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    A S ER O L O GI C R E C A P I T U L A T I O N O F P A S T E X P E R I E N C E S W I T HI N F L U E N Z A A ; A N T I B O D Y R E S P O N S E T O M O N O V A L E N T

    V A C C I N E *BY FRED M . DAVENPO RT, M.D ., ~ ALBERT V. HENNESSY$, M.D.

    (From the Department of Epidemiology and Virus LaboragorySchool of Public Health, An n Arbor)(Received for publication, April 2, 1956)

    The resul ts of previous s tudies on the dis t r ibut ion by age of ant ibodies toinfluenza viruses have shown a remarkable correlat ion between the type ofant ib ody found now in the sera of persons at three s tages of l i fe , and theant igenic character of the s t rains prevalent during the chi ldhood of each agegroup (1-4) .

    For example , the pr inc ip le an t ibody of ch i ldren born a f t e r the appearanceof influenza A-prime in 1946 is ant ibody that reacts with A-prime s t rains . Theprinciple ant ibody of young adul ts who were chi ldren during the period ofprevalence of influenza A, which extended unt i l 1943, is ant ibody that reactswith s t rains of Type A influenza virus . Likewise, in persons over 30 years ofage, the principal ant ibody recognized is one that reacts with swine influenzavirus . Many of the persons now over 30 years of age were chi ldren during aperiod wh en influenza viruses ant igenical ly closely related to swine s t rains arepresumed to have prevai led. This period included the pandemic of 1918 (5, 6,1--4) . Analogous resul ts have been found with respect to ant igenic variants ofType B influenza virus and influenza B (1, 2) .To explain these phenom ena the thes is was presen ted that a t the t ime ofthe ini t ia l infect ions with influenza viruses , which occur predominant ly inchi ldhood, the ant ibody-forming mechanisms are pers is tent ly oriented bythe dom inant an t igens of the s t ra ins encounte red . Upon subsequent exposure toinfluenza viruses of varied but re lated ant igenic composi t ion reinforcement ofthe level of ant ibody to the s t rains of primary infect ion occurs while theserologic response to prevai l ing viruses may be dam pened. This thes is has beenepi tomized in a col loquial express ion as " the doctr ine of original ant igenics in." I t was previously s ta ted that the data which led to formulat ion of this"doc t r ine " were in pa r t de r ived by measur ing in te repidemic l eve l s of an t ibody

    * These studies were conducted under the auspices of the Commission on In fluenza, ArmedForces Epidemiological Board , and were supported by the Office of the Surgeon General,Department of the Army, Washington, D.C.:~ Wi th the technical assistance of Miss Phy llis H. Fabisch.

    85

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    86 ANTIBODY RESPONSE TO MONOVALENT VACCINEwith prototy pic strains of virus. Under these circumstances, the time, rate, andcharacter of prior antigenic exposures of the popul ation studied are not preciselyknown. I n order to define more accurate ly the dimensions of the persistentserologic influences of the do min an t antigen s of the st rains of childhood infec-tion, it was decided to control these variables by vaccin ation with mon ovale ntvaccines contain ing representative strain s of swine influenza, influenza A, a ndinfluenza A-prime. The vaccines were given to children born d uring the periodof prevalence of influenza A-prime, to adults who were children during the epochof influenza A, and to adults over 30 years of age. An tibo dy response in eachage group was measured with each strain of virus. In addition, it was recog-nized that the data obtained might provide a serologic index of the relativeextent of the antigenic experience of these segments of the population withinfluenza A, A-prime, and swine-like strains. It is believed tha t this use ofvaccines to assess the relative frequency of infection in a populatio n representsa new development in serologic epidemiology.

    M a t e r i a l s a n d M e t h o d sVazo/nes.--Monovalent influenza virus vaccines, each containing 750 CCA unit s of virusper ml., were prepared by a commercial pharmaceutical fi rm with the following stra ins:Swine 1976 (1931), PR8 (1933), FM1 (1947), and Cuppett (1950). The viruses were inacti-vated with formalin (1:4000). Merthiolate (1:10,000) was added as a preservative. Inad-vertently, the monovalent Cuppett vaccine contained a trace of Conley virus (1952 A'),but in an amount judged to be too small to influence the results obtained.Subje c t s . - -Ant ibody response to these experimental vaccines was studied in childrenaged 4 to 10 (median ffi 7), military recruits aged 17 to 28 (median ffi 18), and in adults 30or more years of age (median ffi 47). The children and persons over 30 years were inmatesof State mental institutions. Military recruits were airmen stationed at Sampson Air ForceBase, Geneva, New York, for basic training.1Immu nization and Bleeding Schedu les.--In groups of 20 to 25, children, recruits, and

