Antigenic relationships between type A influenzaviruses of human, porcine, equine, and avian origin

Bull. Org. mond. Sante' 1972, 47, 453-460 Bull. Wld Hlth Org. Antigenic relationships between type A influenzaviruses of human, porcine, equine, and avian origin BELA TUMOVA'1 & G. C. SCHILD 2 This paper summarizes the available information on the relationship of two envelope antigens (haemagglutinin and neuraminidase) of influenzaviruses isolated from different hosts. The relationship of the haemagglutinin antigens was based on the results ofhaemag- glutination inhibition tests with postinfection sera and that of the neuraminidase antigens on the results of neuraminidase inhibition and gel precipitation tests with hyperimmune and monospecific sera. On the basis of the antigenic specificity of the haemagglutinin, the influenzaviruses of human origin are divided into several subtypes (HO, HI, H2); viruses of equine origin could be divided into two subtypes (Heqi, Heq2). Porcine influenza strains are regarded as belonging to a single subtype, all of them being related to the proto- type swine influenzavirus A (swine/lIowa/15/30). Within the avian influenzaviruses, 6 antigenic subtypes were described in earlier studies. Antigenic relationships between the haemagglutinin of strains from different hosts were infrequent but were demonstrated and confirmed between human A/Hong Kong/68 and equine viruses and between A/Hong Kong/68 and swine/Taiwan/69. The swine/Taiwan/69 virus also shared the related neur- aminidase with A/Hong Kong/68 virus, and represents the only isolation from nonhuman sources of an influenzavirus identical with a human pandemic strain. The studies on the antigenic specificity of the neuraminidases demonstrated 8 antigenic varieties of neurami- nidase among avian influenzaviruses and also that the neuraminidase grouping did not correspond with the antigenic grouping with regard to haemagglutinin. The relationships between human and nonhuman influenzaviruses are emphasized because of their significance to studies on the origin of influenza pandemics in man. The influenzaviruses form a morphologically homogeneous group of agents containing four major antigenic components. The type-specific ribonucleo- protein antigen is located internally in the virus particle and is antigenically stable, forming the basis for the division of influenza isolates into types A, B, and C. A further internal protein of the virus, antigenically distinct from ribonucleoprotein, is asso- ciated with a low molecular weight polypeptide component (Skehel & Schild, 1971; Schild, 1972) and also appears to be typespecific for influenza viruses type A and type B. The virus envelope contains two virus-coded antigenic components, the haemag- 1 Institute of Hygiene and Epidemiology, Czechoslovak National Influenza Centre, Prague, Czechoslovakia. 2 WHO World Influenza Centre, National Institute for Medical Research, Mill Hill, London, England. glutinin and the neuraminidase, which are antigeni- cally distinct and subtype-specific, and which undergo considerable antigenic variation. The isolation of human influenzavirus A was first achieved in 1933 (Smith et al., 1933). However, even before this, virus isolations from nonhuman sources were reported that were only subsequently identified as type A influenzaviruses. Fowl plague viruses were isolated from domestic birds as early as 1902 and were recognized as a significant cause of avian disease (reviewed by Easterday & Tumova, 1971) and the virus of swine influenza was isolated in 1930 (Shope, 1931). On the basis of its morphology and the demon- stration of antigenic relationships between its ribo- nucleoprotein antigen and that of human type A influenzaviruses, Schafer (1955) suggested that fowl plague virus was in fact a type A influenzavirus. The 2916 - 453 B. TUMOVA & G. C. SCHILD influenza isolates from swine were also identified as type A influenzaviruses. Since these early obser- vations numerous isolations oftypeA influenzaviruses from swine and avian sources have been reported and, in addition, type A influenzaviruses have been isolated from horses with respiratory disease (Sovi- nova et al., 1956; Waddell et al., 1963). However, there are no confirmed