A Randomized Comparison of Reactogenicity and Immunogenicity of Two Whole-Cell Pertussis Vaccines

A Randomized

Comparison

of

Reactogenicity

and

Immunogenicity

of

Two

Whole-Cell

Pertussis

Vaccines

Mark

C.

Steinhoff,

MD*;

George

F. Reed,

PhD;

Michael

D.

Decker,

MD,

MPH;

Kathryn

M.

Edwards,

MDII;

Janet

A.

Englund,

MDI;

Michael

E. Pichichero,

MD#;

Margaret

B. Rennels,

MD**;

Edwin

L. Anderson,

MD;

Maria

A.

Deloria,

MS;

and

Bruce D. Meade, PhD

ABSTRACT. Objective. To compare prospectively the

reactogenicity

and

immunogenicity

of

two licensed

whole-cell pertussis vaccines.

Methods. We conducted a prospective, randomized,

dou-ble-blinded assessment of two licensed whole-cell

pertus-sis vaccines

with diphtheria and tetanus toxoids that were

included in a multicenter trial evaluating 13 acellular

per-tussis vaccines. Infants were immunized at 2, 4, and 6

months of age with a single lot of Lederle (309 infants) or

Massachusetts Public Health Biologic Laboratories

(MPHBL; 94 infants) vaccine.

Results. The group receiving the Lederle vaccine demon-strated significantly higher antibody titers to pertussis toxin by enzyme-linked immunosorbent assay (ELISA) and by the Chinese hamster ovary cell pertussis toxin neutraliza-Hon assay, and to fimbrial antigens by ELISA, as well as

higher mean agglutinin titers. In contrast, the group

receiv-ing the MPHBL vaccine demonstrated higher ELISA anti-body levels to filamentous hemagglutinin and pertactin.

Similar differences were observed in the proportions of

vaccinees

seroconverting

to these

antigens.

Rates

of

sys-temic and local reactions were relatively low for both

vac-cines. Although the Lederle product had substantially

lower reactogenicity in this study than previously reported for that vaccine, the MPHBL vaccine was significantly less reactogenic in nearly all clinical categories.

Conclusion. The two whole-cell vaccines demonstrated statistically significant differences in postimmunization antibody levels to all six evaluated pertussis antigens.

Whether these statistically significant differences in

an-tibody levels have clinical relevance is not clear. Rates of nearly all local and systemic reactions were significantly lower among the MPHBL group than the Lederle group.

From the *Departments of International Health and Pediatrics, School of Medicine, Johns Hopkins University, Baltimore, MD; Division of Microbi-ology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD; Departments of §Preventive Medicine, §Medicine (Infectious Diseases), and IlPediatrics, Vanderbilt University School of Med-icine, Nashville, TN; llDepartments of Microbiology and Immunology and Pediatrics, Baylor College of Medicine, Houston, TX; #Department of Pe-diatrics, University of Rochester School of Medicine, Rochester, NY; **De.. partment of Pediatrics and the Center for Vaccine Development, University of Maryland School of Medicine, Baltimore; Department of Medicine, St Louis University School of Medicine; and §Division of Bacterial Products, Center for Biologics Evaluation and Research, Food and Drug Administra-tion, Rockville, MD.

Presented in part at the 61st Annual Meeting of the Society for Pediatric Research, Baltimore, MD, May 5, 1992.

The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does men-tion of trade names, commercial products, or organizations imply endorse-ment by the US government.

Reprint requests to (M.C.S.) Johns Hopkins University, Department of International Health, 624 N Broadway, Room 125, Baltimore, MD 21205. PEDIATRICS (ISSN 0031 4005). Copyright © 1995 by the American Acad-emy of Pediatrics.

Licensed whole-cell diphtheria-tetanus-pertussis vac-cines produced by different manufacturers cannot be assumed to be similar in reactogenicity or immunogenic-ity. Pediatrics

1995;96:567-570;

pertussis vaccine, infants, immune response, antibody, controlled trial.

ABBREVIATIONS. DTP, diphtheria and tetanus toxoids combined

with whole-cell pertussis vaccine; MPHBL, Massachusetts Public

Health Biologic Laboratories; ELISA, enzyme-linked

immunosor-bent assay; PT, pertussis toxin; FHA, filamentous hemagglutinin;

PRN, pertactin; FIM, fimbrial protein; MLD, minimum level of

detection; CHO, Chinese hamster ovary; AGG, agglutinin; GMT,

geometric mean antibody concentration or titer.

