candidates are developed using empirical approaches, historically running
the pathogen through a medium that substantially reduces its pathogenicity,
or killing or dissecting the virus after cultivation and using it with adjuvants,
or in multiple doses to prompt immune response.
37 More recent approaches
like “reverse vaccinology” start from genomic sequences and, by computer
simulation, predict those antigens that are most likely to be vaccine
38 Vaccine candidates are then tested in animals after developing
models for immunogenicity and safety.
After animal testing, a Zika vaccine sponsor would apply for
Investigational New Drug (“IND”) status from the FDA which authorizes the
sponsor to undertake clinical trials on humans for safety, efficacy, and,
licensure. Phase I trials are designed to assess the safety, immunogenicity
and dose-response of the vaccine in, typically, 20-100 healthy volunteers.
The IND application describes the vaccine, its method of manufacture and
quality control tests for release, information about the vaccine’s safety and
ability to prompt a protective immune response in animal testing, and the
proposed clinical studies protocol.
Phase II studies involve several hundred healthy volunteers and
investigators focus on safety as well as immunogenicity.
42 Phase II studies
focus on dose-ranges and vaccine components.
43 Phase III vaccine trials
enroll up to thousands or tens of thousands of human subjects in order to
detect sometimes rare adverse events.
44 In 1998, for example, a rotavirus
vaccine was licensed for use in the United States after phase III trials on
approximately 10,000 infants showed safety and efficacy.
45 However, when
administered to a larger population, physicians and researchers observed an
association between the vaccine and bowel obstruction.
46 If larger phase III
studies confirm safety and efficacy, the vaccine is approved for marketing
after additional review of study data.
37. Rino Rappuoli, Reverse Vaccinology, a Genome-Based Approach to Vaccine
Development, 19 VACCINE 2688, 2689 (2001) (illustrating conventional vaccine development
in Figure 1).
38. Id. at 2690.
39. Id. (including animal models as an essential feature of reverse vaccinology).
40. See FDA IND Content & Format Rule, 21 C.F.R. § 312.23 (2017).
41. Vaccine Product Approval Process, supra note 34.
45. See L. Simonsen et al., More on RotaShield and Intussusception: The Role of Age at
the Time of Vaccination, 192 J. INFECTIOUS DISEASES S36, S36 (2005).
47. NIH, FAQ - Clinical Trial Phases, U.S. NAT’L LIBRARY OF MED. (Jan. 1, 2001),
https://www.nlm.nih.gov/services/ctphases.html#top (last updated Apr. 18, 2008).