Temperature-sensitive Mutants of Influenza A Virus: Response of Children to the Influenza A/Hong Kong/68-ts-1[E] (H3N2) and Influenza A/Udorn/72-ts-1[E] (H3N2) Candidate Vaccine Viruses and Significance of Immunity to Neuraminidase Antigen

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Abstract
Extract: The influenza A/Hong Kong/1968-ts-1[E] (H3N2) candidate live virus vaccine strain, which had previously been shown to be safe and protective in seronegative adult volunteers, was administered intranasally to 21 children at a dose of 105 TCID50. One group contained 15 children (5–11 years of age) who lacked serum anti-body to the hemagglutinin (≤ 1:8), but possessed serum antibody to the neuraminidase antigen. The second group included six children (2 4/12–3 10/12 years of age) who lacked serum antibody to both hemagglutinin and neuraminidase surface antigens of the influenza A virus. Twelve of the 15 children in the first group were infected, but only one child developed mild rhinitis; 6 of the 12 infected vaccinees shed virus for a short interval, while 11 of the group developed an immunologic response. In contrast, each of the six vaccinees who lacked serum antibody for both surface of the virus shed a relatively larger quanity of virus over a longer interval than those in the first group, and each child developed an immunologic response. Four of the doubly seronegative vaccinees developed a febrile response during their infection and three had rhinitis. Two additional children who lacked serum antibody to both surface antigens of influenza virus were given the influenza A/Udorn/1972-ts-1[E] recombinat virus which had the same genetic temperature-sensitive (ts) lesions as the Hong Kong virus but possessed a more contemporary hemagglutinin. this recombinant virus infected both of the children and induced transient fever in one. None of the total of 23 vaccinees developed signs or symptoms of lower respiratory tract involvement. Although the Hong Kong and Udorn ts-1[E] recombinants possessed two discrete ts lesions, evidence of genetic instability was detected during infection of two of the eight young children who lacked immunity to both surface antigens of the virus. It seems likely that a complete assessement of the virulence of vaccine candidate influenza a viruses can only made in individuals who lack immunity to both surface antigens of the influenza A virus. Speculation: These findings suggest the following. 1. Antineuraminidase antibody (ANAB) to previously experienced influenza strains can modify clinical response to infection with attenuated influenza virus as well as natural infection. 2. The full expression of virulence of ts recombinants or any live influenza vaccine may be mainfest only in individuals lacking both hemagglutination-inhibition (HI) antibody and ANAB. 3. Evaluation of the immune and clinical response to viruses such as the ts-1[E] recombinant in young infants and children who lack both HI antibody and ANAB has value both because of their potential as vacciness and also as a model for an attenuated vaccine against the next pandemic influenza variant. 4. Standards for future ts or other live influenza vacciness must include genetic stability in individuals lacking HI antibody and ANAB and failure to induce a febrile response in such individuals.

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