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Last Monday’s newsletter about randomized controlled trials in vaccine development generated fascinating discussion and important questions from our readers. Many of you reached out with specific concerns that deserve a thorough response. Let's address the main points of feedback:

Your Comments:

• "Vaccines aren't always compared to saline placebos – they're sometimes compared to other vaccines. This seems problematic."

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• "The COVID vaccine trials were unblinded after just a few months. Doesn't this invalidate the results?"

• "Where's the evidence that childhood vaccines went through proper RCTs? Show us the historical data."

• "Vaccine inserts state they weren't tested for cancer risks and other long-term outcomes. How can you claim proper safety testing?"

These are excellent questions that get to the heart of how vaccine trials are designed and conducted. Let's break down each one.

Understanding Placebos and Controls in Vaccine Trials

Not all placebos are created equal – and for good reason. In vaccine trials, researchers use three main types of control groups:

1. Inert (True) Placebos- These are typically saline solutions containing no active ingredients. They're the gold standard for testing completely new vaccines or vaccine technologies. When the first mRNA COVID vaccines were tested, they used saline controls because this was a novel technology requiring the clearest possible safety data.

2. Active Placebos- These contain some vaccine components (like aluminum adjuvants) but not the actual antigen that creates immunity. They help researchers understand whether side effects come from the antigen itself or other vaccine ingredients. Think of it as isolating variables in a scientific experiment.

3. Comparator Vaccines- Here's where it gets interesting – and where some of you expressed concern. Sometimes researchers use existing licensed vaccines as comparators instead of placebos. But this only happens in specific circumstances where there is already a standard-of-care option, and after initial safety is established.

Understanding these different control groups is essential because they each serve distinct scientific purposes. While saline placebos show us the total effect of a vaccine compared to no intervention, active placebos and comparator vaccines help us answer more specific questions: Is this new component safe? Is this new vaccine at least as good as what we already have? The choice of control group reflects both our existing scientific knowledge and our ethical obligations to study participants.

Why Use Comparator Vaccines?

The reason comes down to medical ethics. Once a safe and effective vaccine exists for a disease, it becomes ethically questionable to give study participants a placebo, effectively leaving them unprotected. This principle is outlined in the Declaration of Helsinki, which sets ethical guidelines for medical research. In such cases, scientists can propose alternative controls—such as another approved vaccine—which regulatory authorities then evaluate for suitability. These studies are still rigorously scrutinized by regulators and designed to be statistically robust, ensuring reliable results regardless of the type of control used.

For example: If we're testing a new measles vaccine, giving half the children a saline placebo would leave them vulnerable to a potentially deadly disease when a proven vaccine already exists. Instead, researchers compare the new vaccine to the current standard to prove it's at least as safe and effective (i.e. demonstrate noninferiority).

An expert panel from the World Health Organization notes that there are specific circumstances where using a saline placebo in a vaccine trial is ethically and scientifically sound, even if an effective vaccine already exists:

• When determining the local burden of disease

• When an existing vaccine is not appropriate locally (as determined by epidemiologic or demographic factors, such as the cost of a vaccine)

• When developing a vaccine that is locally affordable

• When investigating the local safety and efficacy of an existing vaccine

The Development and Testing of HPV Vaccines - Understanding Comparator Choice

A systematic review of 24 clinical study reports reveals how and why modern vaccine trials use comparator vaccines instead of saline placebos. The HPV vaccine trials, which included 95,670 participants, made specific choices about control groups for scientific and ethical reasons:

Nearly all control participants (48,289 of 48,595, 99%) received active comparators rather than saline placebo. This design choice reflects several key scientific and ethical principles:

• The aluminum adjuvant system was already proven safe and necessary for the vaccine to work, so testing focused on the HPV-specific components

• Using similar adjuvants in the control group allowed researchers to isolate the effects of the HPV components while controlling for known adjuvant effects

• Using comparator vaccines like hepatitis vaccines provided a rigorous control group (similar injection schedule, known safety profile) while giving participants protection against another disease

• This design maintained proper blinding through similar injection site reactions, ensuring reliable data collection

The key point is that using comparator vaccines doesn't reduce safety monitoring - it actually helps researchers better understand the specific effects of the new vaccine components while building on established safety data.