    persons over 30 were bled and vaccinated according to the following plan. Four groups ineach age category received three doses of monovalent vaccines containing either swine, PR8,FM1, or Cuppett virus. Six groups received 4 different monovalent vaccines alternated sotha t the order in which swine, PR8, or Cuppett strains of virus was given, was varied toinclude all possible permutations, and each group received FM1 as the last vaccine. Vaccina-tion was carried out at 2-week intervals. Bleedings were obtained before each vaccinationand a t 2 and 4 weeks after the last. The dose of all vaccines was 1 cc. subcutaneously.Treatment of Sera.--Serum was promptly separated f rom each blood sample, and mer-thiolate was added to yield a final concentration of 1:10,000. Pools of sera derived fromsamples obtained before and after each vaccination were made by combining appropriatealiquots. Sera were stored at 4C. and heated at 56C. for 30 minutes prior to use.Hemagglut inat ion-Inhibi t ion Ti trat ions . - -The hemagglutination-inhibition titer of serumpools was determined by a pattern method with 4 units of virus and 0.5 per cent chickenerythrocytes suspended in saline. (7).Solutions.--Saline refers to 0.15 ~t NaCI buffered at pH 7.2 with 0.01 ~ phosphate.

    x It is a pleasure to acknowledge the assistance of Dr. Harold B. Houser, Director, and ofthe officers and enlisted men of the Laboratory on Housing and Illness, Sampson Air ForceBase.

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    FRED M. DAVENPORT AND ALBERT V. HENNESS 87E X P E R I ~ E I N F f A L

    Antibody Response in Children to Mono~alent Vaccines.--Antibody r e s p o n s e st o s w in e , P R 8 , F M 1 , a n d C u p p e t t s t r a i n s w e r e m e a s u r e d i n p o o l s o f s e r u mo b t a i n e d b e f o r e a n d 2 w e e k s a f t e r v a c c i n a t io n w i t h m o n o v a l e n t v a c c i n e s c o n -t a i n i n g t h e s e v i r u s e s . I n F i g . 1 , p r e - a n d p o s t - v a c c i n a t i o n a n t i b o d y t i te r s a r es h o w n a s p a i r e d b a r g r a p h s . O p e n b a r s r e p r e s e n t a n t i b o d y l e v e ls m e a s u r e d

    TEST S T R A I N SS W I N E P R 8 F M I C U P P E T T

    1 0 2 4 ~ S W I N E2 5 6 1 :

    1 0 2 4 ~ P R 8 _ _ [ ]2 5 6 ~

    i 0 2 41 2 F M I2 5 6 1 :- -1 6 3 8 4 ~

    1 0 2 4~ C U P P E T T2 5 6 1 :FIG. 1. Antibody response in children aged 4 t o 10 years to monova lent influenza virusvaccines.

    w i t h t h e s t r a i n u s e d f o r va c c i n a t io n . H a t c h e d b a r s r e p r e s e n t a n t i b o d y l e ve l sm e a s u r e d w i t h h e t e r o l o g o u s s t r a i n s . A n t i b o d y t o s w i n e v i r u s w a s n o t d e t e c t e di n t h e l o w e s t d i l u t i o n o f p r e v a c c i n a t i o n s e r a t e s t e d . A s w o u l d b e e x p e c t e d , ah i g h l e v e l o f h o m o l o g o u s a n t i b o d y w a s f o u n d 2 w e e k s a f t e r v a c c i n a t i o n w i t h t h es w i n e s t ra i n . O f g r e a t e r i m p o r t i s th e a n t i b o d y r e s p o n s e a f t e r s w i n e v a c c i n e t oh e t e r o l o g o u s v ir u s e s . N o t e t h a t b e f o r e v a c c i n a t i o n , a n t i b o d y t o P R 8 w a s i n-a p p a r e n t a n d t h e l e v e l d e v e l o p e d a f t e r v a c c i n a t io n w a s l o w . I n c o n t r a s t ,p o s t v a c c i n a t i o n a n t i b o d y l e v el s t o F M 1 a n d C u p p e t t w e r e h ig h , a n d t h e l e v e lsr e a c h e d r e p r e s e n t a m a r k e d i n c re a s e o v e r t h e a m o u n t s f o u n d b e f o r e v a c c i n a -t i o n . A n a l o g o u s r e s u l t s w e r e o b t a i n e d b y v a c c i n a t i o n w i t h P R 8 . T h e h o -