reports of isolations type B or type C influenzaviruses from nonhuman sources. Early studies on the antigenic relationships of the subtype-specific envelope analysis oftypeA influenza- viruses were largely confined to studies on the virus haemagglutinins. It is only comparatively recently that antigenic relationships specific to the neur- aminidases of influenzaviruses have been studied. The first clear demonstration of the existence of antigenic relationships between the envelope antigens of type A influenzaviruses isolated from different species was between the human virus-A/Singaporel 1/57 (H2N2)-and an influenzavirus A strain isolated from North American turkeys. Pereira et al. (1967) showed that these viruses contained antigenically identical neuraminidase, but distinct haemagglutinin antigens. Since this finding, numerous other anti- genic relationships have been observed between the neuraminidase antigens of type A influenzaviruses from human, avian, porcine, and equine sources. This paper summarizes the available information on such antigenic relationships. ANTIGENIC RELATIONSHIPS OF HAEMAGGLUTININS Relationships between strains isolated from the same host type Antigenic comparisons of influenzavirus haemag- glutinins have usually been based on the results of haemagglutination inhibition (HI) tests with post- infection sera. In recent studies (Schild, 1970; Schild et al., 1972), antigenic comparisons have been carried out using precipitin tests with monospecific sera prepared against purified haemagglutinin sub- units but such studies have so far been limited to a small number of strains. Strain specific complement fixation tests (Lief & Henle, 1959) have been used in antigenic comparisons but cross-reactions in such tests are observed with influenzaviruses containing related neuraminidases as well as related haemag- glutinins and the interpretation of the results of such tests is difficult. Type A influenzaviruses of human origin are divid- ed into a number of subtypes on the basis of haemag- glutination inhibition tests. The HO subtype was prevalent from 1933 to 1946, the HI subtype from 1947 to 1957, and the H2 subtype from 1957 to 1968. In 1968 the A/Hong Kong/68 variant appeared and was found to contain a haemagglutinin (H3) anti- genically distinct from that H2 of the formerly pre- valent Asian virus (Coleman et al., 1968; Schild et al., 1972). In contrast to the results ofHI tests, precipitin tests with monospecific sera prepared against purified HO haemagglutinin have indicated the existence of antigenic determinants shared between human HO and HI haemagglutinins (Schild, 1970) but similar tests with antiserum against purified A/Hong Kong 68 haemagglutinin H3 failed to reveal antigenic re- lationships with that of the former Asian viruses (Schild et al., 1972). Pereira et al. (1969) described the existence of six main subtypes of avian influenzavirus on the basis of the antigenic specificity of their haemag- glutinins. Recently, two additional haemagglutinin subtypes have been described-namely, subtype 7, represented by duck/Ukraine/1/63 (Hav7Neq2) (Tu- mova et al., 1972), and subtype 8, represented by turkey/Ontario/6118/68 (Hav8Nav4) (Lang et al., 1972). However, the division of avian influenzaviru- ses with distinct haemagglutinin subtypes is complex since, when a large number of strains are included in antigenic comparisons, minor antigenic cross- reactions between some strains of different subtypes are observed. The division of avian influenzaviruses into haemagglutinin subtypes should therefore be regarded as an arbitrary and provisional one, which nevertheless serves a practical purpose in epidemio- logical and diagnostic work. Equine influenzaviruses are clearly divided into two subtypes, one being represented by the strain A/equine/Prague/56 (HeqlNeql), and the other being represented by A/equine/Miami/63 (Heq2Neq2). Viruses of " classical " swine influenza are regarded as belonging to a single subtype, the members of which are all related to the prototype swine influenza- virus A, swine/Iowa/15/30 (HswlNI) (Meier-Ewert et al., 1970). However, in 1969, the isolation from swine in Taiwan of virus strains antigenically identi- cal to human A/Hong Kong/l/68 (H3N2) virus