1. New Pneumococcal Vaccines
Ray Borrow
Vaccine Evaluation Unit, Health Protection Agency, Manchester, UK
21st April 2010

2. (MCC can be given at 5 months)
Sept 2006 UK schedule
2 months  DTaP/IPV/Hib + pneumococcal vaccine
3 months  DTaP/IPV/Hib + MCC vaccine
4 months  DTaP/IPV/Hib + MCC + pneumococcal vaccine
(MCC can be given at 5 months)
12 months  Hib/MCC
13 months  MMR + pneumococcal vaccine

3. The impact on Invasive Pneumococcal Disease
Children Under 2 yrs: Serotypes contained in PrevenarTM

4. The impact on Invasive Pneumococcal Disease
Children Under 2 yrs: Serotypes NOT contained in PrevenarTM

5. The impact on Invasive Pneumococcal Disease
Persons ≥ 5 yrs: Serotypes contained in PrevenarTM

6. The impact on Invasive Pneumococcal Disease
Persons ≥ 5 yrs: Serotypes NOT contained in PrevenarTM

7. IPD incidence in England and Wales by serotype: children < 5 yrs old 2/4/13 month schedule
Change 2008/9 vs 2005/6; All IPD -40% (-48, - 30)
VT -92% (-94, -89); NVT +88% (+23, +187)
Change 2008/9 vs predicted incidence in 2008/9 All IPD -51% (-60, -41)
VT -93% (-95, -90); NVT +35% (-22, +134)

8. Long term trends in serotypes unrelated to PCV7, for example ST 1 in UK, changes mainly in 5-64 year olds
Scottish data: Flasche S, Robertson C et al. Trends in serotypes among cases of invasive pneumococcal disease (IPD) in Scotland after the introduction of PCV7. 7th International Symposium on Pneumococci and pneumococcal diseases, Tel’Aviv, Israel, March 4-18, 2010.
England & Wales data, HPA unpublished data.

9. Annual number of serotypes pre PCV7 (average 2004/5 & 2005/6) Vs post-PCV7 year 2008/9 by vaccine category < 5 year olds: England and Wales

10. Cumulative weekly number of reports of Invasive Pneumococcal Disease due to serotype 7F
Children aged < 2 Years in England and Wales by Epidemiological Year: July-June (2003- To Date)

11. Cumulative weekly number of reports of Invasive Pneumococcal Disease due to serotype 19A
Children aged < 2 Years in England and Wales by Epidemiological Year: July-June (2003- To Date)

12. Higher valency pneumococcal conjugates
Prevenar13 Synflorix 1 3 1 4 5 4 5 6A 6B 6B 7F 9V 7F 9V 14
18C 14
18C
19A
19F
19F
23F
23F
NTHi

13. Polysaccharides (10 serotypes*)
Design of Synflorix™ (GSK) A new generation of vaccine
with a novel carrier protein
Synflorix™ designed to:
include 10 pneumococcal serotypes (1, 5 and 7F added to the 7 of Prevenar™)
minimize risk of interference with co-administered vaccines
provide protection against NTHi
Non-typeable
H. influenzae
S.pneumoniae
protein D
[carrier protein]
Polysaccharides (10 serotypes*)
* 2 polysaccharides conjugated on Tetanus and diphtheria toxoid respectively

14. NTHi Protein D Surface exposed1 Highly Conserved
Expressed in all Hi and NTHi strains tested1
Genetically stable2
Virulence factor
Contribute to the inhibition of ciliary beating3
Important factor in otitis media4,5
Anti-PD antibodies are protective in animal models5-7
Prevents AOM in Chinchilla model, also as carrier protein5,6
Increase bacterial lung clearance in Rats models7
Immunogenic in Humans1,8
1. Akkoyunlu et al ; 2. Janson, unpublished ; 3. Janson H et al. J Infect Dis. 1999; 4. Janson et al. 1994; 5. Bakaletz Infect & Imm 1999; 6. Novotny 2006; 7.Poolman Vaccine 2000; 8. Prymula et al., Lancet 2006

