Immunogenicity of combined vaccines in infants

Helena Käyhty, PhDNational Public Health InstituteDept of VaccinesHelsinki, Finland

Combined vs. reference administrationhexavalent vaccines

• Gylca et al. Vaccine 2001: DTaP-HBV-IPV / Hib vs. DTwP-IPV mixed with Hib +HBV at 6, 10, 14 weeks

• Schmitt et al. J Ped 2000: mixed vs. separate DTaP-HBV-IPV / Hib at 2, 3, 4 months

• Mallet et al. PIDJ 2000: DTaP-HBV-IPV-Hib vs. DTaP-IPV-Hib / HBV at 2, 4 and 6 months

Combined vs. reference administration

0 1 2

D

T

HB

Polio 1

Polio 2

Polio 3

PTA

FHA

PRN

Hib Mallet ea

Schmitt ea

Gylca ea

fold difference

Eskola et al. Lancet 1996Vaccinations at 4 and 6 mo

DTaP / Hib/ IPV

DTaP-IPV/ Hib

DTaP-Hib/ IPV

DTaP-Hib-IPV

GMC, g/ml 3.9 3.1 0.4 0.6

%>0.15 g/ml 93 93 78 79

% >1.0 g/ml 87 77 19 48

Three doses, combined vs. separate administration in different studies

0

2

4

6

8

10

12

14

16

18combined

separate

Anti-Hib

Mechanisms???

• Missing adjuvant effect of wP• Epitopic supression - antigenic competition• Physicochemical interference

Immunogenicity trials in Sweden (3,5,12 mo) and Finland (4,6,14 mo)

0,9

9,8

2

15

1

12

5

35

0

5

10

15

20

25

30

35

40

6/7 mo 13/15 mo

An

ti-H

ibPRP-T/DT+IPV

PRP-T/DT/IPV

PRP-T/DT/IPV/aP

PRP-T+DTP, FIN

T

B

B

B

B

HELP

Anti-CHO Ab

Anti-Tetanus Ab

CHO

Tet

B

HELP

Anti-CHO Ab

Anti-Tetanus Ab

PncT, PRP-T and T simultaneouslyDose of PncT and response to PRP-T and

Tetanus toxoid (Dagan et al. 1998)

0

2

4

6

8

10

12

Placebo PncT01 PncT03 PncT10

Hib

0

1

2

3

4

5

Placebo PncT01 PncT03 PncT10

Tetanus

Concomitant administration 2 cm apart in the same leg at 2, 4 and 6 mo

Eskola et al.

0

2

4

6

8

10

12

mixed separate differentlegs

separate sameleg

2 mo

6 mo

7 mo

anti-Hib

Clinical implications?

• Are the induced anti-Hib responses high enough for protection?

• Experience from Finland, Sweden, the UK and Germany

Protective efficacy vs. antibody response

Study 1: PRP-D at 3, 4, 6 and 14 months

Anti-Hib 7 mo 14 moGMC, µg/ml 0.53 0.37% > 1 µg/ml 40 22% > 0.15 µg/ml 68 67% >0.06 µg /ml 85 85

Protection 90 (70-96) %

Eskola et al, 1990

Protective efficacy vs. antibody response

Study 2: PRP-D at 4, 6 and 14 months

Anti-Hib 7 mo 14 moGMC, µg/ml 0.63 0.38% > 1 µg /ml 32 24% > 0.15 µg /ml 77 72% >0.06 µg/ml 86 90

Protection 87 (69-96) %

Peltola et al, 1994

Immunogenicity trials in Sweden (3,5,12 mo) and Finland (4,6,14 mo)

0,9

9,8

2

15

1

12

5

35

0

5

10

15

20

25

30

35

40

6/7 mo 13/15 mo

An

ti-H

ibPRP-T/DT+IPV

PRP-T/DT/IPV

PRP-T/DT/IPV/aP

PRP-T+DTP, FIN

Three doses, combined vs. separate administration in different studies

0

2

4

6

8

10

12

14

16

18combined

separate

Anti-Hib

DTaP/Hib/(IPV) combinations in Germany Schmitt et al 2001

• 2 year follow up after the introduction of combined vaccines

• Overall VE 97.5 % (96.3-98.4)• 1 dose 88.6 % (76.1-94.3)• 2 doses 95.1 % (92.2-97.0)• 3 doses 98.8 % (98.2-99.3)

Measurement of the immune response to vaccination

Vaccine Sample Antibody

Capsular polysaccharides (PS)

• Antibodies protective• Poor and short lasting immune response in infants

and children• Long lasting antibody response in older children

and adults• TI-antigens -> no memory -> protection is based on

existing antibodies

Conjugate vaccines????

• immunogenicity improved by conjugating PS to carrier proteins -> TD properties -> antibody response even in infancy

• development of memory• protection may last longer than detectable antibody• memory B cells triggered upon challenge -> high and

quick antibody response• increase in avidity -> antibodies may function better

How to test development of memory

• Memory B cells• Priming with conjugate and booster with PS

– PS mimics contact with bacteria– more memory B cells to be triggered by PS– high antibody response of IgG isotype

• Avidity maturation

Increasing Affinity / Avidity

104 108 1012

Geometric mean titer (GMT) and GM avidity index (GMAI)

Goldblatt et al., JID 177, 1998, 1112-5

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

10.0

100.0

0.1

1.0

14121086420

Avi

dit

y In

dex

(G

MA

I)

An

ti-P

RP

Igg

(G

MT

µg

/ml)

Age (months)

AvidityTitre

Poolman et al Vaccine 2001

Avidity of anti-6B Pnc PS- primary seria at 2,4,6 mo with a conjugate - booster at 14 mo with conjugate or PS

30

35

40

45

50

55

60

65

70

75

80

5 10 15 20

Age, mo

AI

PncCRM

PncD

30

35

40

45

50

55

60

65

70

75

80

5 10 15 20

Age, mo

AI

PncCRM

PncD

PncT

Laboratory surrogates for evaluation of new conjugates, modified from Frasch 1995

• antibody response in infancy• persistence of antibodies (up to booster dose)• induction of immunologic memory

• PS-vaccine• avidity

• isotype/subclass distribution and avidity of antibodies• functional activity of antibodies

(opsonic or bactericidal activity)

Mucosal immune response

• is or may be important when• local mucosal infection• colonization precedes disease

• the role as a surrogate test unknown