Estimation of the Effective Doses of Nasal-Inactivated Influenza Vaccine in Humans from Mouse-Model Experiments

Abstract

Mouse models of influenza play an important role in developing effective human influenza vaccines. We have demonstrated that intranasal immunization with inactivated subvirion (SV) vaccines, in conjunction with a cholera toxin B subunit adjuvant (CTB*), provides more effective cross-protection than parenteral immunization in BALB/c mice. In addition, the minimal effective dose of nasal vaccine for providing complete protection against a lethal influenza virus infection is 0.1 µg SV vaccine (containing about 30 ng hemagglutinin [HA]) (with 0.1 µg CTB*) in BALB/c mice (20 g body weight) immunized twice intranasally 4 weeks apart. The effective dose in humans can be estimated to be roughly 100 µg SV vaccine (containing approximately 30 µg HA) (with 100 µg CTB*)/20 kg body weight by using the dose/body weight ratio from actual vaccination trials. This estimation can be rationalized by the hypothesis that the distribution of strains (or individuals) in a mouse (or human) population, in relation to their HA antigen responsiveness, follows a normal distribution, and by the fact that BALB/c mice are intermediate responders for anti-HA antibody responses, and correspond to human intermediate responders, which form the largest population. We also discuss the use of innate immune responses, as well as antibody responses, in BALB/c mice to assess the efficacy of unknown adjuvants and the development of other adjuvants for nasal vaccines that should be clinically safer than CTB*.