The COVID Trial Unblinding Discussion

Several readers expressed concern about the unblinding of COVID-19 vaccine trials. This decision, while controversial, followed established ethical principles. Once clear statistical evidence showed the vaccines were both safe and effective, researchers faced an ethical imperative to offer the vaccine to placebo group participants – many of whom were healthcare workers at high risk.

This follows the principle of "equipoise" in medical research: once we have clear evidence that one treatment is superior, we have an ethical obligation to offer it to all participants, especially those at the highest risk of poor outcomes.

Concluding that every evaluation of a vaccine must contain a saline placebo opens the door for unnecessarily risking the health and safety of those participating in a clinical trial. Leaving patients intentionally untreated or undertreated when there is a known treatment or vaccine to compare against is unethical. As Dr. David Gorski puts it:

“The only time that a placebo-controlled RCT of a vaccine can be ethically justified is when there currently does not exist a safe and effective vaccine against the disease for which the experimental vaccine has been designed.”

As such, there are many cases where this criteria is not met, and the ethical conduct of research requires that we not leave research participants completely untreated when it is not absolutely necessary.

When unblinding is a consideration, we must strike an ethical balance in vaccine trials by prioritizing vaccination for those at the highest risk while maintaining opportunities for lower-risk participants to remain in placebo groups. During the COVID-19 vaccine trials, once the vaccine was authorized for emergency use, participants in the placebo group who were at high risk were offered the opportunity to receive the vaccine outside of the trial. This approach addressed the ethical obligation to provide access to a potentially life-saving intervention for vulnerable populations, ensuring that no participant was denied timely protection against a serious disease.

To preserve the integrity of the trial, many studies implemented a "crossover" design, allowing placebo participants to receive the vaccine while still being monitored under the same study protocol. This ensured that researchers could continue collecting valuable data on long-term safety and efficacy across both groups. In balancing these ethical and scientific considerations, COVID-19 vaccine trials not only protected high-risk individuals but were also able to continue investigating the vaccine's performance.

This crossover design raised some challenges for the continued assessment of the efficacy and safety of the vaccines while maintaining the integrity of the study in the absence of a true placebo, but this was overcome in several ways:

1. Crossover was blinded so that vaccine durability and long-term efficacy could continue to be measured against a valid control, with sophisticated statistical modeling accounting for the timing of crossover and vaccination status.

2. Trials were subject to continued efficacy and safety monitoring by independent Data and Safety Monitoring Boards (DSMBs) and a combination of active and passive surveillance systems.

3. The combination of real-world evidence and data from immunological assays allows researchers to continue to understand long-term efficacy in the absence of placebo groups.

4. Large sample sizes (>30,000 participants in major trials) maintained statistical power above 90% even after accounting for crossover effects.

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Historical Evidence of Childhood Vaccine RCTs

Many readers asked for evidence that childhood vaccines underwent proper randomized controlled trials (RCTs). Here's the historical data, tracking how vaccine testing evolved from early saline-placebo studies to modern trial designs:

Polio Vaccine (1954) - Setting the Standard

Participants:

• 623,972 children received vaccine or saline placebo

• Additional 1+ million children as "observed controls"

Design: True double-blind RCT with saline placebo

Results:

• 80-90% effective against paralytic polio

• No unexpected side effects

Impact: Cases dropped from 58,000 (1957) to 161 (1961)

Measles Vaccine (1968) - Multiple Vaccine Comparison

Participants: 444 children total

• Children in the vaccine group were divided into four subgroups, each receiving one of the four different vaccines.

• The remaining children were assigned a saline placebo

Design: RCT comparing four vaccines against saline placebo

Results:

• Strong immune response in vaccine groups

• Low adverse event rates

• Safe and effective compared to placebo

Impact (2000-2003): prevented 60 million deaths globally.

Rotavirus Vaccine - Modern Trial Design

2009 Rotavirus Efficacy and Safety Trial (REST)

The development of rotavirus vaccines has been backed by large-scale controlled trials that demonstrated both their safety and efficacy. One of the most extensive and thorough trials was published in 2009.

