New Pneumococcal Vaccines Ray Borrow Vaccine Evaluation Unit, Health Protection Agency, Manchester, UK ray.borrow@hpa.org.uk 21st April 2010

(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

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

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

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

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

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)

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 England & Wales data, HPA unpublished data.

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

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)

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)

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

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

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. 1991 ; 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

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

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

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.

Serotype 3 Poolman J. et al. Vaccine 2009; 27: 3213-22.

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: 3213-22.

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 (http://uploads.renegadedigital.com/Istanbul/ kieninger.pdf; accessed on April 17, 2009) 0.1 1.0 10.0 100.0 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

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 http://www.advisorybodies.doh.gov.uk/jcvi/Pneumococcal_subgroup_minutes_15_January_2009_v2.pdf

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.

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

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.

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.

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.

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

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.

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

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 2005. These cohorts were used to estimating vaccine effectiveness and the period used for analysis.

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;46:1015-23.

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 399-434.

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?

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