Pneumoccocal vaccines in the elderly (conjugated vs polysaccharides)

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1 Aging and Immunity II Campus Novartis, Siena April 24, 2012 Pneumoccocal vaccines in the elderly (conjugated vs polysaccharides) Paolo Bonanni Department of Public Health University of Florence, Italy

2 Millions of people worldwide are at risk for pneumococcal disease Risk factor Global prevalence Smoking 1 billion 1 Age 65 years 518 million 2 Asthma 300 million 3 Diabetes 230 million 4 COPD 210 million 5 Alcohol use disorders 125 million 6 HIV 33 million 7 1. WHO. Tobacco key facts. Accessed June 23, US Census Bureau. Table 094. Midyear population by age and sex Accessed June 23, WHO. Asthma. Fact sheet. Accessed June 18, World Diabetes Foundation. Diabetes facts. Accessed June 18, WHO. Chronic obstructive pulmonary disease (COPD). Fact sheet. Accessed June 18, WHO. The global burden of disease: 2004 update. Accessed May 5, WHO. World health statistics Accessed June 23, 2009.

3 Co-morbidities are commonly present in patients with pneumococcal disease, England and Wales Proportion of hospital admissions with 1, 2-4, and 5 diagnoses reported during a hospital stay (England and Wales, HES, ) a 100% 90% 80% 70% 60% 50% 40% 5 diagnoses 2-4 diagnoses 1 diagnosis 30% 20% 10% 0% Age group Melegaro A et al. J Infect. 2006;52(1): a Hospitalizations including an occurrence of one of the pneumococcalrelated ICD-10 codes; HES=hospital episode statistics

4 Age is an independent risk factor for CAP, Italy Viegi G et al. Resp Med 2006;100:46 55

5 M2 In patients >40 years, case-fatality rates for CAP increase with age, Germany Ewig S et al. Thorax 2009;64:

6 Diapositive 5 M2 Synergy to redraw Marie; 15/11/2010

7 Case-fatality rates for hospitalised patients with IPD and CAP have remained constant over time 1-4 Mixed patient populations in different settings and countries LETHALITY 1 LETHALITY 2 LETHALITY 3 LETHALITY 4 *CAP=Community acquired pneumonia # average of 30-day and 90-day mortality in ICU vs ward patients, with average of 2 rates ~ 12% 1. Austrian R et al. Ann Intern Med. 1964;60: ; 2. Fine MJ et al. JAMA. 1996;274: ; 3. Feikin DR et al. Am J Pub Health. 2000;90: Restrepo MI et al. Chest. 2008;133:

8 US, 2009 : high incidence of IPD in subjects aged >50 years Incidence < 5yrs: 21.1/ , 65+: 38.7 / Nb of cases and deaths per related to Invasive Pneumococcal Diseases (IPD) in 2009 in the US in surveillance areas representing 29 million persons all ages. Number of Cases Rates of deaths per CDC, Active Bacterial Core Surveillance (ABCs) Report Emerging Infections Program Network Streptococcus pneumoniae, accessed on

9 The polysaccharide capsule The bacterial polysaccharide capsule is highly antigenic It is the virulence factor, and defines the serotype Capsular polysaccharide inhibits complement and interferes with opsonisation by phagocytes Different serotypes have different invasive, carriage and disease potentials Jones C. An Acad Bras Cienc 2005;77:

10 Pneumococcal polysaccharide 23-valent vaccine (PPV23): antigenic composition PPV23 contains 25 µg x 23 capsular polysaccharides of S. pneumoniae 1 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A,11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, 33F Serotype coverage 2, % of serotypes responsible of invasive pneumococcal diseases Cross-protection 1 Serotype 6B is partially protective against serotype 6A (not included in the vaccine) 1. CDC, MMWR, Fedson, Musher, in Vaccines, Geslin et al., Méd Mal Infect, 1992

11 PPV23 in IPD prevention Cochrane metanalysis 2008 Invasive pneumococcal infections Favours vaccine Favours control Moberley Cochrane Database Syst. Rev. 3, CD (2007).

