Vaccine Licensure in the United States

In the United States, the Animal and Plant Health Inspection Service (APHIS), a multifaceted agency of the U. S. Department of Agriculture (USDA), is responsible for regulating veterinary biologics (vaccines, bacterins, antisera, diagnostic kits, and other products of biologic origin) intended for the diagnosis, prevention, or treatment of animal diseases. For domestic manufacture, a facility license is required, along with a license for each product to be distributed. Imported products are issued a permit for sale and distribution. This work is done by APHIS’s Center for Veterinary Biologics (CVB).

Before the issuance of a license or permit, the manufacturer of a vaccine intended for sale and distribution within the United States must demonstrate, to the satisfaction of the USDA CVB, that the proposed product is pure, safe, potent, and efficacious. The facility in which the product is prepared must meet USDA standards and pass inspection by the CVB. After licensure, each batch of vaccine is subject to random premarketing testing by the CVB to verify the manufacturer’s quality assurance and quality control.

Purity assures the final product is free of extraneous microorganisms and extraneous material (organic or inorganic).

Safety is defined as freedom from properties causing undue local or systemic reactions when the vaccine is used as labeled. As part of the prelicense process, attenuated (live, whole agent) vaccines are evaluated in dogs to assess the potential of the vaccine organism to revert to virulence and the potential for dogs to shed the vaccine virus and/or bacteria. In addition, field safety studies are performed in a large group of dogs (typically at least 600), a substantial proportion of which must be at the minimum age indicated for administration. Post-marketing surveillance, including investigation of consumer complaints, is intended to identify relatively rare or uncommon safety issues that might not be detected in a prelicense field safety study. It should be noted that safety studies are not a guarantee that a vaccine, once released for sale, will be entirely free of risk.

Efficacy is the ability or capacity of the product to affect the result for which it is offered when the product is used according to its label. Vaccine efficacy is conventionally determined through defined vaccination-challenge studies conducted by the manufacturer. Although challenge methods and criteria for evaluating protection will vary with the immunizing agent, tests are generally conducted under controlled conditions using seronegative dogs of the youngest age recommended on the label.

Potency is the relative strength of a biologic product as determined by test methods approved by the CVB. Potency testing is intended to assure that each serial (batch) of vaccine marketed is equal to, or more potent than, a defined reference serial of known efficacy.

Duration of Immunity (DOI) is noted here due to its interest to practitioners. However, the definition of the term is often interpreted differently in different contexts. The CVB views DOI as confirming, typically by a vaccination-challenge study, that the immunity conferred by the product lasts at least as long as indicated on the label. Practitioners may view these studies as confirming efficacy at a specified point, rather than a demonstration of the maximum reasonable duration of immunologic protection conferred to patients.

Traditionally, vaccine challenge models were intended to demonstrate the onset of immunity in younger dogs using products titrated to the minimum protective dose. These products typically carried the historically based label recommendation for annual revaccination. Therefore, for most of the canine vaccines licensed in veterinary medicine, the CVB has not required manufacturers to conduct DOI studies, unless making a specific claim differing from 1 yr. Current CVB policy requires manufacturers to conduct DOI studies for all rabies vaccines and all new (novel) antigens, regardless of the revaccination interval.

Conditional Licensure

The time to market for a new vaccine can be several years. The USDA utilizes a pathway called conditional licensure to speed the availability to veterinarians of vaccines that address unmet needs, emergencies, or other special circumstances. In this process, a manufacturer is required to demonstrate that the product is safe, pure, has a reasonable expectation of efficacy, and that it is manufactured in compliance with standard USDA regulations. The USDA typically places time limits on such a license, during which the manufacturer must provide data to fully demonstrate efficacy or appropriate progress toward so doing. The USDA requires distinctive labeling to differentiate those products marketed under a conditional license, and the label must state that the product is conditionally licensed. The DOI of a conditionally licensed vaccine has not been confirmed by a vaccination challenge study at the time the product is released for sale in the United States.

Vaccine Licensure in Canada

The Canadian Food Inspection Agency (CFIA), under the legislative authority of the Health of Animals Act and Regulations, is responsible for regulating veterinary biologics in Canada. This regulatory program forms an integral part of Canada’s National Animal Health Program, which strives to protect the health of food-producing animals, domestic pets, wildlife, and the Canadian public, as well as to safeguard the environment by preventing the introduction and spread of infectious animal diseases. Responsibilities of the CFIA in licensing vaccines for use in veterinary medicine include:

  • Licensing of veterinary biologics, including verification of master seeds and prelicensure product evaluation
  • Licensing of veterinary biologics manufacturing facilities
  • Issuance of import and/or export permits to Canadian importers and/or exporters of veterinary biologics
  • Post-licensure monitoring, including:
    • serial release monitoring of veterinary biologics for purity, potency, and safety
    • investigations of consumer complaints
    • inspections of manufacturers and Canadian importers of veterinary biologics
  • Scientific research in support of regulations
  • Technology development, including collaborative research with industry partners

The standards for licensure of any veterinary vaccine in Canada are similar to those required in the United States. Regulated products include vaccines, immunoglobulin products, and diagnostic kits that are used for the prevention, treatment, or diagnosis of diseases in animals, including domestic livestock, poultry, pets, wildlife, and fish. To meet the requirements for licensure, veterinary biologics must be shown to be pure, potent, safe, and effective when used in the target species according to the manufacturer’s label recommendations. In addition, the licensing submission must also contain supporting data demonstrating that the product can be manufactured and used without adversely affecting animal health, human health, food safety, or the environment.