Il futuro della vaccinazione contro lo pneumococco

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1 Convegno SItI Emilia-Romagna HPV e nuove strategie vaccinali Ferrara, 6 marzo 2009 Il futuro della vaccinazione contro lo pneumococco Paolo Durando Dipartimento di Scienze della Salute Sezione Igiene e Medicina Preventiva A.O.U. San Martino di Genova Università degli Studi di Genova

2 PIETRE MILIARI NELLA STORIA DEI VACCINI ANTI- ST. PNEUMONIAE PRIMA GENERAZIONE preparazioni di cellule intere 1930 sviluppo del vaccino polivalente con sierotipi attenuati Metà anni 30 sviluppo di vaccini polivalenti contenenti materiale capsulare parzialmente purificato Fine anni 40 primi studi di efficacia; entrano in commercio i vaccini polisaccaridici polivalenti Primi anni 50 la prima generazione di polisaccaridi pneumococcici esce dal mercato SECONDA GENERAZIONE VACCINI POLISACCARIDICI NON CONIUGATI 1977 il vaccino 14-valente viene registrato negli USA 1983 il vaccino 23 valente viene registrato negli USA VACCINI POLISACCARIDICI CONIUGATI 2000 vaccino eptavalente (PCV-7) viene registrato negli USA e subito successivamente in Europa TERZA GENERAZIONE VACCINI POLISACCARIDICI CONIUGATI A PIU AMPIO SPETTRO (prossima commercializzazione) Vaccini coniugati polivalenti a più ampio spettro del PCV-7: in prossima commercializzazione i preparati 10 e 13-valenti VACCINI PROTEICI, VACCINI ADIUVATI, VACCINI PER VIA MUCOSA (in fase di studio.) Vaccini in fase iniziale di sviluppo, si basano su specifiche proteine dello Pn, quali la pneumolisina, PspA, PspC e Lyt A

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4 CDC's Active Bacterial Core surveillance (ABCs), a population- and laboratory-based system. The total population aged <5 years under surveillance in 2005 was 1.26 million persons.

5 The overall incidence of IPD among children aged <5 years declined from 98.7 cases per 100,000 during to 23.4 cases per 100,000 in 2005.

6 Direct and Indirect Effects of Routine Vaccination of Children with 7- Valent Pneumococcal Conjugate Vaccine on Incidence of Invasive Pneumococcal Disease United States, For persons >5 years, total IPD declined by 29% (CI=25-33) and V-IPD decresead by 62% (CI=50-66) from to 2003, with the absolute rate reduction in people >65 years. MMWR, 2005/54(36);

7 PCV prevented more than twice as many IPD cases in 2003 through indirect effects on pneumococcal transmission (i.e., herd immunity) than through its direct effect of protecting vaccinated children. MMWR, 2005/54(36);

8 Rates of IPD among adults aged >18 years in US, 1998/ (PCV-7 serotypes)

9 Introduction of the 7-PCV into the Routine Infant and Children Immunization Schedule in Liguria - Italy (2003): a Pilot-Project, on a Regional Basis, on behalf of the Ministry of Health

10 LIGURIA REGION Department of Health and Social Services Regional Council Resolution n rd May 2003 TARGET POPULATION RECOMMENDATION SCHEDULE Infants born in 2003 Free of charge 3 doses at months Children aged months Co-payment: Euro 20,66 per dose 2 doses Children aged! 24 months Children in specific risk-categories (Resolution by the Ministry of Health n 11 19th Nov. 2001) Co-payment: Euro 20,66 per dose Free of charge 1 dose According to age

11 LIGURIA REGION Department of Health and Social Services Regional Immunization Plan Regional Council Resolution n th October 2005 Regional Council Resolution n th November 2005 Regional Council Resolution n th February 2006 Recommendations for conjugate pneumococcal, varicella and HAV vaccines TARGET POPULATION RECOMMENDATION SCHEDULE Infants born in 2003 Free of charge 3 doses at months Children aged months Children aged! 24 months Children in specific risk-categories (Resolution by the Ministry of Health n 11 19th Nov. 2001) Free of charge Free of charge Free of charge 2 doses 1 dose According to age

12 VC % Vaccination Coverages (CV%) for 7-PCV among infants by Local Public Health Unit in Liguria (full course with three doses given at 3, 5 and 11/12 months) years

