Temperature-Sensitive Mutants of Influenza Virus. II. Attenuation of ts Recombinants for Man

Abstract

Recombinant viruses were produced that contained the surface H3 antigen of influenza A/Hong Kong/1968 (H3N2) virus and a temperature-sensitive (ts) lesion derived from a ts mutant of influenza A/Great Lakes/1965 (H2N2) virus. Three recombinants, each bearing a genetically distinct ts lesion, were administered intranasally to volunteers who lacked serum neutralizing antibody for the H3 hemagglutinin. The ts recombinants exhibited a decreased virulence for man, but the level of attenuation varied. One of the recombinants, ts-l [E], appeared to possess the degree of attenuation desirable for a virus to be used in a live vaccine. The majority of men who were infected by the ts-l [E] recombinant did not develop symptoms. Those symptoms that did occur were mild. Infection with the ts-l [E]recombinant was extensive enough, however, to stimulate moderate levels of serum and nasal neutralizing antibodies and to induce complete resistance to influenzal disease produced by challenge with a virulent wild-type virus. The ts-l [E] recombinant was genetically stable in man and failed to spread from infected individuals to susceptible cohorts who were in close contact. The use of a ts lesion that imposes a defined and desirable degree of attenuation upon influenza A virus and the transfer of this lesion to new antigenic variants of the virus offer some hope for the rapid development of a live vaccine for containment of pandemic disease.