All licensed whole-cell diphtheria-tetanus-pertussis (DIP)

vac-cines must meet the potency and safety requirements defined in the

Code of Federal Regulations and are considered equivalent by the

American Academy of Pediatrics and the Advisory Committee on

Immunization Practice of the Public Health Service. Older studies

that were not blinded or randomized noted differences in rates of

local and systemic reactions between DTP vaccines from different

manufacturers.3 Variations in reaction rates among different lots of a DiP vaccine from a single manufacturer also have been described.4 Murphy et al5 reported variations in reactogenicity of an unidentified DTP vaccine associated with differences in the adjuvant aluminum salt. More recently, several currently available licensed DIP vaccines were reported to differ in imniunogenidity of selected pertussis an-tigens.67 These recent comparisons of DiP vaccines were post hoc evaluations of multiple lots of the vaccines and analyzed sera

ob-tamed at different times in a number of studies in a variety of

geographic sites. To our knowledge, prospective randomized, dou-ble-blinded immunogenicity comparisons of current whole-cell DTP products have not been published.

Most clinical trials evaluating acellular pertussis vaccines

in-dude recipients of a licensed DTP vaccine as a control group, but

the DTP vaccine selected as the control varies from study to study.

Because previous reports have suggested substantial differences

in reactogenicity and immunogenicity among DTP vaccines, we

used the opportunity of a multicenter evaluation of acellular

per-tussis vaccines to conduct a prospective, randomized, blinded

comparison of two contemporary licensed DTP products that had

been included in the trial.

METHODS

Study Design

The design and subjects of the study have been described

previously.8 This paper reports the comparison of DTP vaccine

produced by Lederle Laboratories (Pearl River, NY) and by the

Massachusetts Public Health Biologic Laboratories (MPHBL,

Bos-ton, MA). Infants were randomized to receive pertussis vaccine at

2, 4, and 6 months of age. All data were collected and the

prelim-mary analyses were carried out in a blinded manner.8 A total of

309 infants enrolled during a 13-month period were randomized

to receive the Lederle vaccine (lot 271-966), and 94 infants enrolled

during a 3-month period were assigned to receive the MPHBL

vaccine (lot 271).

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568 SUPPLEMENT

TABLE 1. Comparison of Vaccine Characteristics

Component or Assay* Manufactur er (Lot No.)

Lederle MPHBLt

(271-966) (271)

Pertussis potency 4 4

Diphtheria toxoid 12.5 10

Tetanus toxoids 5 5

Thimerosal 1:10 000 1 :10 000

Aluminumil 0.1 mg 0.15 mg

Opacity9l 10.0 3.9

Potency# Pass Pass

Toxicity** Pass Pass

* Expressed as content per single human dose (0.5 mL of vaccine

product).

-I.Massachusetts Public Health Biologic Laboratories.

:1:

Defined as protective units per dose.

§

Limit of flocculation units per dose.

IIOpacity

units, aluminum equivalent per dose.

#{182}

With respect to US Opacity Standard.

#As determined in the pertussis potency test.

** Mouse weight gain test; pass, no weight loss by 72 hours, an

average weight gain of 3 g per mouse at 7 days, and deaths in 5%

or less of animals after intrapentoneal injection of 0.25 mL of

vaccine diluted with 0.25 mL of saline.

Vaccines

Characteristics of the vaccines are shown in Table I, which is

derived from the package inserts, manufacturers’ reports, and

Food and Drug Administration-required lot release testing. The

vaccines differed in the techniques of propagating and killing the

bacteria and of detoxifying the suspension of bacterial cells (Siber

G, MPHBL, and Hackell

J,

Lederle Laboratories, personal

commu-nications, 1994), but both production processes were approved by

the Food and Drug Administration. Both vaccines were

formu-lated to contain four protective units of pertussis vaccine, as

required by federal regulations. Bacterial content, measured in

opacity units using the US Opacity Standard, was determined by

the manufacturer at time of harvest. Potency of the whole-cell

pertussis component was measured as described with respect to

US Standard Pertussis Vaccine lot 9, defined as 8 protective units!

mL.9 Vaccine toxicity was assessed by the mouse weight gain test.9

Serologic Assays

Serum was obtained before immunization, at 2 months of age, and approximately I month after the third dose, at 7 months of age.

