Barbara J. Kuter, PHD, MPH 

“What’s in that vaccine?” “Is it safe?” “How was it made?” “How many children previously received this vaccine?” “How was it tested?” These are questions that most pediatricians and family physicians receive every day. This article aims to help clinicians answer these tough questions by providing more information on how vaccines are developed, manufactured, and evaluated in the United States, both before and after licensure by the US Food and Drug Administration (FDA).

The production and evaluation of vaccines is highly regulated by the FDA and other regulatory agencies around the world. Regulation of vaccines in the United States began more than 100 years ago and has developed into a comprehensive framework for vaccine development. The lack of standardization in the preparation of diphtheria antitoxins, which resulted in several deaths, led the US Congress to first adopt the Biologics Control Act of 1902.

Regulating vaccines and biologics, initially overseen by the National Institutes of Health, became a part of the FDA in 1972. The Center for Biologics Evaluation and Research, established by the FDA in 1987, has rigorously evaluated the use of vaccines in the United States for the last 35 years.

The details of vaccine evaluation are well documented in the Code of Federal Regulations (Title 21), and FDA guidance documents that form the “Bible” for vaccine manufacturers (known as sponsors) to follow.

 The guiding principles for vaccine evaluation can be summed up in 3 words––safety, efficacy, and quality. The benefits of any vaccine must far outweigh its risks for it to be licensed, especially when we appreciate that most vaccines, unlike drugs, are administered to millions of healthy children and adults. “Vaccines are among the most carefully evaluated medical products.”

Vaccine development often starts as a collaboration between academia and industry, but later-stage development requires the resources and expertise of the pharmaceutical industry. Key examples of collaboration include the development of a rotavirus vaccine with Children’s Hospital of Philadelphia and a human papillomavirus (HPV) vaccine with Australian researchers, both in the 1990s, and more recently, COVID-19 vaccines with numerous academic teams, including the National Institutes of Health. Vaccine development first begins in the laboratory, where the goal of basic research is to understand the complex interactions between pathogens and their human hosts and to generate the knowledge and technology essential for developing a vaccine candidate.

 In advancing the development of a vaccine candidate, scientists build on the extensive research accumulated from the development of more than 80 vaccines currently licensed in the United States and elsewhere while also accessing new technological advances, including improvements in adjuvants and the development of mRNA technology, used in several COVID-19 vaccines.

Before any vaccine is tested in humans, preclinical research, involving animal studies (eg, with rodents or nonhuman primates) and/or in vitro testing is required. These studies help to identify the approximate dose(s) and route of administration that might be safe and immunogenic in humans as well as providing important toxicology data.

 Many vaccine candidates never make it into humans because of safety concerns or failure to elicit the necessary immune response at this early stage of testing. 

For promising vaccine candidates, an important meeting with the FDA, called a pre-IND (Investigational New Drug) meeting, is held to discuss the details of the proposed manufacturing process, animal and laboratory data, clinical study design for the first clinical trials, and compliance with regulations.

 If the FDA is in general agreement with the data and plans, a formal IND application is submitted by the sponsor that includes this information. The FDA has 30 days to review the application and either approve or reject it, or request additional information or studies. Importantly, the FDA determines whether study participants could be exposed to any unacceptable risks.

Once an IND has been approved, the first human trial is initiated in a small number (perhaps 20-100) of healthy adults. Even when a vaccine is ultimately recommended for routine use in children, the FDA requires that the safety and immunogenicity of the vaccine be evaluated in adults first.

All human studies are required to be conducted under Good Clinical Practice (GCP) regulations established by the FDA as well as the Declaration of Helsinki, a statement of ethical principles for medical research first written in 1964.

The safety and human rights of study participants are rigorously enforced in every clinical trial through well-defined processes for informed consent, study oversight, and protection of privacy.

Safety is the first and most important element of any clinical trial. Each study is carefully monitored for any safety concerns by the sponsor, FDA, the Institutional Review Board, and often an independent Data and Safety Monitoring Board. Serious and unexpected safety findings are required to be reported to the FDA under strictly prescribed timelines, usually within days of their coming to light, and the FDA may ask the sponsor to pause enrollment while it reviews safety data. Routine safety evaluations, including comparing vaccine versus placebo, are incorporated into study protocols based on study milestones (eg, after a prespecified number of participants are vaccinated or all participants complete a particular dose). For example, in a phase 1 trial it would be standard practice to review all local and systemic reactions after the first 10 participants complete 1 to 2 weeks of safety follow-up after receiving the first vaccine dose. A second dose would not be administered if a safety signal was identified after dose 1. Careful, stepwise evaluation of safety is critical, especially when the vaccine dose has yet to be established or when the vaccine is first administered to vulnerable populations, including infants, children, elderly individuals, and immunocompromised individuals.

As studies progress to phases 2 and 3, more data are gathered on the safety, immunogenicity, and efficacy of the vaccine in a larger number of individuals, often through randomized, double-blind, controlled trials. With larger sample sizes, the chance to identify less common adverse events increases. Most vaccines have been required to have a prelicensure safety database of at least 3000 participants vaccinated with the dosing regimen intended for licensure.

Assessment of safety in 3000 individuals allows for a 95% chance of detecting the occurrence of more common adverse events in 1 in 1000 participants (the “rule of 3”).

 The COVID-19 trials for mRNA vaccines for adults were considerably larger (>15,000 and >13,000 vaccine recipients followed for safety); subsequent studies to authorize use in 6 months to 4 to 5 year olds involved several thousand children followed for a median of 2 months.

