Simultaneous Administration of Live Attenuated Measles Vaccine With DTP Vaccine

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Simultaneous

Administration

of Live Attenuated

Measles

Vaccine

With

DTP Vaccine

A. Marshall McBean, M.D., Claude Gateff, M.D., Charles R. Manclark, Ph.D., and

Stanley 0. Foster, M.D.

From the Organization Pour hi Lutte Contre les End#{232},niesen Afrique Centrale, Yaound#{233},Canieroon; the

Division ofBacterial Products, Bureau ofBiologics, U.S. Food and Drug Administration, Bethesdij, Maryland;

and the Bureau of Smallpox Eradication, Center for Disease Control, Atlanta

ABSTRACT. Live attenuated measles vaccine was adminis-tered to Cameroonian children 12 to 39 months of age alone or with either diphtheria-tetanus toxoids or diphtheria and

tetanus toxoids and pertussis (DTP) vaccine. Among children

who were initially seronegative for measles hemagglutina-tion inhibition antibodies, seroconversion rates and postvac-cination geometric mean titers were similar in all groups. Pertussis antigen in the DTP vaccine was judged to be potent by laboratory potency testing and serologic response in

recipients of the vaccine. Thus, the two vaccines may be

administered simultaneously without compromising their immunogenicity. These results allow greater flexibility in planning individual or mass immunization schedules. Pediat-Tics 62:288-293, 1978, immunizations, measles vaccine, DTP, simultaneous immunizations.

The American Academy of Pediatrics, the U.S.

Government (Immunization Initiative), and the

World Health Organization (Expanded Program on Immunization) have assigned high priority to immunization programs. Prevention of morbidity and mortality requires effective immunizations before the age at which disease occurs.

Immunization schedules that maximize the

coverage attained in limited numbers of visits,

using safe and effective vaccine, need to be

developed to meet specific identified program

needs.

Simultaneous administration of multiple

vaccine antigens permits earlier and more

complete immunization of children than when each vaccine must be given separately. This is

particularly important in developing countries

where certain diseases, such as measles and

pertussis, occur at a young age. Further, modest

health budgets require that, whenever possible, several antigens be given concurrently in order to reduce the cost of vaccine administration.

Simultaneous administration of certain

combi-nations of presently available vaccines has proven

safe

and effective. These include diphtheria and tetanus toxoids with pentussis (DTP) vaccine’; the three oral polio vaccine strains2; DTP with monovalent oral polio vaccine’4; live measles vaccine with smallpox vaccine 7; live measles

vaccine with smallpox and yellow fever vaccines8; live measles with BCG’; and live measles with smallpox, yellow fever vaccines, BCG, and teta-nus toxoid.’#{176}

Although the majority of the associations tested have given acceptable results, simultaneous sepa-rate administration of certain vaccines has produced significantly lower titers of antibodies

than

when the same vaccines were administered separately. Cholera vaccine has been reported to reduce antibody response of simultaneously administered yellow fever vaccine during the first 30 days after vaccination.” Felsenfeld et al.’2 described a decrease in measurable antibodies to yellow fever and cholera as the time between the administration of the two vaccines decreased. Following the simultaneous administration of cholera and measles vaccines, Gateff et al.” found normally high rates of measles seroconversion in Cameroonian children. However, the

postimmu-nization titers in the children who received both

vaccines were lower than in those who received measles vaccine alone.

Received May 2; revision accepted for publication July 10,

1978.

Dr. McBean is now with the Vermont Department of Health, Burlington, and Dr. Gateff is now with the Institut National de Sante Publique, Abidjan, Ivory Coast.

ADDRESS FOR REPRINTS: (A.M.M.) Vermont

Depart-ment of Health, 60 Main Street, Burlington, VT 05401.

at Viet Nam:AAP Sponsored on September 8, 2020 www.aappublications.org/news

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TABLE I

IMMUNIZATION AND BLOOD COLLECTION SCHEDULE

#{176}Placebo= physiologic saline.