12 Efficacy in IPD*: Results of 9 different meta-analyses Range RR (IC 95%) Range VE % All serotypes All population High-risk population 0.17 ( ) to 0.37 ( ) 1.56 ( ) to 0.58 ( ) 83 to 63 0 to 42 Vaccine serotypes All population High-risk population 0.17 ( ) to 0.27 ( ) 0.53 ( ) to 0.98 ( ) 83 to to 2% Studies show efficacy in adults without risk factors, in elderly patients (to a lesser extent), but not in high-risk patients Gaillat J. Exp Rev Resp Med 2009 *IPD is mainly CAP with positive blood culture

13 Efficacy in pneumonia: Synthesis of 9 meta-analyses Range RR (IC 95%) Range VE % Pneumonia all-cause High-risk population 0.71 ( ) to 0.89 ( ) 0.89 ( ) to 1.08 ( ) 11 to to 0 Suspected Sp pneumonia All population High-risk Vaccine serotypes 0.47 ( ) to 0.64 ( ) 0.68 ( ) to 1.20 ( ) 0.27 ( ) to 0.39 ( ) 53 to to 0 61 to 73% There is heterogeneity within controlled studies; no meta analysis supports efficacy against all-cause pneumonia Gaillat J. Exp Rev Resp Med 2009 *Pneumonia is either all-cause pneumonia or suspected pneumococcal pneumonia mainly from sputum

14 PPV23 in mortality prevention (IPD* or pneumonia**): Synthesis of 9 meta-analyses Range RR (IC 95%) Range VE % Death all-cause High-risk population Death and pneumonia High-risk 0.84 ( ) to 1.01 ( ) > ( ) to 0.88 ( ) 0.51 ( ) to 1.10 ( ) 16 to to to 0 Effect on mortality very limited, if any There is heterogeneity within controlled studies Gaillat J. Exp Rev Resp Med 2009 *CAP with positive blood culture **Pneumonia is either all-cause pneumonia or suspected pneumococcal pneumonia based mainly from sputum

15 Summary of evidence and controversy on PPV23 efficacy PPV23 is effective in preventing invasive infections in healthy adults and, to a lesser extent, in the elderly No definitive conclusion possible for high risk subjects (very heterogeneous) Inconsistent data on efficacy against CAP (heterogeneous studies, insufficient statistical weight), evidence of effectiveness from some observational studies Most studies conclude there is no impact on mortality

16 WHO position paper on PPV23 Despite multiple studies conducted during > 30 years, the efficacy and effectiveness of PPV in children and adults remain poorly defined and the subject of controversy. There is a need for more efficacious conjugate vaccine covering the majority of pneumococcal serotypes that cause serious diseases in older children and adults worldwide and that are responsible for resistance to commonly used antimicrobial drugs WHO supports the ongoing efforts to develop such products WHO position paper on 23-valent pneumococcal polysaccharide vaccine, 2008

17 The main principles of vaccine conjugation Conjugation covalently links capsular polysaccharides from encapsulated pathogens to carrier protein antigens Transforms T-cell independent antigens into T- cell dependent antigens to: Elicits a stronger T-cell dependent response Activates helper T cells to assist B cells in humoral response and producing IgG antibodies Activates T cells to assist B cells in priming memory cells Induces a booster response Siber GR, et al (Ed). Pneumoccocal Vaccines. The impact of conjugated vaccines. ASM Press. 2008

18 Plain polysaccharide vs conjugated vaccines Plain polysaccharide vaccines activate B cells but do not induce immunological memory 1,2 Short-lasting immune response, no booster effects on re-challenge No reduction in carriage Conjugated vaccines induce immunological memory by activating B cells and T cells 3 Carrier protein conjugate antigen helps B cells to differentiate both into memory B cells and plasma cells 1. Overturf GD, Committee on Infectious Diseases. Pediatrics. 2000;106: Ada G. N Engl J Med. 2001;345: Pollard et al. Nature Reviews Immunology. 2009;9:213

19 Immunogenicity one dose PCV7* vs PPV23 ELISA OPA * * * * * * GMT * * * * * *p < 0.01 De Roux C I D. 46, (2008) PCV7* N = 110; PPV23 N = 104 *PCV7 is not approved for adults

20 Pneumococcal Conjugate Vaccine (PCV13) in adults > 50years: immunogenicity studies

21 Pivotal non-inferiority comparisons of immune responses Definitions for the 12 serotypes in common Noninferiority (primary endpoint) Lower limit of the 95% CI for the GMT ratio is > 0.5, PPV HIGHER ANTIBODY RESPONSES NON- INFERIORITY PCV 13 HIGHER ANTIBODY RESPONSES Geometric Mean Ratio (GMR) Statistically significantly higher (secondary endpoint) Lower limit of the 95% CI for the GMT ratio is > 1 PPV HIGHER ANTIBODY RESPONSES NON- INFERIORITY PCV 13 HIGHER ANTIBODY RESPONSES Geometric Mean Ratio (GMR) CI: confidence interval GMT: geometric mean titre Pfizer property Do not distribute EU-PREV-2011/10/0024. Subject to local review. 20

