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Milwaukee, Wis.


T HAS been demonstrated conclusively in recent years that subcutaneous injection of

influenzal virus vaccine will produce an immune response in most 2 It has

been shown also that this response, which consists of an increase in serum antibody titer,

is directly related to immunity to clinical influenza.3

Francis and Magill’#{176} and Rickard and Horsfall’1 have found that the serum of the

newborn infant has about the same antibody titer as that of its mother, but that after the

first month of life there is a marked drop in titer which lasts from the 12th to 18th month

when it begins to rise, reaching the maximum in the 20 to 40 year age group. Children,

especially those under the age of five years, need the protection which immunization may


Relatively little is known about the response of infants and children to the injection

of influenzal vaccine. Cohen and Schneck12 have reported recently data on the

subcutane-Ous injection of the vaccine in 100 children and found that those under two years of

age did not delop any increase in antibody titer, whereas the response was present in

the 2 to 13 year old group.

Tuft13 recognized the value of the skin as an immunologic organ and demonstrated that adequate immunity could be produced against typhoid fever by the intracutaneous

injection of small amounts of typhoid vaccine. Later, satisfactory immune responses were

obtained by the intracutaneous injection of diphtheria toxoidl4tO and scarlet fever

toxin.17-19 Van Gelder et al.2#{176}reported results obtained by both the intracutaneous and

the subcutaneous injection of infiuenzal vaccine. They found that one injection of 0.1 ml. of vaccine injected intracutaneously produced a higher serum antibody titer than 1.0 ml.

subcutaneously or two intracutaneous injections at one week intervals. Because of these

results, it was decided to investigate the response by children to the intracutaneous

injec-tion of influenzal vaccine.


From Nov. 1947 to Feb. 1948, 49 children ranging in age from 4 mos. to 13 yrs. were given 0.1 ml. each of influenzal virus vaccine, types A and B,* intracutancously. Blood for serum antibody titer determination was drawn at the time of vaccination and again 4 wks. later. Four wks. was chosen as the interval for the determination of titers as it has been demonstrated that the immune response

is probably the greatest at that time. Antibody levels were determined by a modification of the method described by Hirst.f” Each child’s temperature was taken every 4 hrs. for 24 hrs. following vaccination, or longer if the temperature was elevated.


Table I is a summary of the pre- and postvaccination titers together with the fold increase. As all of the antibody titers were not done on the same day with the same lot of antigens, the titers on the

From the Milwaukee County Hospital Department of Pediatrics and the Home for Dependent Children, Milwaukee, Wis.

(Received for publication Oct. 29, 1948.)

* Furnished by Eli Lilly, Co., Indianapolis, Ind., in September 1947.

1’ Titers were determined by Dr. H. M. Powell of the Eli Lilly Co.