METHODS Immunizing Schedule

Vaccines

Ruben et al.” simultaneously administered live

measles, smallpox, and yellow fever vaccines to

Nigerian children 9 to 24 months of age with or

without DTP. The measles seroconversion rate in the children who received only the three live

virus vaccines was 90%. However, when the DTP

was added, the measles senoconversion rate drop-ped to 71%. The seroconversion rates to the other

antigens administered were normal. On the other

hand, Marshall et al.’5 found virtually identical, albeit low, seroconversion rates in small groups of Guatemalen children who received live measles

vaccine with or without DTP: 86% and 85%,

respectively. However, they did not evaluate the

potency or effectiveness of the DTP antigen.

Gateff et al.,’ working in Cameroon, adminis-tered a highly potent tetanus toxoid (120

Lf)

in

combinations with measles, smallpox, and yellow

fever vaccines and BCG. The immunogenicity of

the tetanus toxoid was demonstrated by the fact that greater than 85% of the previously suscepti-ble children had protective levels of antitoxin ( 0.02 lU/mi) after one dose of toxoid. Measles

seroconversion rates and geometric mean titers

(GMTs) were the same in the children receiving

measles and smallpox vaccine and those who

received measles and smallpox vaccine plus

teta-nus toxoid. Noonan (unpublished data)

adminis-tered measles, smallpox, live polio, and yellow fever vaccines and DTP simultaneously to Nigeni-an children. The diphtheria and tetanus toxoids were potent as assessed in the laboratory before and after use, and high protection rates were seen

in vaccinated children. No suppression of measles

seroconversion was seen. Unfortunately, the

pertussis component of the DTP vaccine was not

potent. The present controlled field trial under-taken in Cameroon, therefore, focuses on the role, if any, which pertussis antigen has on the

simul-taneous separate administration of measles

vaccine in young children.

Three hundred sixty-eight children 9 to 36

months of age residing in the Department of

M#{233}fou, Canieroon, who reported negative histo-ries for measles, diphtheria, pertussis, and tetanus

disease and immunization were included in the

study.

Commercially licensed measles vaccine,

diph-thenia-tetanus toxoid (dT) vaccine, and DTP

vaccine were used. The attenuated live measles

vaccine was Moraten strain from lot 2639 R

(Merck Sharp & Dohme) (inclusion of trade

Day 0 Day 90 Day 125

Blood Blood A Blood B

collection Immunization

Group 1 Placebo#{176} Group 2 Placebo#{176}

Group 3 dT

Group 4 DTP

Placebo#{176} Measles dT & measles DTP & measles

DTP & measles DTP & measles DTP & measles DTP & measles

names is for identification only and does not

imply endorsement by the Public Health Service

of the U.S. Department of Health, Education and Welfare). The dT and DTP vaccines were from lots 23201 and 58710, respectively (Wyeth Labo-ratonies).

Measles vaccine was titened before and after the study. Undiluted vials of measles vaccine were chosen at random from (1) those vials received in Cameroon but not taken to the field, and (2) those

vials taken to the field but not diluted. These vials

were returned frozen to the Center for Disease Control (CDC) for titration had titers 4.5 log

tissue culture infective dose 50 per 0.5 ml. The dT

lot 23201 contained 6 units of diphtheria toxoid and 6 units of tetanus toxoid in three 0.5-mi immunizing doses. The DTP lot 58710 contained 22.9 units of pentussis vaccine, 12 units of tetanus toxoid, and 12 units of diphtheria toxoid in three

0.5-ml immunizing doses. The dT and DTP

potency testing was done by the Bureau of

Biologics, U.S. Food and Drug Administration. Both the dT and DTP vaccines were adsorbed with aluminum hydroxide adjuvant. The former contained 0.14 mg/mI of adjuvant, and the latter, 0.34 mg/mi.

