained when reporting on such claims in the past.
“The way aluminum is processed is that the vaccine stays near the injection site and is released more slowly over time,” Charlotte Moser, co-director of the Vaccine Education Center at the Children’s Hospital of Philadelphia, told us. The prolonged exposure makes for a strong immune response, but does tend to cause pain, redness and inflammation at the injection site. Including the adjuvant in the control “makes the experiment more robust,” Moser said.
In other cases, other vaccines are used as a control, both to preserve blinding and because of ethical concerns.
“Often what you’re doing is comparing a new vaccine with an old vaccine,” Edwards said. If a vaccine against a particular pathogen already exists, it usually is unethical to withhold the vaccine. “Unvaccinated children can contract dangerous illnesses,” the American Academy of Pediatrics explains. “Parents of children in the placebo group would not know they didn’t get the vaccine and that their child is unprotected.” And in many cases, part of the scientific question is whether the new vaccine is at least as good as the old one.
Other vaccines may still be used as controls even with a new vaccine if it’s determined that doing so would be needed to provide some benefit to all participants.
The New York University medical ethicist Arthur Caplan and colleagues wrote in a July 2025 article published in EMBO Reports that placebo controls “are very rarely ethical in vaccine trials,” and only permitted if there is genuine uncertainty — or what researchers call equipoise — about the benefit of the vaccine.
The issue of placebos is particularly fraught with studies involving children. Although the FDA has not traditionally had its own guidelines for placebos in vaccine trials, it has issued specialized guidelines for medical products involving children, emphasizing that trials should “maximize benefit and minimize risk.”
The agency told us in 2023 that a “placebo control, such as saline, is not required to determine the safety (or effectiveness) of a vaccine” and that in some cases is “considered unethical.”
The use of an adjuvant or other vaccine as a control does not mean the vaccine hasn’t been sufficiently studied for safety, experts told us.
“The concerns being raised around the need for fully inert placebos aim to distract,” Moser said, adding that the “notion that companies are making vaccines and not testing them appropriately is completely unfounded.”
“Every childhood vaccine is studied extensively before licensing, and the FDA and its counterparts around the world have to agree to the study designs before those studies are even conducted,” Grabenstein said. “It’s up to the FDA to choose the acceptable comparator.”
When the FDA reviews a product, Grabenstein noted, regulators scrutinize the data by reviewing information on each study participant.
“You’re seeing a part of the tip of the iceberg,” he said of the information presented in a vaccine’s package insert. “Regulators have reviewed far more extensive original data.” (Grabenstein worked for Merck Vaccines for more than a decade. He said he has no financial ties to the company now.)
Before licensure of any major new vaccine, an independent committee of experts typically also advises the agency on whether to approve the vaccine; a similar process occurs within the CDC when the agency decides how approved vaccines will be used.
In an email, Bigtree objected to the notion of accepting non-inert placebo trials if the FDA allows them, saying “that this is what consumer advocacy groups like ICAN,” Bigtree’s nonprofit, “are for,” and going on to point to instances of FDA failures. He allowed that efficacy trials could use other controls, but said that for safety trials, the placebo must not have any pharmacological effect. “To establish a true safety baseline equivalent to a person receiving ‘nothing at all’, only a saline placebo is acceptable,” he said. “That is not my opinion, that is scientific fact.”
Bigtree also said that “virtually every independent expert who has evaluated systems like VAERS,” the CDC and FDA’s Vaccine Adverse Event Reporting System, “describes them as inaccurate, underpowered, and fundamentally unreliable,” although he still thought they could “yield meaningful studies … if there were any institutional appetite for transparency and honest inquiry.”
As we have explained before, VAERS is just one of several surveillance systems the government uses to monitor vaccine safety. While VAERS is passive, accepting voluntary, unverified reports of potential vaccine side effects, other systems are active, automatically collecting information at regular intervals. While no system is perfect, the surveillance systems have successfully identified problems with certain vaccines, which led to restrictions on or the removal of some from the market.
A placebo “can mean saline, and it can be something else considered inert. However, that would not include, for example, adjuvants,” a senior partner for Siri’s law firm said when we asked several questions about Siri’s statements in his presentation before ACIP. “Mr. Siri’s publicly available presentations and writings make plain the issues with post-licensure safety.”