was described (Kundin, 1970). The epidemiological significance of these isolates is discussed in detail elsewhere (Harkness et al., 1972). Relationships between strains from different hosts Although previous authors have described nume- rous examples of cross-reactions in haemagglutina- tion inhibition tests between type A influenzaviruses 454 ANTIGENIC RELATIONSHIPS BETWEEN TYPE A INFLUENZAVIRUSES from different hosts few of these have been confirmed in tests with monospecific antihaemagglutinin sera. Some of the main antigenic relationships so far demonstrated in haemagglutination inhibition tests are summarized in Table 1. Cross-reactions have Table 1. Antigenic relationships in haemagglutination inhibition tests Antisera Antigens 1 2 3 4 5 6 1 A/WS/33 4- +Ca 2 swine/lowa/i 5/30 +a + 3 equine/Miami/63 + + 4 duck/Ukraine/i /63 + 5 A/Hong Kong/68 + + + + 6 swine/Taiwan/69 + + + + a The existence of antigenic relationships between the haem- agglutinins of human strain A/WS/33 and swine/lowa/15/30 viruses could not be demonstrated in Hi or immunodiffusion tests using monospecific antisera to purified haemagglutinin (Schild, 1970). In addition to the relationships shown in this table, antigenic relationships have been demonstrated between the haemagglutinins of human A/Hong Kong/68 virus and certain - classical ' strains of swine influenza A virus (see Schild et al., 1972). been demonstrated between swine/Iowa/15/30 and human A/WS/33 (HONI) virus (Andrewes et al., 1935; Tumova, unpublished observations), between equine/Miami/63 and duck/Ukraine/l/63 and be- tween equine/Miami/63 and A/Hong Kong/68. How- ever, considerable caution is necessary in interpreting the results of haemagglutination inhibition tests, particularly where such tests are performed with hyperimmune sera. Under certain conditions anti- neuraminidase antibody may inhibit haemagglutina- tion presumably by steric interference at the virus surface (Webster & Pereira, 1969; Schild et al., 1971). It therefore seems appropriate where possible to attempt to confirm the findings obtained with hyperimmune or postinfection sera in HI tests by the use of monospecific antihaemagglutinin sera in HI and precipitin tests. Attempts to confirm the re- lationship of swine/Iowa/15/30 and human A/WS/33 virus with antisera prepared against purified HO haemagglutinin gave negative results (Schild, 1970). It therefore seems probable that the antigenic re- lationship demonstrated in conventional HI tests with postinfection sera (which contain both anti- haemagglutinin and antineuraminidase antibodies) resulted from the fact that classical swine influenza- viruses and human viruses containing HO and HI haemagglutinins possess antigenically related neura- minidases (NI) (see Table 2). In contrast, it has been found that monospecific antiserum prepared against purified A/Hong Kong/68 haemagglutinin reacted both in HI tests and in precipitin tests with equine/ Miami/63 virus (Schild et al., 1972), thus providing strong evidence that these two viruses contain anti- genically related haemagglutinins. Similar evidence was obtained that certain strains of " classical " swine influenzavirus contain haemagglutinin anti- genically related to that of human A/Hong Kong/68 virus (Schild et al., 1972). The swine/Taiwan/69 virus isolates (Kundin, 1970) were found to contain haemagglutinin and neur- aminidase antigens (H3N2) identical to that of the human A/Hong Kong/68. This finding was con- firmed by precipitin tests with monospecific antisera against purified A/Hong Kong/68 haemagglutinin and neuraminidase antigens (Schild et al., 1972). The isolation of the swine/Taiwan/69 virus is of particular interest as the first isolation from a non- human source of an influenzavirus showing complete antigenic identity with a human influenza A virus. ANTIGENIC RELATIONSHIPS OF NEURAMINIDASES Relationships between strains from the same host and type Neuraminidase inhibition (NI) tests (Webster & Laver, 1966) with hyperimmune sera have been widely used in the study of antigenic relationships. However, some studies have employed NI and preci- pitin tests with monospecific sera prepared against purified neuraminidase subunits. Among the human type A influenzaviruses it