On day 0 children were registered into the

study, and identifying information, age, and sex

were recorded. The children were given a consec-utive study number which had been randomly

preassigned to one of the four study groups. They

were then vaccinated according to the schedule in Table I. All vaccinations were given by needle and syringe, 0.5 ml per dose. Measles vaccine was given subcutaneously in the posterior aspect of

the right upper arm, and the dT and DTP

vaccines were given intramuscularly in the poste-nor aspect of the left upper arm. In order to provide optimal protection as soon as possible to

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Po5TISISIUNIZATI0N MEASLES HI TITERS, HI GMTS, AND SEROc0NvER5I0N RATES BY STUDY GROUP

TABLE II

AGE OF STUDY CHILDREN AND SUSCEPTIBILITY TO MEASLES AT STUDY DAY 90

Age (mo)

36-47

Total

r-12-14 15-17 18-35

Group 1

No. (%) susceptiblet Total No. 5 (100) 5 7 (88) 8 21 (34) 62 4 (33) 12 37 (43) 87 Group 2

No. (%) susceptible Total No. 7 (88) 8 6 (86) 7 27 (39) 70 3 (23) 13 43 (44) 98 Group 3

No. (%) susceptible Total No. 6 (100) 6 8 (57) 14 22 (37) 59 6 (46) 13 42(46) 92 Group 4

No. (%) susceptible TotalNo. 7#{176}(100) 7 10 (83) 12 26 (41) 63 4 (44) 9 47 (52) 91 Total

No. (%) susceptible Total No. 25 (96) 26 31 (76) 41 96 (38) 254 17 (36) 47 169 (46) 368

#{176}Onesusceptible child 11 months of age.

tReciprocal HI titer < 10.

the study children in an area where treatment is not always available and disease consequences

may be severe, all four groups were given DTP

and measles vaccines on day 125, the day on which the study terminated.

All vaccines were sent to Cameroon refriger-ated at 4#{176}C.Measles vaccine was then stored at -20#{176}C and subsequently transported to the field

TABLE III

Group

1 2 3 4

Reciprocal HI titer on day 125

<10 10 20 40 80 160 320 640 Total GMT#{176} Seroconversion rate (%)

37 0 1 2

0 0 0 0

0 9 7 7

0 21 19 26

0 13 14 9

0 0 0 1

0 0 1 1

37 43 42 47

5 42.6t 45.6t 43.lt

0.0 100.Ot 97.6t 95.3t

#{176}Reciprocal HI titers < 10 assigned value of 5 for calcula-tion of GMT.

tDifference between study groups 2, 3, and 4 is not statistically significant for both GMT and seroconversion rates (%) (P > .3 and .5, respectively).

in a cold box containing frozen artificial ice. It was reconstituted with refrigerated diluent. After

reconstitution,

the measles vaccine was used for a maximum of one hour. Between vaccinations, the diluted vaccine was returned to the cold box. The

dT

and

DTP

vaccines were stored under constant

refrigeration and were taken to the field and held

in the same cold box as the measles vaccine. Eight milliliters of venous blood was taken and allowed to clot at ambient temperature. The specimens were centrifuged before the end of the day and the serum obtained was stored at -20#{176}C. Serum was kept frozen during transport to the

CDC

in Atlanta, and the Bureau of Biologics,

FDA,

in Bethesda, Maryland, where the serologic tests were performed.

Measles hemagglutination inhibition (HI)

anti-bodies were measured at the CDC, using the

method of Norrby.’6 Pertussis agglutinin titers were measured at the National Institutes of Health, using the micro-method of Manclark.’

RESULTS

Measles

Of 368 children studied, 169 were susceptible to measles as measured by a reciprocal HI titer of

< 10. Table II shows the age distribution of all

children and of measles-susceptible children at

the time of measles immunization for each study

group.