15. Acute Otitis Media France, N= 1504
Bacterial Respiratory Diseases are polymicrobial in nature
Acute Otitis Media France, N= 1504
Acute Sinusitis
USA, N=50
Acute Conjuctivitis
Israel, N= 368
12%
21%
31%
21%
38% 8%
25%
46%
30%
40%
25% 3%
S. pneumoniae
H. influenzae
M. catarrhalis
Others
Non-typeable Haemophilus influenzae together with Streptococcus pneumoniae are leading pathogens in Bacterial URTI
N= Number of children with culture positive samples; % of bacteria isolated ; URTI: Upper Respiratory Tract Infections
1. Gehanno Pediatr Infect Dis J 2001; 20: 570573 ; 2. Wald et al, Am J Med Sc Volume 316(1), 1998,13-20.; 3. Buznach et al, Ped Infect Dis J, 24: 823–828, 2005

16. Otitis media efficacy: POET Study
Double blind, randomized (1:1) study in Czech and Slovak Republics
11-v Pneumococcal conjugate prototype vaccine with H. influenzae Protein D as carrier
1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, 23F
each conjugated to 1 µg of protein D

17. Acute Otitis Media efficacy: POET Study (Experimental 11 valent- vaccine)
Number of episodes
Vaccine Efficacy (%)
Pneumococcal vaccine
Control vaccine
Any (confirmed by presence of middle-ear fluid)
333
499
33.6%
Vaccine pneumococcal serotype 60
141
57.6%
Non-vaccine pneumococcal serotype 23 25
8.5%
H. influenzae 44 68
35.6%
Proof of concept that a Protein D-containing vaccine can induce protection against H influenzae AOM
Prymula R, et al. Lancet 2006; 367:740–748.

18. Serotype 3
Poolman J. et al. Vaccine 2009; 27:

19. AOM efficacy (POET) before and after boosting – serotype 3
Control (N=2452)
11Pn-PD (N=2455)
VE (%)
95%CI
- Any AOM episode 17 20
-17.1
-126.5
39.5
42.2
-114.0
-11.3 19 17
- First AOM episode
74.0
-116.2
25.1 6 8
- First before booster
38.9
-235.8
-43.3 13 9
- First after booster
Poolman J. et al. Vaccine 2009; 27:

20. No protection against serotype 3 AOM in POET: why?
Prevenar13
11Pn-PD in POET
100 90 80 70 60 50 40 30 20 10
11Pn-PD post-primary
HAV post-primary
Percent of subjects
Kieninger et al, ICAAC 2008 ( kieninger.pdf; accessed on April 17, 2009)
Antibody concentration (µg/ml)
Serotype 3 ELISA immunogenicity:
higher responses post-primary than post-booster
Adapted from Prymula et al. Lancet 2006;367:740-8

21. Vaccination with PPV23 does not protect against serotype 3 disease in the elderly
Serotype 3 efficacy against IPD: PPV23 vaccine
Recent England & Wales data for serotype 3
VE = -29% [-73% to -4%]
Statistical significant negative effect

23. Prevenar 13 (Pfizer)
13 serotypes all conjugated to CRM197 carrier protein and adsorbed on aluminium phosphate.
2.2 µg of each serotype, except serotype 6B (4.4 µg)
Licensed for a 2 dose primary series e.g. 2, 4 months of age with third dose recommended between 11 and 15 months.
For unvaccinated children aged 12 to 23 months, the SPC recommends 2 doses, 2 months apart; the Green book, 1 dose.
For children aged 2 to 5 years, both SPC and Green book recommend 1 dose.

24. From Prevenar to Prevenar 13
Infants should complete their course with Prevenar 13.
2 months PCV7 PCV7 PCV7 PCV13
4 months PCV7 PCV7 PCV13 PCV13
13 months PCV7 PCV13 PCV13 PCV13

25. Comparison of pneumococcal IgG GMCs for the 7 common serotypes before and after the toddler dose
PCV at 2,3,4 & 12 months
Grimprel E, Laudat F et al. Safety and immunogenicity of a 13-valent pneumococcal conjugate vaccine given with routine pediatric vaccination to healthy children in France. ESPID June 9-13, 2009, Brussels, Belgium.

26. Comparison of pneumococcal IgG GMCs for the 6 additional serotypes before and after the toddler dose
Grimprel E, Laudat F et al. Safety and immunogenicity of a 13-valent pneumococcal conjugate vaccine given with routine pediatric vaccination to healthy children in France. ESPID June 9-13, 2009, Brussels, Belgium.