Participants: 69,589 infants were assigned a pentavalent human–bovine reassortant oral rotavirus vaccine or placebo (matching liquid formulation without the active vaccine components)

Design: Blinded, placebo-controlled RCT

Results:

• Strongly effective against rotavirus

• No difference in adverse reactions between placebo and vaccine groups

• Safe and effective compared to placebo

Impact (2009-2019):

• 143 million children vaccinated

• Prevented 18.7 million severe cases

• Avoided 153,000 deaths

2020 P2-VP8 Subunit Rotavirus Vaccine Trial - Modern Use of Saline Placebo

A recent trial with saline placebo demonstrated the continued value of true placebo controls when ethically appropriate:

Participants: 30 adults, 30 toddlers and 557 infants were assigned a trivalent P2-VP8 subunit rotavirus vaccine or saline placebo

Design: True double-blind RCT with saline placebo

Results:

• Strong immune response in vaccine group

• No difference in adverse reactions between placebo and vaccine groups

• Safe and effective compared to placebo

Early Development and Licensure of Pertussis Vaccines

The history of pertussis vaccination provides important context for understanding how vaccine testing and licensure requirements have evolved. The first pertussis vaccines were licensed in 1914, in an era with very different regulatory standards than today. Initial licensure was based primarily on basic safety monitoring and evidence of immune response, rather than the comprehensive clinical trials we now require.

In the 1940s, controlled efficacy trials demonstrated that 4 doses of whole-cell DTP vaccine were 70-90% effective at preventing serious pertussis disease. The vaccine's impact was dramatic: cases dropped from over 200,000 annually in the pre-vaccine era to just 15,000 by 1960. By 1970, annual incidence had fallen to fewer than 5,000 cases.

However, concerns about side effects from whole-cell vaccines led to the development of more purified acellular pertussis vaccines in the 1990s. This development was informed by two pivotal Swedish trials described below.

Pertussis Vaccine Development and Evidence

Historical Context (1914-1945):

• Pre-vaccine era: Over 200,000 cases reported annually

• 1914: First whole-cell pertussis vaccine licensed

• 1940-1945: More than 1 million cases reported (averaging over 170,000 cases per year)

• Disease burden: ~150 cases per 100,000 population

Early Efficacy Evidence (1940s-1960s) and Further Developments (1970s-1990s):

• 1948: Combined DTP vaccine introduced

• Controlled efficacy trials showed 70-90% effectiveness with 4-dose series

• By 1960: Cases dropped to 15,000 (8 per 100,000 population)

• By 1970: Further reduced to <5,000 cases annually

• 1980-1990: Average of 2,900 cases per year (1 per 100,000)

• 1991: The DTaP vaccine, which is acellular and causes fewer side effects than DTP, is licensed

Modern Clinical Trials (1988 Swedish Trial):

The first major trial of acellular pertussis vaccines used a placebo* control group, as the vaccine technology was new:

• 3,801 children randomized

• 954 received placebo (vaccine solvent)

• 1,419 received two-component vaccine

• 1,428 received LPF-toxoid vaccine

• Results: Both vaccines ~80% effective

*While it's reasonable to infer that the "vaccine solvent" mentioned in the 1988 pertussis trials refers to a saline solution, without direct access to the trial protocols or detailed reports, this cannot be confirmed with absolute certainty.

The transition from whole-cell to acellular pertussis vaccines illustrates how vaccine trials adapt to advancing science. The 1988 Swedish trial used a placebo because the acellular technology was completely new. Once that trial established basic safety, later studies could focus on comparing the new acellular vaccines to existing whole-cell vaccines - allowing researchers to determine if the new technology provided similar protection with fewer side effects. This shows how trial design evolves to answer the most relevant scientific questions at each stage of vaccine development.

Swedish Comparative Trial:

Following the success of the first trial, subsequent studies compared the new acellular vaccines to existing whole-cell vaccines rather than placebos - an ethical necessity since withholding proven vaccination would have left participants vulnerable to a serious disease:

• 9,829 children total

• 7,255 received acellular DTP

• 2,574 received whole-cell DTP

• Results: Five-component acellular vaccine showed 77.9% efficacy

Recent innovations continue to be evaluated with true saline placebos when ethically appropriate. For example, in 2014, the first placebo-controlled trial of BPZE1, a novel live attenuated intranasal pertussis vaccine, demonstrated both safety and immunogenicity in healthy adults.

