Live Victoria/75- ts -1[E] Influenza A Virus Vaccines in Adult Volunteers: Role of Hemagglutinin Immunity in Protection Against Illness and Infection Caused by Influenza A Virus

To explore the relationship between neuraminidase immunity and the degree of attenuatíon of live influenza A virus vaccines, a comparative evaluation of three Victoria/75- ts -1[E] (Vic/75- ts -1[E]) recombinant viruses in serum hemagglutination-inhibiting-negative (titer, ≤1:8) adult volunteers was performed. These three ts -1[E] viruses had a similar restriction of replication at 38°C in vitro, and each possessed the two attenuating genes of the ts -1[E] donor strain (13). However, Vic/75- ts -1[E] recombinants 81 and 113 possessed both Vic/75 hemagglutinin (H3 75 ) and Vic/75 neuraminidase (N2 75 ), whereas Vic/75- ts -1[E] recombinant 67 had Vic/75 hemagglutinin but the N2 65 neuraminidase. Vic/75- ts -1[E] recombinant 67 was significantly more attenuated than Vic/75- ts -1[E] recombinants 81 and 113 in that fewer local and systemic signs and symptoms of illness were observed in those volunteers who received clone 67. These findings were consistent with our previous observations which suggested that the following two factors contribute to the attenuation of ts -1[E] vaccine strains in adults: (i) the attenuating effect of the two ts -1[E] genes and (ii) the neuraminidase immunity of the host. Vic/75- ts -1[E] recombinant clone 67 vaccinees developed an immunological response to the H3 75 hemagglutinin in the absence of a response to the N2 75 neuraminidase. To assess the role that anti-hemagglutinin immunity induced by an attenuated live virus vaccine plays in resistance to influenza A virus, vaccinees who received recombinant 67 were challenged with Vic/75 wild-type virus, and their responses were compared with those of Vic/75- ts -1[E] vaccinees who received recombinant 81 or 113. Each of the three groups of ts -1[E] vaccinees was significantly protected against illness induced by wild-type virus infection, although resistance was not complete. However, the clone 67 vaccinees were protected less against infection. The infection-permissive resistance induced by clone 67 resembled that previously described for inactivated neuraminidase-specific vaccines. These results suggested that a ts -1[E] recombinant that possessed the hemagglutinin of a new pandemic variant, the neuraminidase of the preceding subtype, and the two ts -1[E] ts genes would be satisfactorily attenuated for children and adults with neuraminidase immunity and could induce resistance to illness caused by the new pandemic wild-type influenza A virus.