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    88 ANTIBODY RESPONSE TO MONOVALENT VACCINETABLE I

    H -I Antibody Tilers in Pools of Sera Obtained before and after Administralion of M onovalentVaccines to Ckildren Aged 4 to 10"Vaccines given

    SwineSwineSwine

    PR8PR8PR8

    F M IF M 1F M I

    CuppettCuppettEuppett

    ~wineDR8EuppettFM1

    ~wine3uppettPR8FM1

    Group Bleeding

    1 i23~45

    2 I2345

    3 12345

    4 12345

    5 123456

    6 1234

    56

    Ti te r wi th t e s t s t r a i nsSwine PR8 FM!

    0 0 2561,024 128 >16,3841,024 64 >16,3842,048 32 >16,384512 32 8,192

    0 0 1,02464 2,048 2,04864 2,048 2,04864 1,024 2,04832 1,024 2,0480 0 2560 0 4,0960 32 4,0960 32 4,0960 32 2,0480 0 25632 128 4,0960 64 8,1920 32 4,0960 32 4,0960 0 2561,024 32 >16 ,384512 512 8,192256 256 4,096

    256 128 8,192256 128 8,1920 0 2561,024 64 ~>16,3841,024 64 ~>16,384512 1,024 4,096

    512 512 4,096512 1,024 4,096

    Cuppett321,0241,024

    2,04851264128128

    12812832512512

    256256321,024512

    512512322,048

    1,0245125121,024321,0241,024512

    512512

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    FRED M. DAVENPORT AND ALBERT V, HENNESSY 89TABLE I---Concluded

    Vaccines iven

    PR8SwineCuppettFM1

    PR8CuppettSwineFM1

    CuppettPR8SwineFM1

    CuppettSwinePR8FM1

    ControlNo Vaccine

    Group Bleeding

    7 123456

    8 123456

    9 123456

    10 123456

    11 123

    Titer wi th tes t s tra insSwine PR8

    0 0128 2,048256 1,024128 1,024646406464256

    25625606464256

    128128

    1,02451201,0241,024512

    51251202561,024512

    2562560 064 128512 256

    256 512128 128128 128

    0 320 320 32

    I FM1 Cuppett256 644,096 1,0244,096 1,0244,096 512

    4,096 5122,048 256128 322,048 2564,096 5124,096 512

    4,096 5124,096 256256 328,192 1,0248,192 5124,096 512

    4,096 5124,096 512128 04,096 5124,096 512

    4,096 2562,048 2562,048 128

    512 32512 32512 32* The first bleeding was obtained atwere carried out at 2-week intervals.1: Last vaccine given.

    the time of the first vaccination. Successive bleedings

    mologous anti body response was excellent. Low levels of an tibod y to swine virusdeveloped. PR8 vaccine effected a marke d reinforc ement of antibod y to FM1and Cuppet t, although the final yield of A-prime anti body was less tha n th atobserved after swine vaccine. Vaccina tion with either FM1 or Cupp ett yieldeda good homologous antibod y increase. The heterologous anti body response to

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    90 ANTIBODY RESPONSE TO MONOVALENT VACCINEthe corresponding A-prime strain was also of a high order. However, FM1vaccine did not stimulate the production of measurable antibody to swine orPR8 virus, and the response after Cuppett vaccine was minimal.