has been shown that strains containing HO and HI heamagglutinins share anti- genically related neuraminidases of subtype NI (Paniker, 1968; Schild & Newman, 1969). Classical swine influenzaviruses also contain neuraminidase of subtype NI (Schild et al., 1972). The neur- aminidases (subtype N2) of the asian viruses isolated between 1957 and 1967 and of A/Hong Kong/68 virus show antigenic relationships that have been demonstrated in neuraminidase inhi- bition tests and also in precipitin tests with mono- specific antisera (Schild & Newman, 1969). Anti- genic comparisons of the neuraminidases of avian influenza viruses using NI tests have been carried out by a number of workers (Webster & Pereira, 1968; Kendal & Madley, 1969; Schild & Newman, 1969; Madley et al., 1971). The results obtained in the 455 456 B. TUMOVA & G. C. SCHILD Table 2. Antigenic relationships between tt Antiserum to: human strains swine strains Host NA HA Strain of origin subtypeb subHApe b A/34 A/47 A/57 A/68 swine/ swine/(Asian) (Hong Iowa/ Taiwan/ Kong) 15/30 69 Ni HO PR8/34 + + + Ni Hi FM1/47 + + + man N2 H2 Singapore/i /57 + + + N2 H3 Hong Kong/i /68 + + + Ni Hswi swine/lowa/i 5/30 + + + swine N2 H3 swine/Taiwan/69 + + + Neqi Heqi equine/Prague/56 horses Heq2 Heq2 equine 2/Miami/63 Havi FPV/Rostock/34 + + + Ni Hav6 duck/Germany/68 + + + Hav5 chick/Scotland/59 + + + Hav2 duck/ltaly/574/66 + + NT N2 Hav6 turkey/Mass/65 + + NT Hav6 turkey/Wisc/66 + + NT Havi FPV/Dutch/27Neqi Hav2 chick/Germany 'N/49 Hav2 quail/Italy/i 1 7/65 Neq2 Hav6 turkey/Canada/63 Hav7 duck/Ukraine/63 birds Hav3 duck/England/56 Navi Hav4 duck/Czechoslovakia/56 Hav4 duck/England/62 Nav2 Hav5 tern/South Africa/61 c Nav3 Havi turkey/England/63 c Nav4 Hav8 turkey/Ontario/6118/68 a + Indicates cross-reactions in NI tests at titres not less than 10% of the homologous titre of the antiserum. Blank spac, b Neuraminidase and haemagglutinin subtypes are numbered according to recent proposals for a revised system of influenza vin c A minor cross-reaction (approx. 10 % of the homologous titre) detected between turkey/England/63 and tern/South Africa/6 authors' laboratories (unpublished data) are sum- marized in Table 2 and are in general agreement with those obtained by other workers. It can be seen from this table that among avian influenza- viruses 8 antigenic varieties of neuraminidase exist and moreover that the neuraminidase antigenic groupings of these viruses do not correspond with the haemagglutinin antigenic groups. For example, although 3 avian virus strains, chicken/Scotland/59 (Hav5NI), duck/Germany/1868/68 (Hav6NI), and FPV/Rostock/34 (HavINI) contain unrelated haem- agglutinins, they share antigenically closely related neuraminidase antigens. A similar heterogeneity of HA subtypes exists among avian viruses possessing the neuraminidases characterized by that of turkey/ Massachusetts/65 (Hav6N2) virus, i.e., neuramini- dase antigenically similar to that of human Asian viruses. It should be stressed, however, that the results shown in Table 2 have largely been obtained with antisera prepared against whole (unfractionated) virus preparations and that several of the antigenic re- lationships, particularly in the case of avian virus strains, have not yet been fully studied with mono- specific sera prepared against purified neuraminidase antigens. In addition, confirmatory evidence of anti- genic relationships of neuraminidase antigens has been sought in precipitin tests in only a limited heuraminidases of type 457ANTIGENIC RELATIONSHIPS BETWEEN TYPE A INFLUENZAVIRUSES A influenzaviruses from various hosts a Antiserum to: equine strains avian strains equine/ equine/ chicken/ turkey! FPV/ quail/Italy/ duck! tern! turkey! turkey! Prague/56 Miami/63 Scotland/59 Mass./65 Dutch/27 1117/65 England/56 S. Africa/61 England/63 Ontario/68 + +~~~~~ + +~~~~~~ + +~~~~~~~~ + +~~~~~ + +~~~~~~ + + + + ndicate the absence of NI reactions or reactions at titres less than 10 % of the homologous titre. NT indicates not tested. nomenclature (Bull. Wld. Hlth. Org., 1971). number of strains (see Schild & Newman, 1969; Schild et al., 1972). The grouping of avian in- fluenzavirus strains (Table 2) according to their neur- aminidase antigens should therefore be regarded as