13 Department of Health Sciences Section of Hygiene and Preventive Medicine University of Genoa Immunogenicity of Heptavalent Pneumococcal Conjugate Vaccine and Diphteria-Tetanus-Trivalent Acellular Pertussis-Hepatitis B-Inactivated Polio Virus-Haemophilus influenzae Type B Vaccine, Coadministered to Heaalthy Infants at 3, 5 and Months of Age Local Public Health Unit of Genoa Infectious Diseases Unit, IRCCS Gaslini Paediatric Hospital, Genoa

14 Study period (enrollment, blood sampling and lab analyses) years. Study population Healthy infants, regularly immunized at 3, 5 and 11/12 months of age, progressively enrolled in the study at the vaccination-visits within the local Public Health and Paediatric Units in Genoa.

15 Seroprotective levels for anti-pneumococcal PS antibodies, in 146 infants immunized with 7-PCV co-administered with hexavalent vaccine Durando P. et al, WCVII 2008

16 GMCs for anti-pneumococcal PS antibodies, in 146 infants immunized with 7-PCV co-administered with hexavalent vaccine Durando P. et al, Vaccine 2009 Results from our study are in line with those reported by other authors in R-CTs and NR-CTs, using both a 3 or a 4-dose schedule.. Schmitt HJ et al. Vaccine 2003; 21(25-26): Tichmann-Schumann I et al. Pediatr Infect Dis J 2005; 24(1): 70-7 Esposito S et al, Vaccine 2005; 23(14): Käyhty H et al Pediatr Infect Dis J 2005; 24(2): Knuf M et al. Vaccine 2006;24: Goldblatt D et al. Pediatr Infect Dis J 2006;25: )

17 Immunogenicity of DTaP-HBV-IPV-Hib vaccine and PCV7 administered at age 3, 5 and months in healthy infants in Liguria: seroprotection rates, GMCs and GMTs, measured 1 month post-dose3, according to treatment group Durando P. et al, Vaccine 2009

18 J Prev Med Hyg 2008;49:34-46

19 DOCUMENTO GRUPPO VACCINI SItI 2009

20 Department of Health and Social Services Liguria administrative Region Department of Health Sciences Sect. of Hygiene and Preventive Medicine University of Genoa Monitoring the effects of the universal infant immunisation campaign with7-pcv on pneumococcal-associated or potentiallyassociated hospitalizations in children aged < 2 years in Liguria, Italy

21 Monitoring the effects of the universal infant immunisation campaign with PCV-7 on pneumococcalassociated or potentially-associated hospitalizations in children aged < 2 years in Liguria, Italy Methods Hospitalization rates of children belonging to birth cohorts before, , (n=33946) and after, , (n=35452) the introduction of widespread immunization were compared. Study population and data source Data from Liguria Regional database concerning in-patient discharge information on pneumococcal-associated or potentially-associated hospitalizations was collected in children 0-2-years old, in accordance with the International Classification of Diseases, 9 th revision, Clinical Modification (ICD-9CM). Rates of hospital admissions for the following discharge diagnosis, used as main clinical outcomes (Grijalva CG et al., The Lancet 2007; Shah SS et al., CID 2006), were calculated: - all-cause pneumonia ( ) - pneumococcal pneumonia (481) (lobar pneumonia, organism unspecified) - acute otitis media (382, 382.0, 382.9) - bacterial meningitis, non-specified meningitis ( ) - septicemia (038) - urinary tract infections (599.0)

22 Vaccine, 2009 Universal Children Immunisation Against Streptococcus Pneumoniae: the Five-year Experience In Liguria, Italy Durando P, Crovari P, Ansaldi F, Sticchi L, Sticchi C, Turello V, Marensi L, Giacchino R, Timitilli A, Carloni R, Azzari C, Icardi G and the Collaborative Group for Pneumococcal Vaccination in Liguria P value< 0.05 P value< % -70.5% P value< 0.01 P value= NS -36.4%

23 J Int Med Res, 2008 Decline in pneumonia and acute otitis media after introduction of chilodhood pneumococcal vaccination in Liguria, Italy Ansaldi F, Sticchi L, Durando P, Carloni R, Oreste P, Vercelli M, Crovari P, Icardi G 2003

24 Data from Nationwide Inpatient Sample (Agency for Health Care), representing 20% of all US admissions (nearly per year), were analysed with an interrupted time-series analysis that used PNEUMONIA (ALL-CAUSE and PNEUMOCOCCAL) admission rates as the main outcomes. Monthly admission rates estimated for years after vaccination with PCV ( ) were compaared with expected rates calculated from pre- PCV years ( ). The year of vaccine introduction (2000) was excluded. Rates of admission for dehydration were assessed for comparison. The Lancet, April 2007

