Groups of schoolchildren were immunized with an inactivated recombinant influenza virus vaccine specific for the neuraminidase antigen of Port Chalmers influenza A virus (Heq1N2Ch), a conventional biphasic Port Chalmers strain of influenza virus vaccine (H3ChN2Ch), or a placebo. Immunization with either virus vaccine was found to be safe and had no major adverse effects. Immunization with the Heq1N2Ch vaccine resulted in no specific hemagglutination-inhibiting antibody response to H3Ch antigen, although a specific neuraminidase antibody response to N2Ch antigen was observed in greater than 90% of the vaccinees. A subsequent natural outbreak of influenza virus resulted in serologically proven infection with H3Ch virus in 26% of vaccinees receiving H3ChN2Ch virus vaccine, 47% of those receiving Heq1N2Ch virus vaccine, and 44% of those receiving a placebo. However, the protective efficacy against illness was 74.3% for the H3ChN2Ch vaccine and only 51.4% for the Heq1N2Ch vaccine. Regardless of the type of vaccine employed, vaccinees with serologic evidence of infection and clinical illness were found to have very low titers of hemagglutination-inhibiting and neuraminidase antibody. However, vaccinees with serologically proved infection but without clinical illness were found to have titers of antibody to neuraminidase before infection that were four- to eightfold higher than titers in vaccinees who were infected and who had clinical illness.