27. Percentage of subjects reporting systemic reactions within 4 days of vaccination with toddler dose of PCV7 or PCV13 in the UK
PCV7
(%)
PCV13
Fever
>38 but <39oC
16.4
7.7
>39 but <40oC
5.2
0.0
>40oC
Sleep
Increased
40.8
38.6
Decreased
44.8
32.1
Antipyretics
to treat fever
58.3
49.4
to prevent fever
67.5
52.2
Decreased appetite
44.1
39.1
Irritability
76.3
74.2
Any systemic event
86.3
84.5
PCV13 was well tolerated and had a comparable reactogenicity profile to PCV7 but with a notably lower Day 1-4 fever rate.
Hughes JY et al. Immunogenicity of booster doses of 13-valent pneumococcal conjugate and Hib/MenC vaccines given at 12 months of age. ESPID June 9-13, 2009, Brussels, Belgium.

28. Concomitant vaccination
Hib IgG responses
No Hib IgG data on Pediacel at 2,3,4 months with PCV13 & MCC-CRM at 2,4 months
All vaccines given at 2,3,4 months
Pediacel at 2,3,4, PCV7 & MCC at 2,4

29. Vaccination schedule for those in a clinical risk group (Green book)
Vaccine given and when to immunise
Patient age at presentation Prevenar13 (PCV) Pneumovax
At-risk children Vaccination according One dose after the
2 months to the routine immunisation second birthday.
under 12 months schedule at 2,4, 13 months
of age. of age.
At-risk children Vaccination according to One dose after the
second birthday the routine immunisation second birthday.
2 months to under schedule at 2,4 13 months
12 months of age of age.
who have asplenia
or splenic dysfunction
or who are Immunosuppressed.
At-risk children 12 months One dose. One dose after the
to under 5 years of age second birthday after
the final dose of PCV.
At-risk children 12 months Two doses, with an One dose after the
to under 5 years of age who interval of 2 months second birthday and at
have asplenia or splenic between doses. Least 2 months after the
dysfunction or who are final dose of PCV.
immunosuppressed.
At-risk children aged over PCV is not recommended. One dose.
5 years and at-risk adults.

30. Proposed changes to Green Book for clinical at risk groups:
HIV Change from Pneumovax to 2 x PCV
BMT Change from Pneumovax to 2 x PCV
Chronic renal PCV every 5 years

31. Vaccine efficacy estimates for each age cohort
Pneumovax
Vaccine efficacy estimates for each age cohort
62 to 73 years 40% (13% to 59%; 95% CI)
74 to 79 years 25% (-12% to 49%; 95% CI)
80+ years 8% (-21% to 30%; 95% CI)
Vaccine efficacy = 23% (6% to 36%; 95% CI) for all age groups.
Vaccination of older people commenced in 2003, starting with people 80 years and over in August 2003, people aged from 75 years in April 2004 and from 65 years in April These cohorts were used to estimating vaccine effectiveness and the period used for analysis.

32. Prior polysaccharide blunts the response to conjugate vaccination
Comparison of Pneumococcal conjugate and polysaccharide vaccines in the elderly (≥70 years)
Prior polysaccharide blunts the response to conjugate vaccination
De Roux et al. Clin Infect Dis 2008;46:

33. All groups then challenged with polysaccharide vaccine at age 5 years.
Serogroup C serum bactericidal antibody responses of children in the Gambia challenged with meningococcal A + C polysaccharide vaccine at an average age of 5 years.
The children vaccinated at 2 to 6 months
and again at 20 months of age with:
Conj, Conj: Conjugate vaccine at both ages;
Conj., IPV, Conjugate vaccine then IPV;
Conj., PS, Conjugate vaccine then polysaccharide vaccine
None, nil; Vaccine-naïve control children
All groups then challenged with polysaccharide vaccine at age 5 years.
The group given conjugate vaccine then polysaccharide vaccine lost their ability to mount a memory response.
Granoff DM, Harrison LH, Borrow R. Meningococcal vaccines. In: Vaccines. Fifth edition, edited by S.A. Plotkin, P. Offit and
W.A. Orenstein. W.B. Saunders Company, Philadelphia. 2008, pages

34. Conclusions & more questions
Despite replacement disease, the reduction in IPD in children is substantial.
The phenomenon of replacement needs to be confronted and investigated.
Role of even higher valency conjugate vaccines?
Role of protein based pneumococcal vaccines?
Future of 23-valent pneumococcal polysaccharide vaccine?

35. Acknowledgements
HPA CfI: Liz Miller, Stefan Flasche, Pauline Kaye, Rashmi Malkani, Yoon Choi, Nick Andrews, Mary Slack, Robert George.
HPA Manchester: Elaine Stanford.
Pfizer: Paul Balmer
GSK: Jan Poolman