Enzyme-linked immunosorbent assays (ELISAs) were performed as

previously described8’0 to measure immunoglobulin G antibodies to

four purified proteins: pertussis toxin (PT), filamentous

hemaggluti-nm (FHA), pertactin (PRN), and a mixture of fimbrial serotypes 2 and 3 (FIM). Results were expressed in ELISA units!mL, using a standard

serum as reference)#{176} For each assay, the minimum level of detection (MLD) was estimated; for calculations, any result faffing below the MLD was arbitrarily assigned a value of half the MLD.

PT-neutral-izing antibodies were measured by the Chinese hamster ovary

(CHO) cell PT neutralizing assay.8’1#{176}The agglutinin (AGG) titer for

each serum was determined by the agglutination assay using

Borde-tella pertussis strain 460 (serotype 1.2.3.4.6)10 Samples that were neg-alive by CHO assay or AGG titer were arbitrarily assigned a value of half the first dilution tested. Diphtheria and tetanus antibodies were

assessed in a randomly selected subgroup of 41 and 14 Lederle and

MPHBL vaccine recipients, respectively, at St Christopher’s Hospital for Children (Philadelphia, PA) using standard techniques described elsewhere.8

Vaccine Reactions

The definitions of local and systemic reactions have been

de-scribed and are summarized below. Rectal temperature was

recorded using digital thermometers. Local reactions of redness

and swelling were measured in millimeters at the widest

diame-ter. Pain was coded as I, minor reaction to touch; 2, crying or

protesting when touched; and 3, crying when the leg was moved

passively. Fussiness was coded as 1, periodically more irritable

than usual but had normal activity; 2, prolonged drying and

refused to play; and 3, persistent drying and could not be

com-forted. Parents recorded assessments of reactions at 3 and 6 hours

after immunization and at bedtime for 7 days.

Statistical Analyses

Antibody titers were log transformed for analysis, and

geomet-rid mean antibody titers or concentrations (GMTs) for each vaccine

were compared using analysis of variance. Rates of

seroconver-sion (defined as a fourfold increase over both the

preimmuniza-tion titer and the minimum level of detection) and rates of

read-tions were compared by Fisher’s exact test or the x test for trend.

Comparisons manifesting a two-tailed P value greater than .05

were considered not significant.

RESULTS

Immunogenicity

Preimmumzation GMTs did not significantly differ between

the two vaccines for any of the eight antibody assays (Table 2).

After three doses of each product, there were statistically

signifi-cant differences in GMTs of antibody for all pertussis antigens.

The group

that received

the Lederle

product

demonstrated

signif-icantly higher GMTs to PT by ELISA and CHO assay and to FIM

by ELISA, as well as higher mean AGG titers. In contrast, infants

who received the MPHBL vaccine had significantly higher

anti-body responses to FHA and PRN. Similarly, the proportion of

vaccinees seroconverting to each evaluated antigen also differed

significantly between the vaccines (Table 2).

The

two

vaccine

products

did not differ in the proportion of

infants manifesting protective antibody levels’2 for diphtheria

(92% to 93%) or tetanus (100%).

Reactogenicity

The MPHBL vaccine was less reactogenic in nearly all

evalu-ated categories. After each dose, a significantly lesser proportion

of MPHBL than Lederle vaccinees reported fevers of 101#{176}F

TABLE 2. C ompariso n of Antibody Responses After 1mm unization With Whole-Cell DTP Vaccines Assay

Lederle N

MPHBL

Preimmunizationt Postimmunization* P Seroconve

Lederle

rsion (%)t MPHBL

P

Lederle MPHBL Lederle MPHBL

PT FHA FIM PRN AGG CHO DIP TET 309 309 309 309 308 288 41 41 94 94 94 94 94 84 13 14

1.4 (1.3-1.6) 1.7 (1.4-2.1)

3.6 (3.2-4.1) 4.4 (3.5-5.5)

9.9 (8.5-11.5) 8.1 (6.1-10.9)

5.2 (4.7-5.7) 5.4 (4.4-6.6)

12.8 (11.5-14.3) 11.3 (9.2-14.0) 36.0 (32.7-39.6) 39.3 (31.4-49.1)

0.07 (0.04-0.13) .06 (0.02-0.15) 2.57 (1.52-4.36) 3.37 (1.74-6.51)

66.7 (53.5-83.1) 19.6 (12.8-30.0) 3.0 (2.7-3.4) 50.8 (42.2-61.1)

191.0 (160-227) 70.0 (47.9-102)

