Heterotypic protective immune reactions in mice infected with distinct serotypes of human influenza virus.

Infection of mice with subtype A0 OR A2 human influenza viruses, by a non-respiratory route causing no lethality, renders the animals markedly resistant to subsequent respiratory challenge with a strain differing from the first one through its haemagglutinin and neuraminidase antigens. This state of heterotypic immunity which appears rapidly (5 days) after the first infection, manifests itself during the second infection by a much reduced mortality, by less extensive lung lesions than in the control mice and by a final drop in lung virus titre (while in controls this titre stays at a high level until death) associated with a rapid rise of serum antibody levels against the haemagglutinin of the challenge virus and the "soluble" antigen common to type A strains. The development of this state of heterotypic immunity is dependent on the capacity of the first virus inoculated to replicate actively in the mouse. The role played by cell-mediated immunity in this phenomenon is evidenced by the fact that both the induction and the expression of this state of heterotypic resistance may be abolished by treatment of the mice with anti-thymocyte serum, while they are not affected by cyclophosphamide. Furthermore, in the mouse infected with an influenza A0 or A2 virus, it has been possible to demonstrate completely cross-reactive delayed type hypersensitivity reactions against the virions or their products. The fact that heterotypic immunity is not demonstrable between influenza viruses of type A and B favors the hypothesis that an antigen (matrix or nucleoprotein) common to all A subtypes--but different in B type strains--plays a role in these reactions of cross-protection.