22 PCV13 impact on functional antibody responses in adults aged years not previously vaccinated with PPV23 Trial 004: OPA responses elicited by PCV13 for the 12 serotypes in common: Non-inferior to PPV23 for all of the serotypes in common* Statistically significantly superior to PPV23 for 10 of the serotypes in common** and for serotype 6A* PPV HIGHER ANTIBODY RESPONSES NON- INFERIORITY PCV 13 HIGHER ANTIBODY RESPONSES F C 19A 6B 7F 9V 23F * Primary endpoints ** Secondary endpoints Geometric Mean Ratio (GMR) 1 month after dose The response to serotype 6A, which is unique to Prevenar 13, was assessed by demonstration of a 4-fold increase in the specific OPA titer above previously vaccinated levels. (Prevenar 13 Summary of Product Characteristics, Dec 2011) 21

23 Responses to PCV13 in all subjects were similar, regardless of comorbidities* *ad-hoc analysis OPA response to PCV13 in adults aged years not previously vaccinated with PPV23 CV, cardiovascular diseases; CPD, chronic pulmonary diseases; Diab, diabetes mellitus; GMT, geometric mean titre. 22

24 PCV13 impact on functional antibody response in adults 70 years of age previously vaccinated with PPV Trial 3005, OPA responses elicited by Prevenar 13 for the 12 serotypes in common: Non-inferior to PPV for all of the serotypes in common* Statistically significantly superior to PPV for 10 of the serotypes in common** and for serotype 6A* PPV HIGHER ANTIBODY RESPONSES NON- INFERIORITY PCV 13 HIGHER ANTIBODY RESPONSES F 9V 18C 19A 19F 4 6B 23F * Primary endpoint ** Secondary endpoint Geometric Mean Ratio (GMR) 1 month after dose The response to serotype 6A, which is unique to Prevenar 13, was assessed by demonstration of a 4-fold increase in the specific OPA titer above previously vaccinated levels. (Prevenar 13 Summary of Product Characteristics, Dec 2011) 23

25 004 Extension: Evaluation of the Immunogenicity and Safety of PCV 13 Compared with PPV upon Revaccination at Years Trial type: Phase 3, randomized, active-controlled, modified double-blind Trial population: Adults years old, not previously vaccinated with PPV Jackson L et al IDSA

26 004 Extension: secondary comparisons of antibody responses (OPA GMT), PPV / PPV vs PPV, adults aged years Serotype PPV / PPV (n a = ) GMT b PPV (n a = ) GMT b GMT Ratio c (95% CI) ( ) ( ) ( ) ( ) 6A d ( ) 6B ( ) 7F ( ) 9V ( ) ( ) 18C ( ) 19A ( ) 19F ( ) 23F ( ) Revaccination with PPV resulted in OPA GMTs statistically significantly lower for 8 of the 12 serotypes common to both vaccines compared with the first dose of PPV Jackson L et al IDSA 2011 a: Adults with determinate antibody titer for the specified serotype; b: GMTs calculated using all evaluable subjects with data for a given blood draw; c: Ratio of GMTs calculated by back transformation of the mean difference between vaccine groups on the logarithmic scale; d: Serotype 6A is not included in PPV 25

27 004 Extension: Primary comparisons of antibody responses (OPA GMT), PCV 13 / PPV vs PPV / PPV, adults aged years Serotype Prevenar 13 / PPV (n a =99-107) GMT b PPV / PPV (n a = ) GMT b GMT Ratio c (95% CI) ( ) ( ) ( ) ( ) 6A d ( ) 6B ( ) 7F ( ) 9V ( ) ( ) 18C ( ) 19A ( ) 19F ( ) 23F ( ) Administration of PPV after PCV 13 resulted in OPA GMTs statistically significantly greater for the 12 serotypes in common to both vaccines compared with OPA GMTs after revaccination with PPV Jackson L et al IDSA 2011 a: Adults with determinate antibody titer for the specified serotype; b: GMTs calculated using all evaluable subjects with data for a given blood draw; c: Ratio of GMTs calculated by back transformation of the mean difference between vaccine groups on the logarithmic scale; d: Serotype 6A is not included in PPV 26

28 Immunogenicity studies PCV7-13 / PPV23 in adult subjects Pfizer property Do not distribute EU-PREV-2011/10/0024. Subject to local review. 27

29 Coverage of invasive pneumococcal disease serotypes by PPV23 versus PCV13 Country (Region) Lead Author, Journal, Year Age Group (y) Interval Analyzed Proportion of Isolates Corresponding to Types in: PPV23 PCV13 Δ UK Miller, Lancet Infect Dis, % 91% 58% 63% 23% 28% France Grall, Eur J Clin Microbiol Inf Dis, % 70% 19% Germany Spain (Tarragona) Imöhl, Int J Med Microbiol, 2010 Vila-Córcoles, Vaccine, 2011 > % 71% 14% % 63% 6% Portugal Horacio, Vaccine, % 68% 16%