Following administration of measles vaccine, 132 of the 135 measles-susceptible children devel-oped reciprocal HI titers equal to or greater than

10. Seroconversion rates were 100%, 97.6%, and

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TABLE IV

PERTUSSIS AGGLUTININ TITERS, GMTs, AND FOURFOLD RISES IN TITER

Group 1

f----A B

Group 2

----A B

Group 3

---A B

Group 4#{176}

E____&___Th

A B

Reciprocal agglutinin titers

16 0 1 1 1 0 0 0 0

32 1 0 2 1 2 1 0 0

64 5 13 17 10 5 7 8 2

128 36 29 42 53 46 43 33 19

256 39 36 32 29 32 31 36 36

512 3 7 4 3 7 8 9 25

1,024 2 1 0 1 0 2 4 7

2,048 1 0 0 0 0 0 0 1

Total 87 87 98 98 92 92 90 90

GMT 188 172 143 151 169 178 207 296

No. (%) with four- 2 (2.2) 2 (2.0) 4 (4.3) 13 (14.4)t

fold rise in titer

#{176}Senimquantity from one child insufficient to measure pertussis agglutinin.

tP < .01.

95.3% in study groups 2, 3, and 4, respectively

(Table III). Seroconversion did not occur in three

children aged 19, 20, and 33 months who received

measles vaccine. None of

37

controls in group 1

developed antibodies, which indicates that wild

measles virus activity was low or nonexistent in

the study population during the study period. Among the 199 children who were seropositive

for measles at the time of measles vaccination,

. four (2.0%) showed a fourfold rise in HI titer.

Pertussis

Pertussis agglutinin titers for the four study

groups before and after vaccination are presented

TABLE V

in Table IV. The number of children in study group 4 who increased their pertussis agglutinin level fourfold or more was significantly greater than the number of children showing seroconver-sion in any of the other study groups. In addition,

only in study group 4 was there an increase in the

pentussis agglutinin GMTs between blood

speci-mens A and B. The low seroconversion rates in

study groups 1, 2, and 3 indicates that wild

pertussis activity was low during the period of the

study. The frequency of fourfold rise in pertussis

agglutinin titer between days 90 and 125 accord-ing to agglutinin titer at the time of pertussis vaccination is shown in Table V.

FREQUENCY OF FOURFOLD RISE IN PERTU55I5 AGGLUTININ TITER BETWEEN DAYS 90 AND 125 ACCORDING TO AGGLUTININ TITER AT TIME OF PERTu5SI5 VACCINATION

Reciprocal Groups , 2, & 3 Group 4#{176} Total

Alutinin

-

-Titer No. at Risk

No. (%) %VitI Fourfold Rise

No.

(It

Risk

No. (%) With Fourfold

Rise

No.

(it

Risk

No. (%) Wit/i Fourfold

Rise

16 1 1(100.0) 0 0 1 1(100.0)

32 5 2(40.0) 0 0 5 2(40.0)

64 27 1(3.7) 8 3(37.5) 35 4(11.4)

128 124 2(1.6) 33 7(21.2) 157 9(5.7)

256 103 2(2.0) 36 3(8.5) 139 5(3.6)

512 14 0 9 0 23 0

1,024 2 0 4 0 6 0

2,048 1 0 0 0 1 0

Total 277 8(2.9) 90 13(14.4) 367 21(5.7)

#{176}Sen,mquality from one child insufficient to measure pertussis agglutinins.

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DISCUSSION

The immunogenic effect of measles vaccine is not suppressed by the simultaneous administra-tion to children of DTP vaccine containing potent pentussis antigen. In the absence of wild measles virus activity, we have shown a normal high, acceptable rate of seroconvension in all groups receiving measles vaccine. In addition, the simi-lanity of the distribution of the postvaccination

measles titers and their GMTs makes unlikely any

qualitative difference in the immunologic response in the study groups that received measles vaccine.