    The most striking characteristic of these results is that all the vaccinesinduced a marked heterologous antibody response to A-prime strains, whilenone produced more than minimal heterologous antibody levels to PR8 orswine. These findings are a clear demonstration of persistent orientationto antibody formation resulting from initial experience with influenza. Theprimary infections of this age group were influenza A-prime, and a markedheterologous antibody response to A-prime strains resulted even though thevaccines given were as remotely related antigenically to influenza A-prime asPR8 and swine.Table I shows antibody levels determined before and at 2-week intervalsafter multiple vaccinations with swine, PR8, FM1, or Cuppe tt given alone orin the sequences indicated. Maximal antibody levels to homologous andheterologous viruses were generally reached at 2 weeks (Groups I to IV). It isnoteworthy that repeated vaccination of children with the same strain did notlead to a broadening of heterologous antibody response to PR8 or swine. Thedependence of the development of significant levels of antibody to PR8 orswine in children upon vaccination with these viruses is emphasized by thefindings in Groups 5 through 10. In all instances the appearance of high levelsof antibody to swine or PR8 was delayed until 2 weeks after the use of thehomologous vaccine.Close scrutiny of the data in Table I yields several provocative observations.In children, swine vaccine induced higher levels of antibody to FM1 and Cup-pert than did vaccination with either of these A-prime strains. (Group I, c . f .Groups 3 and 4). Vaccination with PR8 was less effective in stimulating highlevels of anti-influenza A-prime antibodies than swine, FM1, or Cuppett vac-cines. (Group 2, c.f. Groups 1, 3, and 4). These findings suggest tha t swine viruscontains a more representative selection of the antigenic components commonto strains of influenza A-prime than are apparent in either PR8, FM1, or Cup-pet t viruses. However, prior vaccination with PR8 or Cuppet t viruses appearedin most instances to suppress the capacity of swine vaccine to stimulate maximalA-prime antibody levels (Groups 7 to 10, c.f. Groups 5 and 6). Further examplesof suppression of maximal antibody yield when different vaccines were given insequence are the lower titers of swine antibody found when PR8 or Cuppettstrains were administered before swine vaccine (Groups 7 to 10, c.f. Groups 5and 6), and the lower titer of PR8 antibody resulting when swine vaccine(Group 5) or Cuppett and swine vaccines (Group 10) were used before PR8vaccine (c.f. Groups 2, 7 to 9). The mechanism of these results canno t beexplained at present. Suppression of maximal antibody yield when vaccinesare given in sequence could result through neutralization of antigen by anti-

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    F R E D M . D A V E N P O R T A N D A L B E R T V . H E N N E S S Y 91bodies already evoked by the preceding vaccines, or perhaps antigens givenafter the initial one may fail to provide a maximal challenge to an antibody-forming mechanism already stimulated to produce antibodies to closely relatedviruses. Whatever the mechanism may be, the results illustrate the suppressiveeffect of prior experience with antigenic variants of influenza viruses upon theantibody response to strains subsequently experienced. In this sense, the find-

    16384~4096~1024~256~16384~40961024~256~16384l~4096~1024~2561~16384~4096~1024~2 5 6 f

    ,SWINEVACCINESSWINE

    T E S T S T R A I N SPR 8 FMI CUPPETT

    PR8

    FMI

    CUPPETT ~[~

    FIG. 2. Antibody response in recruits aged 17 to 26 years to monovalent influenza virusvaccines.ings herein described after vaccinat ion are similar to those reported previouslyafter infection (2, 4).Antibody Response in Military Recruits to Monovalent Vaccines.--The samevaccines were given to military recruits whose initial infections at childhoodoccurred during the period of prevalence of influenza A. Fig. 2 shows antibodylevels found in pools of sera obtained before and 2 weeks after each vaccina-tion. In contrast to the results in children, swine virus vaccine produced inrecruits a marked reinforcement of antibody to PR8, and only slightly rein-forced A-prime antibody levels. The final titer of homologous antibody toPR8 vaccine was greater than in children but the heterologous antibody in-

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    92 ANTIBODY RESPONSE TO MONOVALENT VACCINEcrease measured with A-prime strains was considerably less. Vaccination ofrecruits with A-prime strains stimulated levels of A-prime antibody, whichwere lower than those observed in children. The A-prime vaccines supportedantibody levels to PR8, though to a lesser extent than did swine vaccine.Minimal heterologous antibody levels to swine virus followed the administra-tion of PR8 and A-prime viruses. The dominant effects of the initial influenzaA infections of this segment of the population upon their antibody responsewhen subsequently exposed to influenza viruses are again demonstrated byreinforcement of PR8 antibody levels by all vaccines even though they were asdistantly related antigenically to PR8 as swine and A-prime strains. I t will berecalled t ha t persons cur rently of milita ry recruit age have repeatedly beenexposed to influenza A-prime since 1946. The spectrum of antibodies at thisage in interepidemic periods is broader than in childhood and comprises anti-body to many A and A-prime strains (1, 2, 4). The suppressive effect of thisbroader composite of antibody upon the serologic response to influenza virusesis seen by the development of lower levels of antibody to swine and A-primestrains in recruits, than in children, when the homologous vaccines were given.