30 Main results to date with PCV13 and remaining issues Registered in Europe for the prevention of invasive pneumococcal diseases based on immunogenicity data. It elicits higher levels of functional antibodies both in naive subjects and in individuals already vaccinated with PPV23 If a sequential vaccination is recommended, PCV13 should be always administered as first vaccine The incremental serotype coverage of PPV23 vspcv13 ranges from 6 to 28% in different countries (average around 15%) No efficacy data available up to now (awaited 2013) Pfizer property Do not distribute EU-PREV-2011/10/0024. Subject to local review. 29

31 Screening/Recruitment 84,496 Healthy, > 65 years R Placebo PCV13 Timeline Start of enrollment Sept 2008 End of Recruitment Jan.2010 Results available ~ I Quarter 2013 Pfizer property Do not distribute EU-PREV-2011/10/0024. Subject to local review

32 CAPiTA: Study Objectives Primary Efficacy of PCV13* for prevention of first episode of vaccine-type (VT) Community-Acquired Pneumonia (CAP) Secondary Efficacy of PCV13 for prevention of first episode of non-bacteremic VT- Community-Acquired Pneumonia (CAP) Efficacy of PCV13 for prevention of first episode of VT- Invasive Pneumococcal Disease (IPD) Additional exploratory objectives Efficacy of PCV13 for the prevention of all episodes of CAP Efficacy of PCV13 for the prevention of death Investigate trends in efficacy by age Assess economic effect of PCV13 Pfizer property Do not distribute EU-PREV-2011/10/0024. Subject to local review

33 PCV13 ongoing studies Age expansion (6-49 years) (1Q2012) HIV infected 6 years in PS naive subjects 18 years PS pre-immunized subjects (4Q2012) Sickle cell disease ( 6 years) (2Q2012) Bone marrow transplant recipients ( 2 years) (2Q2014) Antibody persistence and re-vaccination at 5y (4Q2013) Pfizer property Do not distribute EU-PREV-2011/10/0024. Subject to local review. 32

34 PCV 7 g 1 m PCV 7 g 1 m 6 m 6 m PPV 7 g 1 m PPV PCV PCV Pfizer property Do not distribute EU-PREV-2011/10/0024. Subject to local review. 33

35 Effetto di una dose di PCV o di PPV sulle Cellule B di Memoria ad un mese dalla vaccinazione PPV PCV Before any vaccinaion, 86% of subjects had some basal level of antibody-secreting MBC to at leaast 1 of 7 serotypes, although being naive 28 days after vaccination in those receiving PCV7 Those who received PPV23 showed a decreasing trend of memory B cells compared to basal levels Memory B cells Clutterbuck E at al, J Infect Dis, Access 28 Mar 2012 Pfizer property Do not distribute EU-PREV-2011/10/0024. Subject to local review. 34

36 Effect of a dose of PCV or PPV on memory B cells 6 months after immunization PPV 6 months after vaccination, memory B cells (MBC): PCV Decrease to basal levels in those receiving PCV7 Further decrease in those receiving PPV23 Clutterbuck E at al, J Infect Dis, Access 28 Mar 2012 Pfizer property Do not distribute EU-PREV-2011/10/0024. Subject to local review. 35

37 Age-based vs at-risk recommendations Age-based Easy access to target group Exiiting infrastructure to administer vaccines Establishment of community protection (Herd effect) Overall higher levels of immunity achieved At-risk High-risk people relatively inaccessible (e.g. socially disadvantaged); Many at-risk patients are missed At-risk recommendations may not cover all possible situations Vaccination responsibility lies with different professionals

38 Target: subjects aged > 64 years (one or more cohorts by age) Vaccination with PCV13 (priming) + PPV23, 1 year apart (to be discussed) Opportunistic vaccination?: co-administration with influenza vaccine Possible extension of vaccination offer in all seasons (single injection)

39 Conclusions Plain polysaccharide vaccines showed 50-80% efficacy against IPD in healthy adults, with a downward trend in the elderly, no definitive demonstration of efficacy in high risk groups They do not generate helper T cells or induce lasting and adequate immune memory Conjugate vaccines may induce a stronger immune response and memory compared with polysaccharide vaccines They had a dramatic impact on IPD and pneumonia in children Their efficacy/effectiveness in adults has not yet been demonstrated A recent study shows a depletion of memory B cells after PPV vaccination compared with PCV vaccination The best vaccination scheme and schedule needs to be investigated in the near future

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