Vaccine development

ABSTRACT

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 past 35 years.1,2 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.3 The guiding principles for vaccine evaluation can be summed up in 3 words-safety, efficacy, and quality. 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.5 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.6-8 Preclinical testing in nonhumans 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. 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 1964.11,12 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. Most vaccines have been required to have a prelicensure safety database of at least 3000 participants vaccinated with the dosing regimen intended for licensure.13 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").14 The COVID-19 trials for mRNA vacci nes for adults were considerably larger (> 15,000 and > 13,000 vaccine recipients followed for safety);subsequent studies to authorize use in children aged 6 months to 4 to 5 years involved several thousand children followed for a median of 2 months.7,8,15,16 Clinical trials for other vaccines have included safet y data on more than 5900 infants for the pen-tavalent DTaP, IPV, Hib-combina-tion 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.17-19 The FDA may request a larger safety database if a possible safety signal is identified or in response to new information from other vaccines.