The potency and immunogenicity of the

pertussis

antigen used in this study were docu-mented by titration and by the assessment of the

serologic response to DTP administration. As

indicated earlier, titration showed that the

vaccine contained acceptable levels of antigen. Two hundred forty-four of 277 (88.1%) study

subjects in groups 1, 2, and 3 had reciprocal

prevaccination pentussis agglutinin levels equal to or greater than 128, a level associated with significant clinical protection.18 Because these three groups had no previous exposure to

pentus-sis vaccine, the titers indicate a significant

pre-study exposure to pertussis disease. This

come-lates well with Morley and co-workers’ obsenva-tion at Imesi, Nigeria, where 56% of children

suffered

clinical pertussis during the first year of life.’9 Taylor (personal communication, 1972) has reported large numbers of pertussis cases in the forest areas of Camenoon. The two-shot DTP schedule selected for this study is based on Wilkins’ observation that two DTP injections two months apart are as effective in stimulating agglu-tinin formation as three injections one month apart. The higher GMT in blood A of group 4 children strongly suggests a booster effect of the initial dose of the DTP. The eight fourfold rises in titers in groups 1, 2, and 3 between days 90 and 125 indicate probable pertussis disease in the

study population. A similar background rate of

seroconversion is assumed to have occurred in

group

4 children; however, the significant higher percentage of fourfold titers rises in this group and the significant increase in GMTs between

days 90 and 120 in that group document that the

vaccine which was titered as potent in the labo-natory was immunogenic on administration.

In contrast to the high percentage of serocon-version among vaccinated measles-seronegative

children, only four of 199 (2%) of those who had

measurable measles antibodies at the time of vaccination had a fourfold rise in titer. This

inability to stimulate further antibody formation in children with preexisting antibodies has also been reported by Bass et al.’#{176}for measles and by Wyll et al.” and Brandling-Bennett et al.” for

rubella

vaccine. As can be seen in Table V,

fourfold titer rises in pentussis agglutinins were

limited to those children with prevaccination titers of 1:256 or less. Further, the percentage of

children who demonstrated fourfold rises in titer

decreased with increased prevaccination recipro-cal titers. For the two live virus vaccines, the presence of measurable preexisting antibody is

sufficient to prevent multiplication of the measles

or rubella vaccine virus. Thus, the observed results underscore the futility of revaccinating

children already immune to measles. The

expla-nation for the failure to respond to pertussis vaccine is unclear; however, it appears to be related to the preexisting immune status of the child.

We did not evaluate the possible adverse reac-tions to the simultaneous administration of measles vaccine with DTP. However, Ruben et al.’4 described no increase in either adverse local reactions or systemic symptoms when measles vaccine and DTP were given simultaneously at different body sites with yellow fever and small-pox vaccines.

The evidence presented in this article concern-ing the immunogenicity of simultaneously

admin-istened

measles vaccine and DTP, as well as the

previously reported safety of the association, may

permit the design of more efficient immunization

schedules. The study design-one dose of DTP

given

90

days before the simultaneous administra-tion of DTP and measles vaccine in the frequent presence of significant naturally occurring

pertus-sis agglutinin-simulates the antibody status of

American children. They will have most often received an initial two or three doses of DTP during the first year of life. For children in the United States, the American Academy of Pediat-nics currently recommends measles immunization

at 15 months of age and DTP booster at 18

months. In the majority of children, physician

visits at both 15 and 18 months may be

unneces-sary. The data presented here support the

immu-nogenicity of simultaneously administered

mea-sles vaccine and DTP. The subsequent simulta-neous administration of DTP and measles vaccine

during the second year can provide both

enhanced protection against pentussis and the

desired protection against measles. This article

does not address the feasibility of combining

mea-sles, mumps, rubella vaccine, which is

current-ly recommended by U.S. Public Health Service

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Advisory Committee on Immunization Practices for children 15 months of age, whith DTP.

In areas of modest economic resources, the simultaneous administration of vaccine antigens

poses obvious advantages. The cost of the vaccine

in most mass delivery programs accounts for only 10% to 25% of the program costs. Where separate

visits for DTP and measles immunization are

required, vaccine administration costs may elimi-nate the possibility of offering both vaccines to children in need. In such situations, simultaneous

administration of measles and DTP is not only

effective but recommended.