    The results of other experiments in which the same vaccines were givenrepeatedly or alternately, as described in the preceding section on antibodyresponse in children, were confirmatory of the observations illustrated andwill not be presented in detail. Broadening of antibody response in recruits onrepeated administration of the same vaccine was not observed.

    Ant ibody Response in Persons over 30 Years o f Age to Monovalent In f luenzaVi rus Vacc ines . - -The results of previous studies led to the inference that peopleover 30 years of age had probably encountered strains of influenza virusantigenically closely related to those of swine influenza at the time of theirchildhood experience with influenza (1-4). To test this inference further andto evaluate the antibody-orienting capacity of such childhood experiences, thesame monovalent vaccines were given to adults aged 30 or more. In Fig. 3representative antibody levels found before and 2 weeks after vaccination arereproduced. In this age group ant ibody to swine virus is present before vaccina-tion (1-4). The level of postvaccination antibody homologous for that strainwas the highest observed in this study. Heterologous antibody response toSwine vaccine, as measured with PR8 or A-prime strains, was the least seen inthe three age groups tested. PR8 vaccine increased heterologous antibodyto swine virus, but did not consistently increase antibody levels to A-primestrains. The homologous antibody response to PR8 was less than tha t observedin children or recruits. A-prime vaccines given to persons over 30 years of ageyielded an antibody response to the A-prime viruses used for testing similar tothat seen in recruits, but considerably less than was found in children. Rein-forcement of antibody levels to PR8 and to swine virus was affected by A-primevaccines, and it is noteworthy that the postvaccination levels of antibody

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    ~'RED ~. DAVENPORT AND ALBERT V. ttENNESSY 93m e a s u r e d w i t h s w i n e v i ru s a f t e r v a c c i n a t i o n w i t h e i t h e r P R 8 o r A - p r im e s t r a i n sw e r e a l m o s t e q u a l t o t h a t o b s e r v e d a f t e r s w i n e v a c c in e w a s g i v e n.T h e r e s u l ts o b s e r v e d i n p e r s o n s o v e r 30 y e a r s o f a g e a d d f u r t h e r s u p p o r t t ot h e i n f e r e n c e t h a t t h e i n i t i a l e x p e r i e n c e s o f t h i s c o h o r t o f t h e p o p u l a t i o n w e r ew i t h v i r u s e s a n t i g e n i c a l l y c l o s e l y r e l a t e d t o s w i n e v i r u s s i n c e r e i n f o r c e m e n t o fa n t i b o d y l e v e l s t o s w i n e v i r u s f o l l o w e d t h e u s e o f a l l o f t h e v a c c i n e s g i v e n .

    T E S T S T R A IN SS W I N F . P R 8 F M C UP P E T T1 8 3 8 4 V A C C I N E S4 0 9 6 11024 SWINEI"2 5 8 6 4 $ I ~< 3 2 ' ,

    1 6 3 8 44 0 9 6

    < 3 2 I ' ~1 6 3 8 44 0 9 61 0 2 4 F M I I

    6 4( 3 2

    1 6 3 8 44 0 9 6 C U P P E T T

    2 5 68 4 _ [ ]< 3 2

    FIG. 3. Antibody response in persons over 30 years of age to monova lent influenza virusvaccines.S u p p r e s s i o n o f a n t i b o d y r e s p o n s e o w i n g t o t h e b r o a d c o m p o s i t e o f a n t i b o d i e sc h a r a c t e r i s t i c o f t h i s a g e g r o u p , w h i c h c o m p r i s e s a n t i b o d i e s t o s w i n e , A , a n ds o m e A - p r i m e s t r a in s , i s s e en i n t h e d i m i n i s h e d h o m o l o g o u s a n t i b o d y r e s p o n s et o P R 8 v a c c in e s . T h e p o s t v a c c i n a t i o n l e v el r e a c h e d w a s t h e l o w e s t o bs e r v e di n t h i s s t u d y . A s i n r e c ru i t s , v a c c i n a t i o n w i t h A - p r i m e s t r a i n s l e d t o l o w e r l e v e l so f h o m o l o g o u s a n t i b o d y t h a n u s e o f A - p r i m e v a c c i n e s i n c h i l d r e n . A d m i n i s t r a -t i o n o f t h e f o u r m o n o v a l e n t v a c c i n e s r e p e a t e d l y o r a l t e r n a t e l y t o p e r s o n s o v e r3 0 y e a r s o f a g e d id n o t p r o d u c e a b r o a d e n i n g o f a n t i b o d y r e s p o n s e .Antibody Response to Monovalent Vacc ines Measured with Ma ny A and A-prime Stra ins R epresentative of the Kn ow n Period of Prevalence of These T ypes of

