256 T. FRANCIS, JR. 



while the interior or more inaccessible portions contained other antigens, 

 and yet, because of the variation in amount or arrangement, each strain or 

 group of strains could be serologically different. Strains at each end of the 

 spectrum might thus exhibit closer relation to a third mid-strain than to each 

 other. Because the studies were done exclusively with virus that had 

 been adapted to mice, some doubt still remained as to whether they reflected 

 the state of native human strains, although no differences were detected 

 between early and late passages of mouse or tissue culture lines (Francis and 

 Magill, 1938). 



b. Analysis by Hemagglutination- Inhibition. In succeeding years a number 

 of investigators, using sera of various kinds, analyzed the serological character 

 of strains isolated from man over various segments in time. The majority used 

 hemagglutination-inhibition techniques (Hirst, 1942) and virus cultivated in 

 embryonate eggs. Hirst (1943) employed strains isolated directly in eggs with 

 convalescent ferret sera. Efforts were made to correct for the variation in 

 sera obtained from different animals, in different lots of erytlirocytes, and in 

 the combining power (avidity) of different strains of virus. Studying 18 

 strains derived from the 1940-41 epidemic, he pointed out the extraordinary 

 homogeneity of the group with no difference between those isolated at the 

 beginning or end of the outbreak. The strains clearly diverged, however, 

 from the earlier WS, PR8, or even 1936-37 strains. Study of strains from the 

 1943 epidemic showed only small differences among them or between them 

 and the 1940-41 strains (Hirst, 1947), indicating a great antigenic stability of 

 epidemic strains. 



In 1947, strains recovered from epidemic influenza A in the Northern 

 Hemisphere were promptly recognized by a number of investigators to 

 represent a new variant, and it was learned that a strain (Cam) isolated in 

 Australia during the preceding winter was of the same character. These 

 strains extended as the predominant influenza A infection throughout the 

 world. The 1947 strains were related to earlier strains by common components, 

 but the dominant group antigen differed more distinctly than had been the 

 case among strains of intervening years. Immune serum from any source 

 demonstrated the individuality and limited cross reaction with other strains. 

 Furthermore, vaccination of man with PR8 1934 and Weiss 1943 strains 

 stimulated no antibody response to the 1947 strains (Francis et ah, 1947), but 

 vaccination with a prototype 1947 strain FMl did induce increased antibody 

 production against PR8, Weiss, and later strains (Francis, 1952; Meiklejohn 

 et ah, 1952). The one-way serological cross reaction was also exhibited with 

 sera of experimental animals. This group of strains was designated A-prime 

 by the Commission on Influenza (1948; Salk and Suriano, 1949). 



In the next several years more extensive serological analyses of type A 

 strains were reported. Van der Veen and Mulder (1950) measured ferret sera 



