Advanced Development of the rF1V and rBV A/B Vaccines: Progress and Challenges

Table 4

Vaccine program status for meeting the requirements of the FDA Animal Rule.

Animal Rule	rBV A/B	rF1V
Requirement 1: well understood pathophysiology and amelioration	The published literature has shown that generation of neutralizing antibodies against BoNT provides protection against inhalational botulism.	The published literature has shown that the F1 and V antigens from Y. pestis can provide protection from pneumonic plague.
	Pathophysiology following aerosol exposure of CD-1 mice and rhesus macaques is comparable to the pathophysiology of disease in humans.	Pathophysiology following aerosol exposure of Swiss Webster mice and CMs is comparable to the pathophysiology of disease in humans.
	Vaccination with rBV A/B elicits a humoral immune response in mice and macaques that provides protection against exposure to aerosolized neurotoxins.	Vaccination with rF1V elicits a humoral immune response in mice and macaques that provides protection against exposure to aerosolized Y. pestis.
Requirement 2: effect is demonstrated in more than one species	The mouse and macaque models have immune responses to vaccination with rBV A/B that are similar to the response in humans. Data obtained to date indicate that vaccination induces neutralizing antibody titers believed to be protective in tested species.	The Swiss Webster mouse and cynomolgus macaque models have immune responses to vaccination with rF1V that are similar to the response in humans. Data obtained to date indicate that antibody titers to F1 and V are induced in tested species.
Requirement 3: the animal study endpoint is related to the desired benefit in humans	Nonclinical efficacy study endpoints measure survival against an aerosol challenge, which is the desired benefit in humans.	Nonclinical efficacy study endpoints measure survival against an aerosol challenge, which is the desired benefit in humans.
Requirement 4: data allows selection of an effective dose in humans	The mouse toxin-neutralizing antibody assay (MNA) provides a species-neutral assay for quantitating the level of neutralizing antibodies.	The Bridge ELISAs are in development as species-neutral assays that permit direct comparison across samples from different species.
	The neutralizing antibody concentration (NAC) determined by the MNA is under evaluation as a correlate of protection.	Bridge ELISA, macrophage cytotoxicity assays, and passive transfer studies are under evaluation for correlation with protection.
	Passive transfer assesses the protective capacity of antibodies present in vivo at the time of aerosol challenge. This is under development as a model to assess the protective capacity of transferred immunoglobulin from human vaccines.	Passive transfer assesses the protective capacity of antibodies present in vivo at the time of aerosol challenge. This is under development for consideration as a model to assess the protective capacity of transferred serum from human vaccines.