HHS did not respond to a request for comment.
It’s worth noting that for some vaccines, placebo or other randomized controlled trials have also occurred after licensure. Activists’ claims about placebo-controlled trials often focus on pre-licensure studies, but studies done after U.S. approval are part of the overall evidence on a vaccine or general vaccine antigen.
Scientists “continue to study vaccines after they are licensed, and yes, controls are included,” Moser said.
Pneumococcal Vaccine
In his presentation before ACIP, Siri repeatedly claimed that childhood vaccines had been insufficiently tested for safety.
“The concern is that not one of them was licensed based on a inert, a placebo-controlled clinical trial,” he said, referring to the “standalone, routine, injected” childhood vaccines on the vaccine schedule. “Nor was any vaccine used as a control to license any of those vaccines licensed based on a placebo-controlled trial.”
As one key example, Siri highlighted the pneumococcal vaccine, noting that the current childhood pneumococcal vaccines were licensed based on trials with earlier versions of the vaccine, but that the first licensed vaccine — Prevnar 7 — had been tested against an investigational vaccine that had not yet been approved.
“That’s not an appropriate control. It does not establish a baseline of safety,” he said. Earlier in the meeting, he said that since Prevnar 7 was the first of its kind, “there was certainly no excuse to not use an inert control for that trial.” Siri, who has represented and advised Kennedy, has filed petitions on behalf of ICAN to pause distribution of vaccines or remove them from the market. He also said that the pneumococcal vaccine trial data “raises some very serious safety concerns.”
Scientists, however, told us there were ethical reasons for choosing an investigational vaccine as the control, and that safety was extensively studied.
“Subjecting what turned out to be half of more than 37,000 children to four injections — and these are infants and young children — with no potential benefit whatsoever was not ethical,” Dr. Steven Black, a pediatric infectious disease specialist and veteran vaccine clinical trialist who was involved in the original Prevnar trial, told us. The pneumococcal vaccine is given at 2, 4, 6 and 12 through 15 months of age.
The initial decision to use another vaccine as the control was his, he said, but when he presented the plan to the study’s Institutional Review Board, an independent committee that protects the rights and welfare of trial participants, he said the group “concurred that given the option of an active control vaccine that could provide benefit, that vaccinating so many children with four doses of saline was unethical.”
“We felt that by providing a control vaccine against meningococcal disease, for which there was not a vaccine in use in the United States at that time, would provide the potential of some protection for those infants,” Black said.
The decision to use an investigational vaccine was out of necessity.
“There was really a limited menu,” Black explained. “Most of the vaccines that you might have chosen were already recommended routinely,” preventing their inclusion as a control in a trial.
The team therefore chose a meningococcal vaccine that, like the pneumococcal vaccine, had been through phase 2 trials. Phase 2 is the step before the main, large trial, but after basic safety testing in phase 1.
Black, who is the co-director of the Global Vaccine Data Network, noted that following the Prevnar trial, the investigational vaccine was used in the U.K. during a meningococcal outbreak. “The U.K. felt comfortable with the safety data from the control,” he said.
Black said the safety assessment in the Prevnar trial “was the most extensive of any safety evaluation for a phase 3 trial that had been conducted in the United States prior to that.” Medical professionals looked each time a child in either vaccine group sought medical attention to see if there was a potential vaccine concern, he said, and any serious event was reported to the FDA.
“When the trial results were presented to the FDA review committee, the chair of the committee commented that in terms of the safety assessment, the bar had been raised by this trial for the conduct of future trials,” Black said.
The data safety monitoring board monitored all the safety events as they were occurring, Black added, and if there had been a cluster of events, the trial would have been unblinded. “We would have notified the FDA,” he said. “So we were not only looking at individual events, we were looking for patterns as well and didn’t see any.”
Additional safety data accrued in post-licensure studies of the original vaccine, as well as in the trials testing newer versions of the vaccine against its predecessors. Today’s pneumococcal vaccines for children target either 15 or 20 pneumococcal bacterial serotypes.
The vaccine, Black said, has been “extremely effective in reducing the risk of invasive pneumococcal disease in children” and indirectly has reduced carriage of the bacteria and disease in parents and grandparents. “The number of lives saved has been tremendous,” he said. “And serious confirmed safety concerns have not been identified despite millions of doses having been given.”
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