Prevaccination Postvaccination Fold Increase

Name Age Titer Titer

Type A Type B Type A Type B Type A Type B

R.McK. 4mos. < 8 8 128 256 >16 32

J. J. 4 mos. 64 32 128 128 2 4

M. D. 5 mos. 32 32 512 512 16 16

R. M. 5 mos. 32 16 128 64 4 4

J. T. 6 mos. 8 32 64 128 8 4

V.M. 8mos. <8 <8 8 16 >0 >2

B.W. 9mos. <8 <16 32 64 > 4 > 4

E. T. 10 mos. 8 8 32 32 4 4

M. P. 10 mos. 16 8 64 64 4 8

M. O’B. 10 mos. 8 16 32 64 4 4

R.F. lyr. 32 32 64 128 2 4

H.O. lyr. 8 <8 128 256 16 >32

S.B. lyr. <8 <8 64 64 >8 >8

H.T. l4yrs. 8 8 <128 < 64 > 8 > 4

S.R. l4yrs. 64 8 128 32 2 4

H.R. l4yrs. < 8 8 16 16 > 2 2

B. S. 2 yrs. 8 8 128 128 16 16

C.C. 2yrs 8 8 64 16 8 2

P.B. 24yrs. 8 8 <256 < 64 >16 > 4

J.B. 3yrs. 8 8 <256 32 >16 4

M. G. 34 yrs. < 8 < 8 32 128 > 4 >16

P.P. 34yrs. < 8 < 8 <128 256 16 >32

M.Z. 34yrs. <8 <8 32 128 >4 >16

R.O. 4yrs. < 8 8 128 32 >16 4

D. F. 4 yrs. < 8 8 128 < 64 >16 > 4

J.A. 4yrs. 16 32 256 256 16 8

A. M. 44 yrs. < 8 < 8 32 32 > 4 > 4

J.F. 44yrs. 16 32 128 64 8 2

A. G. 44 yrs. 16 < 8 128 < 32 8 4

G. S. 5 yrs. 32 < 8 <1024 32 >16 > 4

J.R. Syrs. 32 16 64 32 2 2

S. K. 5 yrs. 16 8 1024 <128 64 > 8

E. L. 5 yrs. 32 16 128 16 4 0

R.T. Syrs. 16 <16 64 < 64 4 4

D I. S4yrs. 8 8 32 16 4 2

J.Mc. S4yrs. <8 8 16 32 >2 4

C. S. 54 yrs. 32 16 256 512 8

K.G. 6yrs. 32 32 128 64 4 2

R. L. 6 yrs. 16 8 32 32 2 4

L. 0. 6 yrs. <16 < 8 128 16 > 8 > 2

F. R. 6 yrs. 16 16 64 256 4 16

K.R. lOyrs. 16 32 <1024 256 32 8

J.A. lOyrs. 16 8 256 256 > 8 32

J.B. lOyrs. 64 128 128 256 2 2

E.J. lO4yrs. 64 32 256 64 4 2

G. D. 11 yrs. 128 32 256 128 2 4

K.K. ilyrs. 64 32 256 128 4 4

M.W. ilyrs. 128 32 512 64 4 2



various subjects cannot be compared. The fold increase in titer is a stable figure and may be used

to compare the response produced in all subjects.

Table II presents a summary of the mean fold increase in titer for the various age groups. Con-sidering a 2-fold increase in titer of doubtful significance and a 4-fold or more increase as an indication of adequate immunity to influenza, it is seen that 68% of the children in the 4 mos. to

2 yr. old group produced a good response to type A and 81% to type B. In the 2 to 5 yr. old group,

100% developed a 4-fold or more increase in titer to type A and 61% to type B. Thus, of the children under 5 yrs. of age, 82% developed adequate immunity to type A and 72% to type B. In the 5 to 13 yr. old group, 70% developed adequate immunity to type A and 65% to type B.




Type A Vaccine

. Age Group Undcr2yrs. 2yrs.to5yrs. Number 16 13 Mean Fold Increase 4.55 9.90 .

Syrs.andover 20 5.10


2 yrs. to 5 yrs.


Type B Vaccine

16 13 20 5.66 6.13 4.14

One child of 8 mos. failed to produce any response to type A and another child of 5 yrs. did not produce a response to type B.


The incidence of reactions was low as would be expected with intracutancous injections. A few of the older children complained of some burning when the vaccine was injected, but on the whole it was no worse than the discomfort produced by a Schick test. Most of the children developed some erythema about the site of injection, but it disappeared within the first 24 hrs. About half of the children under 5 yrs. of age had a fever of 37.8#{176}to 38.1#{176}C. at some time during the first 24 hrs.

One child of 4 yrs. had a temperature of 40#{176}for about 4 hrs. and 8 had temperatures up to 38.8#{176}C. One child’s temperature went up to 38.8#{176}to 39.4#{176}and remained there for 2 days, but the pharynx was red and the child appeared to have an upper respiratory infection.


While the results obtained in children do not compare with those obtained by Van

Gelder2#{176}and his coworkers in adults, they are significant in that they demonstrate that

the majority of children will respond to the intracutaneous injection of influenzal vaccine by increasing the amount of serum antibodies at least four times over the prevaccination level. Because of the low incidence of reactions to the intracutaneous injections and the

slight chance of producing allergic reactions, it would be a more suitable method for immunizing large groups of children. The subcutaneous injection of influenzal vaccine produces severe reactions in some children. In a series of 309 patients from 2 months to 15 years who were immunized by the subcutaneous injection of influenzal vaccine, 36%

had mild reactions and 5.5% severe reactions (fever of 38.8#{176}or more) 23 One child of 11 months developed convulsions and a temperature of 400 C.


determine if multiple injections are more satisfactory in children than in adults. It has

been suggested that the intracutaneous injection acts only as a booster to stimulate

im-munity which the individual developed previously through exposure to influenza, and that

therefore the basic immunization must be produced by means of subcutaneous injections.

If this were true, the subcutaneous injection of the vaccine should have produced much

higher antibody titers than were obtained using the intracutaneous route.

Cohen and Schneck12 obtained no response in children under 2 years of age and the

mean fold increase in type A titer for the 2 to 7 year group was 8.5 times and for type

B, 23.3 times. In the 7 to 10 year old group they produced a mean fold increase in type A

titer of 7 times and type B, 10.5 times.

Larger groups of children must be studied to determine the merits of the intracutaneous and subcutaneous injections. No definite conclusions can be drawn from this study except

that it has shown that infants will develop an immune response to the intracutaneous



Forty-nine children from 4 months to 1 3 years of age were immunized by a single

intracutaneous injection of influenzal vaccine. An immune response, as indicated by the

increase in serum antibody titer, was produced in 99% of the children. The response in

the group below 2 years of age was greater than previously reported responses to the

subcutaneous injection of influenzal vaccine.