63.4 (54.3-74.0) 98.7 (77.1-126) 82.7 (71.6-95.6) 42.7 (32.6-55.8)

260 (215-315) 92.8 (68.6-125)

1.84 (1.06-3.22) 0.63 (0.30-1.31) 22.5 (15.2-33.3) 14.9 (7.4-29.8)

.000015 <106 .000013 .006 .0001 .000015 .04 NS 82.8 10.7 75.1 68.0 67.5 61.5 92.7 100 62.8 74.5 61.7 81.9 50.0 38.1 92.3 100 .0001 <106 .01 .009 .003 .0002 NS NS

* GMT (95% confidence interval), reported in ELISA units!mL for PT, FHA, FIM, and PRN, and in international units (IU),/mL for DIP

and TET.

t Percent achieving a postimmunization titer that was at least four-fold greater than both the preimmunization value and the minimum

detectable level.

:$:

Percent with a protective postimmunization antibody level (diphtheria, 0.1 IU; tetanus, 0.01 IU).

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50 - 10O-1O1#{176}1O1-1O2#{176} 1O2#{176}

Lederle MPHBL

I V

30

____

V

-

-

__

C -

_____

H

20

H

o 1: 2 3

±LJ

Vaccine and Dose

Fig 1. Fever after vaccination: distribution of rectal temperatures

(degrees Fahrenheit) by whole-cell vaccine (Lederle versus

MPHBL) and dose. The proportion of children with fevers greater

than 101#{176}Fis significantly greater for Lederle than for MPHBL after each dose.

(38.3#{176}C) or greater (Fig 1). Both groups showed increasing rates of fever with successive doses of vaccine; this trend was significant for the Lederle group (by injection, 3% vs 5.3% vs 9.9%; P = .0004)

but not for the MPHBL group (1.6% vs 1.9% vs 4.8%).

In contrast, rates of swelling, redness, or pain of grade 2 or

greater seemed to decline with successive doses for both vaccines (Fig 2). Pain, swelling, and inconsolable crying (fussiness of grade 3) were significantly less common after each dose in recipients of

MPHBL vaccine than in those receiving the Lederle vaccinees.

Reported rates of local redness were significantly lower in MPHBL vaccinees than in Lederle vaccinees for the first two doses.

DISCUSSION

These data show substantial differences between the two

eval-uated licensed DTP vaccines. The products differed significantly

30

LilLederle MPHBL

25

20

15

1 8.6 6.1

__

3.2 9

%with Swelling of 20mm or More

30

25

20

15

10

5

0

Dose

1 2 3

25

20

15

Dose

30 with Inconsolable Crying

Lederle

MPHBL

7

3.8 4.7

1.7 2

Dose

10

5

Dose

0

%with Redness of 20mm or More

1 2 3

in immunogenicity for pertussis antigens and in their associated

local and systemic reactions. Unlike previous reports, this study

design was a prospective, concurrent, randomized, and blinded

assessment of single lots of two DTP vaccine products; all the

pertussis ELISA and agglutination assays were conducted in a

single laboratory. Earlier reports were unable to compare rates of

reactions directly, because the study protocols were not uniform.

The present study prospectively assessed local and systemic

read-tions with a single protocol.

Although both vaccines passed the mouse protection test,

sig-nificant differences in immunogenicity in human infants were

observed. The Lederle vaccine was significantly more

immuno-genic with respect to the PT antigen and AGG (3.8-fold and

2.0-fold higher GMTs, respectively, by ELISA). In contrast, the

MPHBL vaccine produced an FHA antibody GMT 16.5-fold higher

than the Lederle vaccine. Because the association between

anti-bodies to specific pertussis antigens and clinical protection is not well defined, it is not clear that these differences are clinically

important.t3 The mouse potency assay and AGG titer each have

been associated with protection against clinical pertussis after

childhood immunization with DTP vaccines)4 PT, A, PRN, and

FIM antibodies separately correlate with mouse protection)5

In general, the MPHBL DTP vaccine was associated with

signifi-cantly lower rates of systemic (fever and crying) and local (redness, pain, and swelling) reactions than the Lederle vaccine. Indeed, rates of adverse reactions after the MPHBL DTP vaccine were more similar to those of the acellular vaccine products.” Nonetheless, the reacto-genicity of the Lederle vaccine seems lower in this study than in

earlier reports. For example, in the present study only 9.9% of the

infants had fevers of 101#{176}For greater after the third dose. Earlier reports noted rates of fever of 100.4#{176}F(38.0#{176}C)or greater ranging from 30% to 51%1-3 flsj variation in reactogenicity may be related to

previously reported variation among lots,4 to alterations over time in production techniques, or simply to variations in antipyretic use or

study design. Although the frequency of fevers seemed to be lower with the contemporary product, the pattern of increasing frequency