provisional until the results of appropriate studies with monospecific sera are available. Relationships between strains from different hosts In contrast to the relatively few antigenic relation- ships observed amongst the haemagglutinins of in- fluenzavirus A from different hosts a considerable number of neuraminidase antigenic relationships have been observed (Webster & Pereira, 1968; Schild & Newman, 1969; Tumovi & Easterday, 1969). These relationships are summarized in Table 2. It is seen that among the neuraminidases of avian influenza A viruses only those of the antigenic varieties contained in tern/South Africa/61 (HavS- Nav2), turkey/England/63 (HavlNav3), turkey/ Ontario/6118/68 (Hav8Nav4), duck/England/62 (Hav4Navl) viruses are unique to viruses of avian origin. The four other antigenic varieties of neur- aminidase of the avian influenzaviruses are antigeni- cally closely related to that contained inhuman typeA influenzaviruses isolated between 1933 and 1946 and in classical swine influenzaviruses (NI), to that of human Asian and Hong Kong viruses (N2), and to those of equine-I (Neqi) and equine-2 viruses (Neq2). B. TUMOVA & G. C. SCHILD) DISCUSSION The studies summarized in the present paper indi- cate that there are a number of different types of antigenic relationship between type A influenza- viruses isolated from different hosts. However, this discussion will mainly concern the antigenic relation- ships between human and nonhuman influenzaviruses because of their possible significance in the origin of human influenza pandemics. The antigenic identity of the ribonucleoprotein antigens of human and nonhuman type A influenza- viruses is well established. One significant aspect of the possession of a common ribonucleoprotein anti- gen is that type A influenzaviruses from different hosts have been shown to be capable of undergoing genetic interactions leading to the formation of re- combinant strains sharing the antigenic characters of both parent viruses. The high degree of antigenic variation found among the type A influenzaviruses may be related to their ability to undergo genetic recombination. Recombinant influenzaviruses pos- sessing envelope antigens derived from their human and avian influenzavirus parents have been pro- duced experimentally in vitro (Tumova' & Pereira, 1965; Easterday et al., 1970). In addition, Webster et al. (1971) have recently demonstrated that recombination may also occur in vivo between different type A influenzaviruses in a doubly infected host. It is tempting to postulate that recombination may play a role in the origin ofnew antigenic variants of influenza. The existence of influenzavirus strains sharing one envelope antigen (usually the neur- aminidase) but not the other (the haemagglutinin), which have been isolated from natural infections of birds (A/turkey/Massachusetts/65 (Hav6N2) and others), appears to support the possibility that re- combination leading to a reassortment of antigenic characteristics of the parent viruses may take place frequently in nature. However, other possible expla- nations for antigenic variation in the influenza- virus A cannot be disregarded including changes brought about by mutation and selection, and the suggestion put forward by Jensen & Francis (1953) that a finite number of antigenic varieties of haemag- glutinin and neuraminidase antigens exist amongst type A influenzaviruses. Few antigenic relationships have been detected between the haemagglutinins of human type A in- fluenzaviruses and those of viruses so far isolated from nonhuman hosts. Furthermore, certain of the relationships that have been demonstrated between human and nonhuman influenza A strains are of doubtful significance since they have been observed only in tests with hyperimmune sera or, as is the case with the cross-reactions detected between A/ Hong Kong/68 and A/Equine/Miami/63 virus, they are not reciprocal. In contrast, studies on the neuraminidase antigens of type A influenzaviruses have revealed a consider- able number of antigenic relationships between the neuraminidases of viruses of human and nonhuman origin. The neuraminidases (N1) of human influenza- viruses isolated between 1933 and 1946 are anti- genically related to those of