25 Year 2004 Trends in monthly US admission rates ( ) for all-cause and pnpneumonia, before and after routine immunization of children with 7-PCV. Grijalva CG, The Lancet 2007 Year 2004 This annual decline in all-cause pneumonia admissions of 506 per children younger than 2 years represented about pneumonia admissions prevented in This decline represented about 17 fewer admissions per children in During the 8 study years, (2%) children <2 yrs admitted with pneumonia were coded as having pneumococcal disease.

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27 Bacteria can be responsible for 60-70% of clinical episodes of AOM, being St. pneumoniae the cause of 30-40% of all these cases, and even of a greater fraction of the severe ones Pneumococcal AOM may present with more severe clinical signs and symptoms than AOM caused by either H. influenzae and M. catharralis (Palmu AA et al CID 2007) Our reported decline in hospitalization rates for AOM (36.4%) is in the range of vaccine-efficacy (10-50%) of the FinOM and NCKP clinical trials (long-term follow up) against recurrent episodes or for the prevention of tympanostomy tube placement

28 Italian Network for the Special Surveillance of bacterial meningitis and sepsis: results in children aged < 5 yrs from Liguria ( years) START UP OF THE 7-PCV IMMUNIZATION by St. pneumoniae by unidentified agents overall

29 Consensus Conference sulla vaccinazione universale antipneumococcica dei nuovi nati. Roma, novembre 2007 E fondamentale effettuare un accurata sorveglianza con metodiche sensibili per evidenziare possibili mutamenti epidemiologici. I metodi molecolari (Realtime PCR, standard PCR) possono essere utilizzati sia per la diagnosi di germe sia per la sierotipizzazione con alta sensibilità. Questi metodi devono essere utilizzati direttamente su campioni biologici e non su isolati di coltura per consentire la più alta sensibilità. Corless CE, et al., J Clin Microbiol. 2001;39(4): Saukkoriipi A, et al., Mol Cell Probes. 2004;18(3): Poulter MD, Scand J Infect Dis. 2005;37(5): Yang S, J. Clin. Microbiol. 2005;43(7): Suzuki N, J Med Microbiol. 2006;55(Pt 6): Kais M, Diagn Microbiol Infect Dis. 2006;55(3): Morozumi M, J Clin Microbiol. 2006;44(4): Bayram A, et al., J Microbiol Immunol Infect. 2006;39(6): WHO. Position paper. 23 march 2007,82nd year No.12, 2007, 82, Carvalho MD, et al., J Clin Microbiol. 2007; 45(8):

30 Molecular methods performed directly on clinical samples improve diagnostic sensitivity and reveal increasead incidence of IPD in Italian children Azzari et al, J Med microbiol 2008 Bonanni P et al, Vaccine 2009

31 Vaccini antipneumococcici coniugati in commercio* o in prossima commercializzazione in Italia

32 AR-ISS and Surveillance of Bacterial Meningitis Network A total of 773 pneumococcal isolates collected from a nationwide surveillance of IPDs among the general all age population VS: 393 VRS: 93 NVS: 279 TOP TEN PREVALENT SEROTYPES 14 (16.4%) 3 (8.4%) 23F (8%) 19F (7.4%) 4 (5.9%) 7F (5.8%) 9V (5.3%) 6B (4.9%) 19A (4.7%) 1 (3.7%) PCV-7 PCV-10 PCV-13

33 VRS (DSSP: 71%) and NVS (DSSP: 84%) isolates showed a lower rate of penicillin or drug resistance than VS (DSSP: 44.8%). Neverthless. among these, 19A, 35F, 15B/C, and 3 accounted for the majority of Penicillin-Non-Susceptible St. pn. (PNSSP) and Drug-Resistant Penicillin-Susceptible St. pn. (DR-PSSP). Representative isolates of the major VS, VRS, and NVS were also genotyped: the isolates examined were found to belong to 18 international clones and to eight newly described clones; VS isolates sharing clonal groups with VRS or NVS were also detected; evidence of a past history of capsular switching events was observed in five clones.