Fig 2. Rates of redness of 20 mm or more, swelling of 20 mm or more, pain of grade 3 or 4, and inconsolable crying (fussiness of grade

4) by whole-cell vaccine (Lederle versus MPHBL) and dose. For each reaction and dose, except redness after dose 3, rates were

significantly lower for the MPHBL than the Lederle vaccine.

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570

SUPPLEMENT

of fever with successive doses, noted previously with DPT,’ also was seen in the present study.

Our findings confirm those of others6 and suggest that the large

number of DIP products available throughout the world cannot be

assumed a priori to be equivalent in immunogenicity, or consistent in

reactogenicity characteristics, even if they have been subjected to

standard regulatory and licensing procedures. The clinical

impor-tance of this nonequivalence is uncertain, but there clearly are impli-cations both for vaccine efficacy trials and the assessment of

pro-posed combined vaccines. New combination vaccine products are

likely to be based on the addition of antigens (such as polio, hepatitis B virus, and Haemophilus influenzae type b vaccines) to DiP products.

Assumptions regarding the equivalence of whole-cell DTP-based

combined products will have to be prospectively tested by

well-designed direct comparisons, as reported here.

ACKNOWLEDGMENTS

Supported by contracts N01-A172629 and N01-A125135

(Bay-br), N01-AI62515 (Johns Hopkins), N01-A162528 and

NOl-A115096 (University of Maryland), N01-A105049 (University of

Rochester), N01-A105051 (St Louis University), and N01-A102645

(Vanderbilt), from the Division of Microbiology and Infectious

Diseases, National Institute of Allergy and Infectious Diseases,

National Institutes of Health. All vaccines were donated by their

manufacturers.

John La Montagne, PhD, George Curlin, MD, David Klein, PhD,

William Blackwelder, PhD, and Martha Mattheis, MA, at the

National Institute of Allergy and Infectious Diseases, National

Institutes of Health, provided substantial input to the design,

coordination, or analysis of this study. We express gratitude also

to the many participating primary care physicians, nurses, and

parents for their contributions.

REFERENCES

1. Cody CL, Baraff U, Cherry JD, Marcy SM, Manclark CR. Nature and

rates of adverse reactions associated with DTP and DT immunizations in infants and children. Pediatrics. 1981;68:650-660

2. Baraff U, Cody CL, Cherry JD. DTP-associated reactions: an analysis by injection site, manufacturer, prior reactions, and dose. Pediatrics. 1984;73:

31-36

3. Barkin RM, Pichichero ME. Diphtheria-pertussis-tetanus vaccine: reac-togenicity of commercial products. Pediatrics. 1979;63:256-260

4. Baraff U, Manclark CR, Cherry JD, Christenson P. Marcy SM. Analyses of adverse reactions to diphtheria and tetanus toxoids and pertussis vaccine by vaccine lot, endotoxin content, pertussis vaccine potency and percentage of mouse weight gain. Pediatr Infect Dis J.1989;8:502-507 5. Murphy MD, Rasnack J, Dickson HD, Dietch M, Brunell PA. Evaluation

of the pertussis components of diphtheria-tetanus-pertussis vaccine.

Pediatrics. 1983;71 :200-205

6. Edwards KM, Decker MD, Halsey NA, et al. Differences in antibody response to whole-cell pertussis vaccines. Pediatrics. 1991;88:1019-1023 7. Baker pD, Halperin SA, Edwards K, Miller B, Decker M, Stephens D.

Antibody response to Bordetella pertussis antigens after immunization with American and Canadian whole-cell vaccines. JPediatr. 1992;121:523-527 8. Edwards KM, Meade BD, Decker MD, et al. Comparison of thirteen

acellular pertussis vaccines: overview and serologic response. Pediatrics. 1995;96(suppl):548-557

9. 21 CFR §620

10. Meade BD, Deforest A, Edwards KM. et al. Description and evaluation of serologic assays used in a multicenter trial of acellular pertussis vaccines. Pediatrics. 1995;96(suppl):570-575

11. Decker MD, Edwards KM. Steinhoff MC, et al. Comparison of 13

acellular pertussis vaccines: adverse reactions. Pediatrics. I 995; 96(suppl):557-566

12. Orenstein WA, Weisfeld JS, Halsey NA. Diphtheria and tetanus toxoids and pertussis vaccine, combined. In: Halsey NA, de Quadros CA, eds.