several swine and avian influenza strains, while neuraminidase of the same antigenic type as that of human Asian viruses has been detected in a number of avian influenzavirus A strains. Human and nonhuman viruses sharing neuraminidase antigens have been found to contain antigenically distinct haemagglutinins. On the appearance of a new subtype of influenzavirus A in man the previously prevalent subtype is rapidly replaced. In nonhuman hosts, however, antigenically distinct viruses have been frequently detected during the same period and in some cases antigenically distinct viruses have been isolated from the same epizootic in birds (Pereira et al., 1967) or in horses (Tumova' et al., 1971). While type A influenzaviruses containing neuraminidase of subtype NI have not been isolated from man since 1957, viruses containing this antigenic type of neuraminidase still exist in swine (" classical " swine influenzaviruses related to swine/Iowa/15/30) and were isolated from birds as recently as 1968 (Schild et al., 1969). Furthermore, neuraminidase of subtype NI has been demonstrated in the Brescia strain of fowl plague virus isolated in 1902 (Schild, unpublished observation). Since the time of the first appearance of NI neuraminidase in influenzaviruses infecting man is not known, it is not possible to state whether the date of isolation of a nonhuman virus containing Ni neuraminidase pre- dated the appearance of viruses containing this sub- type of neuraminidase in the human population. Neuraminidase related to that of human Asian viruses (N2) has been demonstrated in several avian influenzaviruses isolated in recent years (1965-71). There are no reports of the presence of this neur- aminidase subtype among avian influenzavirus strains isolated before the appearance of Asian viruses in man in 1957. However, it should be men- tioned that relatively few isolates of avian in- fluenzavirus were made before 1957, presumably because relatively little attention was paid to the etiology of influenza in birds before that date. 458 ANTIGENIC RELATIONSHIPS BETWEEN TYPE A INFLUENZAVIRUSES 459 The recent isolation of the swine/Taiwan/69 virus (Kundin, 1970), which is antigenically identical to A/Hong Kong/68 in both haemagglutinin and neur- aminidase antigens, is the only isolation from a non- human source of an influenzavirus A identical to a human pandemic strain. Antibodies to A/Hong Kong/68 virus have been frequently demonstrated in sera from swine in several countries after the human pandemics of 1968-69 and 1969-70 (Rom- vary, personal communication; Styk et al., 1971; Harkness et al., 1972; Tumova et al., unpublished observation). Also, swine/Taiwan/69 virus has been shown to be capable of infecting human volunteers (Beare et al., 1971). These studies indicate that certain influenzaviruses might be capable of crossing species barriers. However, it has not yet been determined whether strains that are capable of crossing host barriers could become established in the new host and produce epidemics of disease. That the type A influenzaviruses from a large and widely distributed group of agents containing at least four different antigenic types of neuraminidase that have not been demonstrated in human influenza- virus subtypes is of particular interest. If the hypo- thesis that recombination between two viruses of different hosts may occur is accepted, we might spe- culate that any of these antigenic types of neur- aminidase might appear in future pandemic strains of human influenzavirus A. The possibility that the haemagglutinin antigens found amongst avian (and other nonhuman) influenzaviruses might appear in future pandemic strains of man should also be considered, but the results of current studies suggest that neuraminidase antigenic relationships are more frequent. The significance of these findings are at present not clear and their understanding requires further studies on the ecology of the influenza- virus. RtSUME RELATIONS ANTIGENIQUES ENTRE DES VIRUS GRIPPAUX DE TYPE A D'ORIGINE HUMAINE, PORCINE, EQUINE ET AVIAIRE Le present article resume les informations actuellement disponibles concernant les relations entre les antigenes d'enveloppe (hemagglutinine et neuraminidase) de virus grippaux isoles