Soviet research on attenuated live virus vaccines began in earnest in the 1950s and has continued; such vaccines are widely used in the U.S.S.R. (Stuart-Harris, 1980).
After the ease with which genetic exchange between influenza viruses (reassortment) could occur was recognized, the use of donor viruses to confer the attenuated phenotype to wild-type viruses was pursued. Host-range mutants, cold-adapted mutants and temperature-sensitive mutants were investigated during the late 1960s and 1970s (Stuart-Harris, 1980).
Some recent work has focused on specific donor-attenuated strains with identifiable genetic lesions that can be transferred to new strains as they emerge. Chanock, at the National institutes of Health, Bethesda, Md., and his associates have been responsible for much of the progress in this area (Stuart-Harris, 1980). One of the major accomplishments has been development of a temperature-sensitive (TS) donor strain that grows in the upper respiratory tract but not in the warmer environment of the lower respiratory tract (Chanock and Murphy, 1979; Stuart-Harris, 1980).
Initial trials of vaccines using this technique were successful in adults but not in children. The vaccine contained live influenza viruses with internal antigens derived from the attenuated parent TS virus and surface hemagglutinin and neuraminidase derived from the wild virus. This combination was antigenic with little reactivity in adults, but when it was given to children and young infants (who had no antibodies to either the hemagglutinin or the neuraminidase of the wild virus) the vaccine viruses underwent limited replication and some TS viruses apparently reverted to the wild (TS+) phenotype (Chanock and Murphy, 1979; Stuart-Harris, 1980). Most work on TS− mutants has been conducted with influenza virus A.
A promising variation of this approach has been to use a cold-adapted donor virus initally developed by Maassab et al. (1969). A series of clinical studies have shown that live vaccines developed using the cold-adapted strain as a donor are stable and act appropriately in transferring genetic traits to other influenza A or B viruses (Davenport et al., 1977). In studies of healthy adults and children, bivalent vaccines have protected against subsequent natural challenge (LaMontagne et al., 1983). The current status of this cold-adapted vaccine candidate suggests that it could become available in several years.
An alternative approach is to improve the current inactivated influenza vaccines. The technology is available to prepare a more purified vaccine containing hemagglutinin and neuraminidase (Frank et al., 1981).
Although the side effects from purified preparations theoretically might be fewer than those from the disrupted vaccines that contain materials in addition to hemagglutinin and neuraminidase, it will be very difficult to show any decrease in reactivity. This belief is based on large clinical studies performed in adults and children in 1976 and 1978, when the A/New Jersey and the A/Russian vaccines were used (LaMontagne, 1983; Seal, 1977). In addition, although it may be possible to give much larger doses of hemagglutinin in a more purified,