Recent Advances in Immunization: a Bibliographic Review. Scientific Publication 451. Washington, DC: Pan American Health Organization; 1983:30-51 13. Storsaeter J, Hallander H, Farrington CP, et al. Secondary analyses of

the efficacy of two acellular pertussis vaccines evaluated in a Swedish phase III trial. Vaccine. 1990;8:457-461

14. Medical Research Council. Vaccination against whooping cough: rela-tion between protection in children and results of laboratory tests. Br Med J.1956;2:454-462

15. Sato H, Sato Y. Bordetella pertussis infection in mice: correlation of specific antibodies against two antigens, pertussis toxin, and filamen-tous hemagglutinin with mouse protectivity in an intracerebral or aero-sol challenge system. Infect Immun. 1984;46:415-421

Description

and

Evaluation

of

Serologic

Assays

Used

in

a Multicenter

Trial

of

Acellular

Pertussis

Vaccines

Bruce D. Meade,

PhD*;

Adamadia

Deforest,

PhD4;

Kathyrn

M.

Edwards,

MD;

Theresa

A.

Romani,

BS*;

Freyja Lynn,

BS*;

Colleen

H.

O’Brien,

BS*;

Christina

B. Swartz,

BS*;

George

F. Reed,

PhD;

and

Maria A. Deloria,

BSI

ABSTRACT. Objective. To describe and evaluate the assays used to measure the antibody responses in infants

From the *Division of Bacterial Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, MD; Depart-ments of Microbiology and Pediatrics, Temple University School of Medi-cine and St Christopher’s Hospital for Children, Philadelphia, PA; §Depart-ment of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN; and IlDivision of Microbiology and Infectious Diseases, National Insti-tute of Allergy and Infectious Diseases, Bethesda, MD.

Presented in part at the 61st Annual Meeting of the Society for Pediatric Research, Baltimore, MD, May 6, 1992.

The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does men-hon of trade names, commercial products, or organizations imply endorse-ment by the US government.

Reprint requests to (B.D.M.) Division of Bacterial Products, Mail Code HFM-490, Center for Biologics Evaluation and Research, Rockville, MD 20852-1448.

PEDIATRICS (ISSN 0031 4005). Copyright © 1995 by the American Acad-emy of Pediatrics.

to 13 experimental acellular pertussis vaccines and 2 li-censed whole-cell pertussis vaccines.

Methods. During a 53-week period, preimmunization and postimmunization sera were assayed for immuno-globulin G antibodies to pertussis toxin, filamentous hemagglutinin, pertactin, and a mixture of type 2 and type 3 fimbriae by enzyme-linked immunosorbent assay (ELISA), for whole-cell agglutinins (AGG), and for per-tussis toxin-neutralizing antibodies by the Chinese ham-ster ovary cell assay. All ELISA reagents were character-ized to assure antigen and isotype specificity of the assays. Intralaboratory reproducibility and temporal

sta-bility were evaluated by analysis of results of control

sera and by assessment of the response to the control whole-cell vaccine. Interlaboratory reproducibility was assessed by repeating the assays on preimmunization and postimmunization sera for 10% of the infants in a second laboratory.

Results. For control sera having antibody concentra-tions at least four times the minimum level of detection,

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1995;96;567

Pediatrics

Deloria and Bruce D. Meade

Englund, Michael E. Pichichero, Margaret B. Rennels, Edwin L. Anderson, Maria A.

Mark C. Steinhoff, George F. Reed, Michael D. Decker, Kathryn M. Edwards, Janet A.

Pertussis Vaccines

A Randomized Comparison of Reactogenicity and Immunogenicity of Two Whole-Cell

Services

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1995;96;567

Pediatrics

Deloria and Bruce D. Meade

Englund, Michael E. Pichichero, Margaret B. Rennels, Edwin L. Anderson, Maria A.

Mark C. Steinhoff, George F. Reed, Michael D. Decker, Kathryn M. Edwards, Janet A.

Pertussis Vaccines

A Randomized Comparison of Reactogenicity and Immunogenicity of Two Whole-Cell

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