 Clinical trials for other vaccines have included safety data on more than 5900 infants for the pentavalent DTaP, IPV, Hib–combination vaccine, more than 7000 infants and toddlers for 3 pneumococcal conjugate vaccines, and more than 15,000 children and young adults (8-26 years) for 3 HPV vaccines.

The FDA may request a larger safety database if a possible safety signal is identified or in response to new information from other vaccines. Such was the case in the clinical development of 2 rotavirus vaccines currently licensed in the United States, RotaTeq and Rotarix, for which considerably larger trials (70,000 and 63,000 participants, respectively) were required to evaluate the potential to cause intussusception, a serious and life-threatening condition found in postlicensure evaluation of an earlier vaccine, RotaShield, that was later withdrawn from the US market.

Studies in young children, for whom many vaccines are ultimately targeted, generally do not start until safety and immunogenicity have been well established in adults. Careful age de-escalation and dose-escalation studies are usually required for pediatric trials as the dose needed is likely to be lower than that for adults. Several vaccines, including for COVID-19 and HPV, were licensed first for adults before being approved in children or adolescents.

Once the key clinical trials have been completed and vaccine safety and efficacy have been demonstrated, the sponsor compiles all preclinical, clinical, and manufacturing data into a standard format, called the Common Technical Document, used by major regulatory agencies. Most files are submitted as a Biologics License Application (BLA), but in public health emergencies, such as the recent SARS-CoV-2 pandemic, an Emergency Use Authorization (EUA) may be filed first followed by a BLA. Both require demonstration of adequate safety and efficacy, but the EUA allows acceleration of vaccine availability. The typical FDA review time for a BLA is 10 to 12 months; demonstration of an unmet medical need may shorten the review time to 6 months. Time to actual approval is often longer depending on the time it takes for the sponsor to address questions from the FDA, do more testing, and/or agree on the wording of the package circular. 

In order for a vaccine facility to be licensed, the sponsor must define and demonstrate a consistent and reliable manufacturing process. All manufacturing must be conducted in accordance with Current Good Manufacturing Practices (CGMPs) and other applicable laws and regulations.

Specifications for potency, sterility, purity, and other in-process testing of each vaccine lot are established and must be adhered to for all doses released. Two key elements required prior to licensure include demonstration of a consistent process and a successful FDA inspection. Process equivalence is confirmed through the manufacturing of 3 to 5 full-scale vaccine lots that meet all predefined manufacturing and testing criteria. The FDA conducts a thorough inspection of the facility with focus on review of the quality of manufacturing procedures, including records, staff training, facility operations, vaccine production and testing, and the systems in place to ensure product quality.

 In 2021, the FDA played a key role in ensuring that a COVID-19 vaccine that did not meet quality standards was not distributed from a proposed vaccine manufacturing facility.

Once a vaccine has been licensed, the FDA may do its own testing before each vaccine lot can be released. The FDA will also inspect the facility at routine intervals, often through unannounced “Team Bio” inspections every 1 to 2 years. Most issues are usually readily resolved. The sponsor recognizes that failure to demonstrate that the process and facility are constantly under control can rapidly result in either suspension of vaccine production until the concerns are remediated or a license being withdrawn.

Additional studies and continued safety evaluation in the postlicensure period

Although the public health community and the sponsor may be very excited when a product has been approved, vaccine evaluation does not stop there. As part of the FDA’s authorization or approval of a vaccine, the sponsor is usually required to conduct more studies (as postlicensure commitments) to gain additional data on vaccine safety, efficacy, and/or quality. This often includes collection of more safety data as a vaccine is used in routine clinical practice. Studies may be carried out to affirm or refute possible safety signals (as is being done with COVID-19 vaccines and myocarditis) or to assess use in more diverse populations (including immunocompromised or younger children). Studies may also assess the duration of vaccine-induced immunity, real-world effectiveness, or extension of the product’s shelf life. 

Evaluation of vaccine safety continues throughout the life of the product through several methods, both passive and active. Some assessments are performed by the sponsor while others are performed by the Centers for Disease Control and Prevention (CDC)and/or FDA. Sponsors are required to collect reports of any adverse events in the postlicensure period and submit them to regulatory agencies on an annual basis (with reports as frequent as monthly shortly after licensure). These reports summarize any new, serious, or unexpected adverse reports not already identified in the package circular. These data are routinely reviewed by the sponsor and FDA, and either party may make a change in the circular as a result of this review.

Two other key sources of data on vaccine safety include the Vaccine Adverse Event Reporting System (VAERS) and the Vaccine Safety Datalink (VSD).

 VAERS is a national passive surveillance (spontaneous reporting) system for adverse events after immunization administered jointly by the FDA and CDC. VSD is a collaborative project by the CDC Immunization Safety Office and 9 US health care organizations that conduct studies about rare and serious adverse events following immunization in large populations. In rare cases, a review of these data has resulted in a product being withdrawn from the market by the manufacturer. An example of this was the Advisory Committee on Immunization Practices (ACIP) 1999 withdrawal of its recommendation to vaccinate infants with RotaShield after intussusception was first identified as a rare adverse event in VAERS; this was followed by the voluntary withdrawal of the vaccine by the sponsor from the US market.

The information in this article may help health care personnel to talk with parents and patients more confidently about the rigorous evaluation and manufacturing of vaccines as well as the important role that FDA plays in the process. Confidence in the safety and efficacy of vaccines is crucial in preventing disease and saving lives. 

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Articles

This article discusses the process of vaccine development, and how health care personnel can confidently discuss the subject with parents and patients.

Barbara J. Kuter, PHD, MPH

Articles

Vaccine development: What every pediatrician should know