chez differents hotes. Pour 6tablir les liens entre les hemagglutinines, on a tenu compte des resultats des epreuves d'inhibition de l'hemagglutination portant sur des serums pr6leves apres une infection grip- pale; les rapports entre les neuraminidases ont ete deter- mines a l'aide d'epreuves d'inhibition de la neuraminidase et de precipitation en gel utilisant des s6rums hyper- immuns et monospecifiques. Sur la base de la specificit6 antig6nique de l'hemagglu- tinine, on peut r6partir les virus grippaux d'origine humaine en diff6rents sous-types (HO, HI, H2) et les virus d'origine 6quine en deux sous-types (Heql, Heq2). Les virus de la grippe porcine sont consid6res comme appartenant a un sous-type unique, toutes les souches isolees etant apparent6es A la souche prototype swine/ Iowa/15/30. Pour les virus de la grippe aviaire, 6 sous- types antigeniques ont et6 d6crits. Des relations antigeniques entre hemagglutinines de souches isol6es chez des hotes diff6rents ne sont pas frequentes. On a demontre et confirme l'existence de telles relations entre le virus humain A/Hong Kong/68 et des virus 6quins ainsi qu'entre le virus A/Hong Kong/68 et la souche swine/Taiwan/69. Cette derniere possede aussi une neuraminidase identique a celle du virus A/Hong Kong/68 et elle est donc la seule souche d'origine animale presentant une identit6 antigenique complete avec un virus humain A. L'etude de la specificite antig6nique des neuraminidases met en evidence 8 vari6tes de cet antigene parmi les virus de la grippe aviaire. Leur r6partition, au sein de ce groupe, est distincte de celle des h6magglutinines. Quatre de ces variet6s de neuraminidases sont tres proches de celles caract6risant les sous-types AO, Al et A2 de la grippe humaine, les virus 4 classiques * de la grippe porcine et les virus 6quine-1 et equine-2. Les quatre autres variet6s sont specifiques des virus de la grippe aviaire. Les auteurs insistent sur l'interet de ces relations entre virus de la grippe humaine et virus de la grippe animale pour l'etude de l'origine des pand6mies grippales chez l'homme. REFERENCES Andrewes, C. H. et al. (1935) Brit. J. exp. Path., 16, 566 Beare, A. S. et al. (1971) Lancet, 1, 305 Bull. Wld Hlth Org., 1971, 45, 119-124 Coleman, M. T. et al. 1968) Lancet, 2, 1384 Easterday, B. C. & Tumova, B. (1971) In: Hofstad, M. J., ed., Diseases ofpoultry, Iowa State University Press 460 B. TUMOVA' & G. C. SCHILD Easterday, B. C. et al. (1969) J. gen. Virol., 5, 83 Harkness, J. W. et al. (1972) Bull. Wld Hlth Org., 46, 709 Jensen, K. E. & Francis, T., Jr (1953) J. exp. Med., 98, 619 Kendal, A. P. & Madley, C. R. (1969) Biochim. Biophys. Acta (Amst.), 185, 163 Kundin, W. D. (1970) Nature (Lond.), 228, 857 Lang, G. et al. (1972) Bull. Wld Hlth Org., 47, 515 Leif, F. S. & Henle, W. (1959) Bull. Wld Hlth Org., 20, 411 Madely, C. R. et al. (1971) J. gen Virol., 12, 69 Mier-Ewart, H. et al. (1970) J. gen. Virol., 6, 409 Paniker, C. K. J. (1968) J. gen. Virol., 2, 385 Pereira, H. G. et al. (1966) Bull. Wld Hlth Org., 35, 799 Pereira, H. G. et al. (1967) Bull. Wld Hlth Org., 37, 553 Pereira, H. G. et al. (1967) Nature (Lond.), 215, 982 Schild, G. C. (1970) J. gen. Virol., 9, 191 Schild, G. C. (1972) J. gen. Virol., 15, 99-103 Schild, G. C. & Newman, R. W. (1969) Bull. Wld Hlth Org., 41, 437 Schild, G. C. et al. (1969) Nature (Lond.), 222, 1299 Schild, G. C. et al. (1970) In: Mahy, B., ed., Biology of large RNA viruses, New York, Academic Press, p. 638 Schild, G. C. et al. (1972) Bull. Wld Hlth Org., 46, 721 Schafer, W. (1955) Z. Naturf., 106, 81 Shope, R. E. (1931) J. exp. Med., 54, 373 Skehel, J. J. & Schild, G. C. (1971) Virology, 44, 396 Smith, W. et al. (1933) Lancet, 225, 66 Sovinova, 0. et al. (1958) Acta virol., 2, 52 Styk, B. & Blaskovic, D. (1971) Acta virol., 15, 211 Tumova, B. & Easterday, B. C. (1969) Bull. WldHlth Org., 41, 429 Tumova, B. & Pereira, H. G. (1964) Virology, 27, 253 Tumova, B. et al. (1972) Amer. J. Epidemiol., 95, 80-87 Tumova, B. et al. (1972) Bull. Wld Hlth Org., 47, 503 Waddell, G. H. et al. (1963) J. Amer. vet. Med. Ass., 143, 587 Webster, R. G. & Laver, W. G. (1967) J. Immunol., 99, 49 Webster, R. G. & Pereira, H. G. (1968) J. gen. Virol., 3, 301 Webster, R. G. et al. (1971) Virology, 44, 317