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    9 4 A N T I B O D Y R E S P O N S E T O M O N O V A L E N T V A C C I N E

    Influenza Virus.--Primary e x p e r i e n c e w i t h i n f lu e n z a v i r u s e s b y v a c c i n a t i o no r i n f e c t i o n l e a d s t o t h e p r o d u c t i o n ~ o f a n t i b o d y o f l i m i t e d s c o p e , w h i c h i ng e n e r a l r e a c t s m o s t r e a d i l y w i t h t h e s t r a i n r e s p o n s i b l e f o r t h a t p a r t i c u l a ra n t i g e n i c s ti m u l u s . F a m i l i a r e x a m p l e s a r e t h o s e s ee n i n t h e a n t i b o d y r e s p o n s e

    T E S TSTRAINS CAM~A G - 8 1 9 2

    2 0 4 64-10 102451 22 56128643 2

    3 0 102,45122 5 612 8

    643 2< 3 2

    .CAM('46'~0EA1~48) OMA~49)T E N 50') ENC,(5 JC.ON Y(5~W RlCr(53)MAI.~K54 )

    d

    FIG. 4. Antibody response to Cupp ett virus vaccine n children, recruits, and persons o ver30 years of a g e a s measured with T ype A-prime strains.o f fe r r e t s , m i c e , c h i ck e n s , a n d o c c a s i o n a ll y o f h u m a n s ( 8 ). H o w e v e r , i t w o u l ds e e m re a s o n a b l e t o e x p e c t t h a t t h e v a r i e t y o f a n t ig e n i c e x p e r i e n c e s o f t h eb u l k o f t h e h u m a n p o p u l a t io n w o u l d b e m u c h r i ch e r t h a n t h a t o f t h e e x a m p le sc i t e d , o w in g t o t h e f r e q u e n t r e c u r r e n c e o f i n f lu e n z a c a u s e d b y t h e p r e v a l e n c eof v i ruses o f d i f f e r en t an t i gen i c compos i t i on . I n consequence , i t s eemed l i ke l yt h a t t h e a n t i b o d y r e sp o n s e o f h u m a n s m i g h t b e b r o a d e r t h a n t h a t s e en ine x p e r i m e n t a l a n i m a l s. T o a s c e r t a i n t h e d i m e n s i o n s o f t h e a n t i b o d y r e s p o n s e o fh u m a n s t o v a c c in e s p r e p a r e d f r o m p r o t o t y p i c v i r u se s , a n t i b o d y l e v e ls in s e r a

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    F R E D M . D A V E N P O R T A N D A L B E R T V . H E N N E S S Y 95

    o b t a i n e d b e f o r e a n d 2 w e e k s a f t e r v a c c i n a t io n w i t h A a n d A - p r i m e s t r a i n s w e r em e a s u r e d w i t h v i r u s e s i s o l a t e d d u r i n g t h e p e r i o d o f p r e v a l e n c e o f t h e s e i n f e c -t i o n s .

    TESTSTRAIN . WS~33) PRS(3~MEL~)BLOOM~'~TO'~i~a~Ulv~40~GIDC40)DSP(,43")WEISS(4~AGE 8192409620484-10 1024512 15612864323 0 I 0 2 45 ~ 2 !2 5 6 !2 8

    < 3 2 ]

    J

    FIG. 5. Antibody response to PR8 virus vaccine in children, recruits, and pe rsons over 30years of age as measured with Type A strains.I n F i g . 4 , t h e a n t i b o d y r e s p o n s e t o C u p p e t t v a c c i n e i n c h il d r e n , re c r u i t s , a n d

