Production of highly cross-reactive hemagglutination-inhibiting influenza antibodies in ferrets.

Ferrets were sequentially infected at time intervals of 3 weeks with different influenza virus A strains. It was found that secondary infection can result in the appearance of antibodies highly cross-reacting with a virus strain closely related to the strain of first infection. Such highly cross-reacting antibodies were designated as HCR antibodies. Evidence is presented that HCR antibodies were not antineuraminidase antibodies and, in addition, were not specifically oriented to the strain with which the crossing was observed. When using time intervals of 3 weeks between infections, no increase after secondary infection of antibodies oriented to the strain of first infection was recorded. However, when time intervals of 4 to 5 months between infections were used, secondary infections resulted in an increase of antibodies oriented to the strain of first infection ("original antigenic sin") but not in the appearance of HCR antibodies. In addition, antibodies combining specifically with both infecting strains, designated as doubly specific antibodies, were found. Thus, the conclusion was reached that the original antigenic sin phenomenon and the appearance of HCR antibodies are mutually exclusive events.