Recent Innovation (2014): BPZE1 Live Attenuated Vaccine Trial

• First saline placebo-controlled trial of new pertussis vaccine technology

• Double-blind study design

• Demonstrated safety and successful colonization in a dose-dependent manner

• 100% seroconversion in colonized participants

From the groundbreaking polio trials of the 1950s to modern pertussis innovations, this historical evidence demonstrates that childhood vaccines have consistently been tested through rigorous controlled trials - using saline placebos when ethically appropriate, and equally rigorous comparative controls when existing vaccines made placebos unethical.

Addressing the Package Insert Argument

Many readers pointed out that vaccine package inserts don't list testing for cancer risks and other long-term outcomes. This reflects a misunderstanding of how safety monitoring works. This is because vaccine trials aren't designed to directly test for cancer risk because the biological mechanism of vaccines doesn't support plausible carcinogenic effects

Here's why: Vaccines work by introducing specific protein antigens or inactivated pathogens that are cleared from the body within weeks. Unlike chemical carcinogens that can cause DNA mutations or persistent biological changes, vaccine components don't remain in the body long-term or interact with cellular DNA. The immune response they generate is similar to what occurs during natural infection, but in a controlled, less dangerous way. Furthermore, the aluminum adjuvants used in some vaccines are largely eliminated from the body within weeks and have been extensively studied for long-term safety. A few other reasons include:

• Cancer typically takes decades to develop, making it impractical for pre-approval trials

• Instead, we have robust post-market surveillance systems (VAERS and VSD to name just a couple!) that monitor for any unusual patterns of disease, including cancers

• Population studies have repeatedly shown no increased cancer risk in vaccinated populations

The aluminum adjuvants used in vaccines have been extensively studied for their safety and clearance from the body. Research has shown that although aluminum is a ubiquitous element in the environment, the small amounts used in vaccines as adjuvants (frequently aluminum hydroxide or aluminum phosphate) are well understood pharmacologically. Studies demonstrate that aluminum from vaccines and diet throughout an infant's first year of life is significantly less than corresponding safe body burden levels established by regulatory agencies. The aluminum is eliminated from the body through normal processes - primarily in the urine, with small amounts being incorporated into bone formation during rapid growth and development. The half-life of aluminum in soft tissues like the liver is short (<2 days), indicating very little accumulation in these organs.

It's important to understand that vaccine package inserts are primarily legal documents required by regulatory authorities, not comprehensive scientific reviews. Their primary purpose is to provide prescribing information and document what was specifically tested in pre-licensure trials, rather than to summarize all available safety evidence. Post-marketing surveillance and epidemiological studies often provide much broader evidence about long-term safety outcomes.

This evolution in vaccine testing reflects growing scientific sophistication. While early vaccine trials relied on simple saline comparisons because everything about the vaccines was novel, modern trials build upon established safety data about components like aluminum adjuvants. This allows researchers to focus their investigations more precisely on new elements while maintaining rigorous safety standards. Far from lowering standards, this progression represents increasingly sophisticated scientific questions backed by accumulating evidence.

The Testing Progression

To put it all together, here's how vaccine testing typically progresses:

1. New Vaccine Technology:

• Starts with true saline placebo trials

• Must establish basic safety before any other comparisons

2. Iterations of Proven Technology:

• May use active placebos or comparator vaccines

• Only after the platform's basic safety is established

3. Competing Products:

• Often compared to existing licensed vaccines

• Must first demonstrate basic safety or have done so in previous studies

• Focus on proving "non-inferiority" to existing options

This systematic approach to vaccine testing has evolved over 70 years, with each new vaccine benefiting from previous research. Understanding this progression reveals how modern vaccine trials make evidence-based choices about control groups while ensuring thorough safety testing. The key principles remain constant:

• New technologies start with the most basic comparisons (saline placebos)

• Proven platforms build on established safety data

• Ethics and science work together to protect both study participants and future vaccine recipients

• Multiple layers of safety monitoring continue long after approval

This careful balance of scientific rigor and ethical responsibility has given us vaccines that are among the most thoroughly tested medical interventions in history.

Stay curious,

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Dr. Jessica Steier is a public health scientist with expertise in public health policy, biostatistics, and advanced analytics. Dr. Sarah Scheinman is a Chicago-based neurobiologist with expertise in basic science, preclinical, and translational biomedical research. Her primary focus is on the molecular mechanisms of aging and neurodegenerative diseases, but she also has subject-matter expertise in cell biology, genetics, epigenetics, and psychology.