Immune Responses:Whole Cell and Acellular Pertussis

Vaccines

Kathryn M. Edwards MD

Sarah H. Sell and Cornelius Vanderbilt Professor

Department of Pediatrics

Vanderbilt University

Nashville, TN

Bordetella pertussis: Many Antigens

• Pertussis toxin (PT)

• Filamentous hemagglutinin (FHA)

• Pertactin (PRN)

• Fimbrial agglutinogens (FIM)

Fimbriae

FHA

Adenylatecyclasetoxin

Pertactin

TCF

Dermonecrotictoxin

TCF

Pertussistoxin

What immune response to what antigen?

Vaccines Used in the NIH-funded MAPT

WCV

ACV

PT: Reverse Cumulative Distribution Curves after Primary Vaccination

Pediatrics 1995;96;557

Febrile Response to Pertussis Vaccines in Infants

NIH-Sponsored Acellular Pertussis Vaccine Efficacy Trials (Sweden and Italy)

Vaccine Manufacturer Vaccine Composition Efficacy Trial Location

SmithKline Beecham PT and FHA 59% Sweden

Connaught Laboratories PT, FHA, PRN, AG 85% Sweden

Connaught Laboratories Whole cell 48% Sweden

36% Italy

SmithKline Beecham PT, FHA, PRN 84% Italy

Chiron-Biocine PT, FHA, PRN 84% Italy

AG=agglutinogens; FHA = filamentous hemagglutinin; PRN = pertactin; PT = pertussis toxoid.

Adapted from Gustafsson et al6, Greco et al7, and Trollfors et al12.

7 Mos. 22 Months

No. GMTs No. GMTs

IgG-PT

DTPwc 449 1.2 (1.1-1.3) 332 1.1 (1.1-1.2)

DTPa3 CB 486 94.3 (88.8-100.3) 403 4.5 (4.0-5.0)

DTPa3 GSK 476 51.3 (47.9-54.9) 389 2.7 (2.4-3.0)

DT 161 1.0 (1.0-1.1) 127 1.1 (1.0-1.2)

IgG-FHA

DTPwc 449 5.03 (4.7-5.8) 332 1.6 (1.4-1.8)

DTPa3 CB 486 52.6 (49.1-56.3) 403 4.7 (4.2-5.4)

DTPa3 GSK 476 146.9 (138.3-156.1) 389 11.4 (10.2-12.8)

DT 161 1.5 (1.3-1.6) 127 1.2 (1.0-1.3)

IgG-PRN

DTPwc 449 9.8 (8.6-11.3) 332 2.3 (2.1-2.5)

DTPa3 CB 486 136.6 (127.0-146.8) 403 9.9 (8.9-11.1)

DTPa3 GSK 476 274.2 (253.6-296.7) 389 17.9 (16.1-20.1)

DT 161 1.6 (1.6-1.7) 127 1.6 (1.5-1.7)

PT-neutralizing antibodies

DTPwc 237 23.0 (21.4-24.6) 176 21.4 (20.2-22.7)

DTPa3 CB 251 787.6 (718.2-863.5) 208 148.7 (124.7-177.4)

DTPa3 GSK 239 223.0 (203.7-259.7) 190 67.9 (56.0-82.3)

DT 81 22.0 (20.2-23.9) 60 21.2 (18.8-23.7)DTPwc,Whole-cell DTP vaccine; DT, diphtheria and tetanus toxoids.

Antibody Titers to Acellular and Whole Cell DTP Vaccines

Th1 Response With Infection

Edwards and Decker: Plotkin Vaccines

Rapid antibody response after Tdap in Adults

Conclusions

• Acellular vaccines (aP) are immunogenic, but humoral immune responses vary with vaccine

• Pertussis antibody titers rapidly decline

• Whole cell vaccines vary in immunogenicity

• aP priming generates mixed Th1/Th2 response

• Pertussis disease generates Th1 response

• Previously primed individuals generate rapid antibody response after vaccination

Mooi and de Greeff Lancet Infect Dis 2007

Maternal Transfer of Pertussis Antibody

Antigen (ELISA)

GMT (95% CI)

Maternal Sera Cord Sera

PT 5 (2-13) 14 (6-32)

FHA 41 (26-66) 27 (15-49)

Aggln 34 (23-50) 35 (24-51)

Van Savage J, Decker MD, Edwards KM, Sell SH, Karzon DT. J. Infect. Dis. 161:487, 1990

Maternal Vaccination Prevents Leukocytosis, not Colonization

Impact of Tdap on infant disease?

Immune Responses and Antibody Decay after

Immunization of Postpartum Women with Tetanus

and diphtheria toxoids and acellular pertussis vaccines (Tdap)

Fortner KB1, Hunter DL2, McDonald WL2,

Rock MT2, Edwards KM2

1Division Maternal-Fetal Medicine, Vanderbilt University 2Division Pediatric Infectious Disease, Vanderbilt University

Are Tdap Vaccines Needed with Each Pregnancy?

Serum ELISA IgG Antibody Geometric Mean Titer (GMT) Results by Individual Antigen

0

20

40

60

80

100

120

Day 0 2 Weeks 6 Weeks 6 Months

GM

T an

d 9

5%

CI

Serum IgG PT

0

50

100

150

200

Day 0 2 Weeks 6 Weeks 6 Months

GM

T an

d 9

5%

CI

Serum IgG FHA

0

200

400

600

800

1000

1200

1400

Day 0 2 Weeks 6 Weeks 6 Months

GM

T an

d 9

5%

CI

Serum IgG PRN

0

500

1000

1500

2000

2500

Day 0 2 Weeks 6 Weeks 6 Months

GM

T an

d 9

5%

CI

Serum IgG FIM

Safety of Tdap in Pregnant Women:

Study Design

• Prospective, observational

• Study population:

• 375 healthy pregnant women at ≥ 20 weeks 0 days gestation through ≤ 34 weeks 0 days gestation and their infants

• 225 non-pregnant women of reproductive age with similar characteristics as pregnant women

Tdap Pregnant Women Enrollment

32

Vaccine History

Yes (%) No (%) Unknown (%)

Prior Tdap 53 28 19

Prior Td/TT 67 10 23

Prior Tdap or Td/TT

84 9 7

Local Reactionsin 361 Pregnant Women

Local Symptom None (%) Mild (%) Moderate (%) Severe* (%)

Pain 31 51 17 <1

Tenderness 18 62 19 <1

Swelling 82 12 5 1

Redness 87 7 4 2

* < 1% indicates only 2 pregnant women had such severe reaction.33

Severe Local Reactions: Pregnant Women

• a

34

Systemic Reactions in 361 Pregnant Women

Systemic Rx None (%) Mild (%) Moderate (%) Severe* (%)

Fever (≥ 100°F)** >99 <1 <1 0

Feverishness 92 4 3 <1

Malaise 67 22 10 <1

Body aches 76 16 7 <1

Headaches 70 23 6 <1

* < 1% indicates ≤ 3 pregnant women had such severe reaction.

**Temperature (°F): two subjects with moderate fever (100.4 °F and 100.9°F)Median: 97.8 °FInterquartile range: 97.5 to 98.3 °F 35

Pertussis IgA Antibody Titers in Breast Milk

Abu Raya: Vaccine 2014

Conclusions• Maternal vaccination with acellular

pertussis vaccines is protective against disease, but not infection

• Need to assess immune responses in infants to primary vaccination

• Continued study of the changing epidemiology of pertussis is needed