REFERENCES

1. Recommandation to the Public Health Service Advisory Committee on Immunization Practices: Diphtheria, Pertussis and Pertussis Vaccine in immunization Against Disease-1972. US Public Health Service, Dept of Health, Education and Welfare, 88, 1972. 2. Hardy GE, Hopkins CL, Linnemann CC, et al: Trivalent

oral poliovirus vaccine: A comparison of two infant immunization schedules. Pediatrics 45:444, 1970. 3. Kelemen C, Rethy L, Maruczi J,Pacsa 5: Sabin vaccine

and combined diphtheria-tetanus-pertussis immuni-zation. Lartcet 1:456, 1961.

4. Benson PF, Butler NR, Custello JM, et al: Vaccination in infancy with oral poliomyelitis vaccine and diph-theria, tetanus, pertussis vaccine. Br Med I 1:641,

1963.

5. Budd MA, Schultens RG, McGehee RF, Gardner P: An evaluation of measles and smallpox vaccines simul-taneously administered. Am I Public Health 57:80, 1967.

6. Sherman PM, Hendrickse RG, Montefoire D, Peradze T: Simultaneous administration of live measles virus vaccine and smallpox vaccine. Br Med I 2:672, 1967.

7. Weibel RE, Stokes J, Buynak EB, et al: Clinical labora-tory experiences with a more attenuated Ender’s

measles virus vaccine (Moraten) combined with smallpox vaccine. Pediatrics 43:567, 1969.

8. Meyer HM, Husteller DD, Bernheim BC, et al:

Response of Volta children to jet injections of combined live measles, smallpox and yellow fever vaccines. Bull WHO 30:783, 1964.

9. Dutertre J: La vaccination simultanee par BCG et vaccin antirongeoleux: Resultats d’un essai controle.

Rennes, France, Ecole National de la Sante Publi-que, 1972.

10. Gateff C, Relyveld EM, Le Gonidec C, et al: Etude d’une nouvelle association vaccinale quintuple.

Ann Microbiol 124B:387, 1973.

11. Gateff C, Le Gonidec C, Boche R, et al: Influence de Ia vaccination anticholerique sur l’immunisation an-tiamarile associee. Bull Soc Pathol Exot 66:258,

1973.

12. Felsenfeld 0, Wolf RH, Gyr K, et al: Simultaneous vaccination against cholera and yellow fever.

Lancet 1:457, 1973.

13. Gateff C, Jan C, Durand B: Le vaccin anticholerique est-il interferogene? Med Trop 34:367, 1974. 14. Ruben FL, Smith EA, Foster SO, et al: Simultaneous

administration of smallpox, yellow fever, and diph-theria-pertussis-tetanus antigens to Nigerian chil-dren. Bull WHO 48:175, 1973.

15. Marshall R, et al: Effectiveness of measles vaccine given simultaneously with DTP. I Trop Pediatr 20:126, 1974.

16. Norrby E: Hemagglutination by measles virus: IV. A simple procedure for production of high potency antigens for hemagglutination inhibition (HIA) tests. Proc Soc Exp Biol Med 111:814, 1962.

17. Manclark CR: The serological response to Bordetella

pertussis. I Med Microbiol 10:115, 1977.

18. Wilkins J,Williams FF, Wehrle PF, Portnoy B: Agglu-tinin response to pertussis vaccine: I. Effect of dosage and interval. I Pediatr 79:197, 1971. 19. Morley D, Woodland M, Martin WJ: Whopping cough

in Nigerian children. Trop Geogr Med 18: 169, 1966.

20. Bass JW, Halstead SB, Fischer CW, et al: Booster

vaccine will live attenuated measles vaccine. JAMA

235:31, 1976.

21. Wyll SA, Herrmann KL, Abrutyn E, et al: Rubella

booster immunization: Serologic response to a

second dose of vaccine. JAMA 216:1451, 1971.

22. Brandling-Bennett AD, Jackson RS, Halstead SB, et al: Serologic response to revaccination with two rubel-Ia vaccines. Am I Dis Child 130:1081, 1976.

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1978;62;288

Pediatrics

A. Marshall McBean, Claude Gateff, Charles R. Manclark and Stanley 0. Foster