    p e r s o n s o v e r 3 0 y e a r s o f a g e , a s d e t e r m i n e d w i t h A - p r i m e s t r a i n s i s o l a t e d b e -t w e e n 1 9 4 6 a n d 1 9 5 4 i s s h o w n . I t i s e v i d e n t t h a t t h e a n t i b o d y r e s p o n s e t oC u p p e t t v a c c i n e a s m e a s u r e d w i t h a n t i g e n i c a l ly a n d c h r o n o l o g i c a l ly r e p r e s e n t a -t i v e s t r a i n s o f i n f l u e n za A - p r i m e w a s g r e a t e s t i n c h i l d r e n , l e s s i n r e c r u i ts , a n dl e a s t i n p e r s o n s o v e r 3 0. M o r e o v e r , w i t h i n e a c h a g e g r o u p , t h e a n t i b o d y r e s p o n s et o t h e v i r u s e s u s e d f o r t e s t i n g w e r e r e m a r k a b l y u n i f o r m . S i m i l a r r e s u l t s w e r eo b t a i n e d w i t h F M 1 v a c c i ne . I n F i g . 5 a n t i b o d y r e s p o n s e t o P R 8 v a c c i n e a sm e a s u r e d w i t h r e p r e s e n t a t i v e s t r a i n s o f i n f l u e n z a A , i s o l a t e d b e t w e e n 1 9 3 3

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    95 ANTIBODY RESPONSE TO MONOVALENT VACCINEand 1943 , i s shown. H i gh l eve l s o f an t i body were i nduced t o a l l o f t he t es tv i ruses, al though the f inal y ield to Melbourne (1935) , Gatenby (1937) , andD SP (1943) were low in chi ldren. The se f indings emphasize the r ichness of thehuman populat ions ' past exper ience wi th the ant igens that comprise inf luenzav i rus , and sharp l y d i f f e r en t i a t es t he an t i body r esponse o f humans f rom t ha tseen in exper imental animals n ot prev iously exposed to influenza vi ruses.

    DISCUSSIONThe exper imental f indings repor ted in th is paper provide a remarkable

    i l lust ration of the persi s tent ant ibody-or ien t ing effects produ ced by the m ajorant igens of the v i ruses encoun tered in the pr im ary infect ions of chi ldhood.Thus, regardless of the s t rain of v i rus g iven by vaccinat ion, the chi ldren re-spond ed by producing ant ibodies to s t rains of inf luenza A -prime, the m i l i taryrecrui t s to s t rains of inf luenza A, and the persons over 30 years of age to ast rain of swine inf luenza. T he c hi ldhood infect ions of these th ree segm ents ofthe populat ion were wi th inf luenza A-pr ime, wi th inf luenza A, and wi th in-f luenza caused b y swine-l ike s t rains respect ively (1 , 2) . Howe ver , the res ul t s ofth is s tudy disclose more than the ant igenic character i s t ics of the s t rains ofpr imary infect ion. They would appear to provide a serologic index of theamoun t o f i n fec t i on wh i ch each o f t hese t h ree age g roups have exper i encedwith influenza A-prime, influenza A, and influenza caused by swine-l ike strains.Such a serologic appraisal bec ome s possible beca use i t was found tha t the ant i -bod y r esponse o f humans t o m onoval en t vacc i nes was s t r i k ing l y t ype-spec i fi c ;i . e . , to swine, A, or A-pr ime st rains , save for those instances wherein ant ibodyresponse to hete rotypic v i ruses could be explained by previous experience. Fo rexampl e , i n ch il d ren l i t t le o r no an t i body t o PR 8 o r swine v i rus was p roduce dexcep t by vacc i na t i on wi t h t he homol ogous s t r a i n . Never t he l ess , very h i ghl eve ls o f A-p r ime an t i bod i es deve l oped af t e r vacc i na t i on wi t h swine , Ty pe A,or A-pr ime vi ruses. Clear ly th is resul t indicates that ant i A-pr ime ant ibodiesproduced in human sera by vaccinat ion show l i t t l e or no in t r insic serologiccross-react iv i ty wi th A or swine s t rains . In l ike vein , recrui t s d id not developmore t han mi n i mal an t i bod y l eve ls t o swi ne v i rus, de sp i t e t he deve l opm en t o fhigh levels of Type A ant ibody. Again the lack of in t r insic serologic cross-reac t iv i ty betw een anti -influenza A ant ibodies and swine vi rus i s emph asized.I f i t is g r an t ed t ha t t he ev i dence p resen t ed war ran t s t he i n ference t ha theterotypic ant ibody response to vaccinat ion largely ref lects pr ior exper iencerathe r th an serologic cross-react iv i ty , it becom es possible to recon st ruct th eprevious ant igenic experiences o f each of the age groups s tudied. The an t ibod yresponse o f t he ch i ld ren t o mon oval en t vacc i nes i nd ica t es t ha t as a g roup t h eyhave h ad l i tt l e exposu re t o t he domi nan t an t i gens o f Typ e A o r swi ne st r a in s .Recrui t s have al so had a l imi ted exper ience wi th the major ant igens of swinevi rus but thei r heterotypic ant ibody response to s t rains of inf luenza A-pr ime