1. Francis, T., Jr., Influenza: Methods of study and control, Bull. New York Acad. Med. 21:337, 1945.

2. Hirst, G. K., Rickard, E. R., Whitman, L., and Horsfall, F. L., Jr., Antibody response of human beings following vaccination with influenza virusesp J. Exper. Med. 75:495, 1942.

3. Henle, W., Hcnlc, G., and Stokes, J., Jr., Demonstration of efficacy of vaccination against

influenza A by experimental infection of human beings, J. Immunol. 46:163, 1943.

4. Hirst, G. K., Rickard, E. R., and Friedewald, W. F., Strides in human immunization against influenza, 3. Expcr. Med. 80:265, 1944.

5. Hirst, G. K., Plummer, N., and Friedewald, W. F., Human immunity following vaccination with

formalinizcd influenza virus, Am. 3. Hyg. 42:28, 1945.

6. Salk, 3. E., Pearson, H. E., Brown, P. N., Smyth, C. J., and Francis, T., Jr., Immunization

against influenza with observations during an epidemic of influenza A one year after vaccina-tion, Am. J. Hyg. 42:307, 1945.

7. Magill, T. P., Plummcr, N., Smillie, W. G., and Sugg, J. Y., Evaluation of vaccination against influenza, Am. J. Hyg. 42:94, 1945.

8. Francis, T., Jr., Salk, J. E., and Brace, W. M., Protective effect of vaccination against epidemic

influenza B, J.A.M.A. 131:275, 1946.

9. Francis, T., Jr., Salk, 3. E., Pearson, H. E., and Brown, P. N., Protective effect of vaccination against induced influenza A, J. Clin. Investigation 24:536, 1945.

10. Francis, T., Jr., and Magill, T. P., Incidence of neutralizing antibodies for human influenza

virus in serum of human individuals of different ages, 3. Exper. Med. 63:655, 1936. 11. Rickard, E. R., and Horsfall, F. L., Jr., Relationship between neutralizing antibodies against

influenza A virus in sera of mothers and infants, J. Immunol. 42:267, 1941.

12. Cohen, P., and Schneck, H., Effect of influenza virus vaccination in infants and children, with antibody studies, 3. Pediat. 32:161, 1948.

13. Tuft, L., Skin as immunological organ with results of experimental investigations and review of literature, J. Immunol. 21:85, 1931.


15. Kern, R. A., Crump, J., and Cope, T. A., Diphtheria immunization of allergic and non-allergic

individuals by intracutaneous injection of alum-precipitated toxoid, J. Allergy 6:525, 1935.

16. Blatt, M. L., Fisher, S., and Van Geldcr, D. W., Intradermal immunization: Diphtheria, Am. J. Dis. Child. 62:757, 1941.

17. Robinson, J. H., Active immunization to scarlet fever by intracutaneous method, J. Immunol.

31:373, 1936.

18. Earle, C. A., Intradermic immunization against scarlet fever, Illinois


J. 74:248, 1938. 19. Fisher, S., and Van Gelder, D. W., Intradcrmal immunization: Scarlet fever, Am. J. Dis. Child.

61:88, 1941.

20. Van Gelder, D. W., Greenspan, F. S., and Dufrcsne, N. E., Influenza vaccination: Comparison

of intracutaneous and subcutaneous methods, U. S. Nay. M. Bull. 47:197, 1947.

21. Hirst, G. K., Agglutination of red cells by allantoic fluid of chick embryos infected with in-fluenza virus, Science 94:22, 1941.

22. Hirst, G. K., Quantitative determination of influenza virus and antibodies by means of red cell

agglutination, J. Exper. Med. 75:49, 1942. 23. Unpublished data.


Vacuna de Influ:nza: Efecto de Ia Inmunizaci#{244}n Intracutanea

en Infantes y Nifios

Se les puso Ia vacuna de influenza de 0.1 mg. tipos A y B. intracutaneamcntc a cuarenta y nueve nilios de 4 meses a 13 a#{241}osde edad. Los titulos dc anticucrpo de sucro fucron determinados antes

de la inmunizaci#{243}n y de nuevo cuatro semanas despu#{233}sde Ia inmunizaci#{243}n. Considerando un aumento

cuatro veces mayor en el titulo de anticuerpo de sucro una indicaci#{243}n del desarrollo de una inmunidad adecuada, se encontr#{243}que en los grupos de cuatro meses y dos aflos dc cdad el 68% dieron una

buena respuesta al tipo A y 81% al tipo B. En el grupo de 2 a 5 afios 100% di#{243}una rcspucsta

adecuada al tipo A y 61% al tipo B. En cI grupo de 5 a 13 aflos de edad 70% produjo una buena respucsta al tipo A y 65% al tipo B. Las reacciones a Ia inyccci#{243}nintracutanea de la vacuna fueron suaves y de poca consecuencia.







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