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    F R E D M . D A V E N P O R T A N D A L B E R T V . H E N N E S S Y 97ind ica te s tha t th i s age g r oup has had cons ide r ab le expe r ience wi th in f luenzaA- pr im e , in add i t ion to the i r p r im ar y in f ec t ions wi th in f luenza A. L ikewisepe r sons ove r 30 yea r s o f age r eac t a s i f a f t e r th e i r in i t i a l in f ec tions wi th swine -l i k e st r a in s , t h e y s u b s e q u e n t l y e x p e ri e n ce d a n i m p o r t a n t a m o u n t o f i n f e c t i o nw i t h i n f lu e n z a A , b u t a g r e a t l y d i m i n i s h e d a m o u n t o f i n f e c t io n w i t h i n f l u e n zaA- pr im e . I t would appea r , the r e f or e , tha t de l inea t ion of the cha r ac te r i s t i c s o fa n t i b o d y re s p o n se o b t a i n e d in t h r e e s e g m e n t s o f t h e p o p u l a t i o n a f t e r v a c c i n a -t ion w i th m o nov a len t in f luenza v i r us vacc ines , p r ov ides a s e ro log ic r ecap i tu la -t ion o f each coh or t ' s pas t expe r iences wi th an t igen ic va r ia n t s o f in fluenza v ir us .The use o f vacc ines f o r th i s pur pose i s be l i eved to be a new deve lopm ent inserologic epidemiology.

    S U M M A R Y

    T h e r e s u lt s o f th e p r e s e n t s t u d y p r o v i d e a s t r i k i n g d e m o n s t r a t i o n o f a n t i b o d yo r i e n t a t i o n p r o d u c e d b y t h e d o m i n a n t a n t i g e n s o f t h e s t r a i n s o f i n f l u e n z av i r u s e n c o u n t e r e d a t c h i l d h o o d . T h e h o m o l o g o u s a n d h e t e r o l o g o u s a n t i b o d yr e sp o n s e t o m o n o v a l e n t v a c c in e s c o n t a i n in g s w in e , P R 8 , F M 1 , o r C u p p e t tv i r u se s s h o w t h a t t h e a n t i b o d y - f o r m i n g m e c h a n i s m s o f c h i ld r e n b o r n a f t e r1943 a r e o r ien ted to s t r a ins o f in f luenza A- pr im e ; o f r ec r u i t s to s t r a ins o f in -f luenza A; an d of pe r sons ove r 30 yea r s o f age to a s t r a in o f swine in f luenza .I t w a s s h o w n t h a t a n t i b o d y r e sp o n s e t o h e t e r o t y p i c v i r u se s a p p e a rs t o p r o v i d e ase ro log ic index of the am ou nt o f expe r ience each of the s eg m ents o f the g ene r a lp o p u l a t i o n s t u d i e d h a v e h a d w i t h a n t i g e n i c v a r ia n t s o f i n fl u e n za v ir u s . F i n a l l yi t w a s d e m o n s t r a t e d t h a t t h e a n t i b o d y r e s p o n s e o f h u m a n s t o s t r a i n s o f i n -f luenza A or in f luenza A- pr im e i s r em ar k ab ly u n i f or m f or i so la te s o f each an t i -gen ic type .

    BIBLIOGRAPHY1. Francis, T. , Jr . , Davenport, F. M., and Hennessy, A. V., Tr. Am. Assn. Physn.1953, 66, 23 1.2. Dav enpo rt, F. M., Hennessy, A. V., and Francis, T. , Jr . ]. Exp. Med.,1953, 98, 641.3. Davenport, F. M., Hennessy, A. V., Stuart-Harris, C. H., and Francis, T. , Jr . ,Lama, 1955, 9.69, 469.4. Hennessy, A. V., Davenport, F. M., and Francis, T. , Jr., J. Immunol., 1955, 75,401.5. Laidlow, P. R., Lama, 1935, 1, 1118.6. Shope, R. E. , ]. Exp. Med., 1936, 63, 6 69.7. Comm ittee on S tanda rd Serologic Procedures in Influenza Studies, ]. Immunol.,1950, 65, 3 47.8. H ennessy, A. V., Dav enpo rt, F. M., and Francis, T. , Jr . , Fed. Proc.,1955, 14, 465.