34 39 laboratori partecipanti alla rete per la sorveglianza dell antibiotico-resistenza (AR-ISS) Pantosti A et al, SANIT, Roma, Maggio 2008

35 Nella popolazione generale i sierotipi più frequenti sono risultati: 14 (12%), 3 (10,4%), 1 (9,7%) e 19A (9,4%) Nei bambini <5 anni i sierotipi più frequenti sono risultati: 14 (28,8%), 19A ( 12,1%), 1 (7,6%) e 7F ( 7,6%) Pantosti A et al, SANIT, Roma, Maggio 2008

36 Pantosti A et al, SANIT, Roma, Maggio 2008

37 Department of Health Sciences Sect. of Hygiene and Preventive Medicine University of Genoa Pneumococcal serotypes distribution and antibiotic resistance in pediatrics: passive surveillance in the Region of Liguria Principal aim To describe the serotype distribution and antibiotic resistance of IPD isolates over time during the introduction of Prevenar in Liguria. Inclusion criteria All consecutive S. pneumoniae isolates, reported by culture and non-culture methods (PCR), during a 24 months observation, from sterile tissues (blood and CSF) in following diseases: Meningitis Pneumonia with Bacteraemia Sepsis Occult Bacteraemia All positive cultures will be tested for antibiotic-resistance level and serotyping.

38 Distribuzione dei sierotipi di pneumococco e malattie invasive associate nella popolazione generale in Liguria Nov Feb 2009 (N=46)

39 Attuale copertura teorica aggiuntiva del PCV-10 e del PCV 13 rispetto al PCV-7 nella popolazione generale in Liguria, dopo l introduzione della vaccinazione universale, con tassi medi di CV=90% (Nov Feb 2009)

40 Rates of IPD among children aged <5 years in US ( )

41 Changes in incidence of NVT in children <5 years in US Hicks LA et al J Infect Dis 2007

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43 The serotype distribuition within all age population of penicillinresistant S. pneumoniae, causing respiratory and invasive diseases, which had a highly significant change (p<0.001), from to , is outlined as follow: Increase: Decrease: 19A (1,5% to 35,4%) 23F (16,1% to 5%) 35B (1,2% to 12,5%) 9V (16,1% to 4,2%) 6B ( 13,7% to 3,8%) 14 (18,5 to 2,9%)

44 2009 PCV-7 serotypes (VS): 4, 6B, 9V, 14, 18C, 19F, and 23F PCV-7 related serotypes (VRS): 6A, 9A, 9L, 9N, 18A, 18B, 18F, 19B, 19C, 23A, and 23B Non-PCV-7 serotypes (NVS): all the others

45 SUMMARY: VS: -73% (p<0.001) VRS: -32% (p=0.08) NVS: +60% (p<0.001) The proportion of Penicillin Non Susceptible-isolates (27%) decreased from 32% to 19% in (p=0.01) but increased from 19 to 30% in (p=0.03).

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47 Current rationale for new wide-spectrum polivalent PCVs Before introduction of 7PCV, vaccine serotypes were responsible for 80% of IPDs in the USA, 70% of the IPD in Europe, 40-80% of IPD in other Regions of the world. Several non-pcv7 serotypes causing IPDs (i.e., 1, 3, 5, 6A, 7F, 19A, 22F, 35B, etc.) have been isolated and some of them have shown a significant increase, with 19A being the most prevalent. The addition of new serotypes in the PCV could increase the percentage of the vaccine-preventable IPD cases in the next future.

48 Department of Health Sciences Section of Hygiene and Preventive Medicine University of Genoa

49 Criteria for the evaluation and targeting of PCV candidates courtesy of G. Siber

50 The relevant role of antibody-response for PCV: a correlate of protection exists World Health Organization WHO Technical Report Series n Recommendations for the production and control of pneumococcal conjugate vaccines A WHO working group has proposed a protective concentration for PCVs in infants: A concentration of IgG anticapsular polysaccharide antibodies measured by ELISA 0.35 µg/ml, one month after primary immunization, was recommended as the minimal protective threshold against IPD. This was established on the basis of three double-blind controlled efficacy trials for IPD performed in Northern California Kaiser Permanenente (Black S. et Al 2000), American Indians (Obrien K.L. 2003) and South Africa (Klugman KB et Al 2003).

51 Applications of a protective antibody concentration for PCV candidates Immunologic correlates of protection then become critical for predicting the efficacy of new or improved vaccines (i.e., 10- and 13-PCV) when placebo-controlled efficacy trials are no longer feasible or ethical.. The protective value could be also used as the benchmark for assessing interference between vaccines given concomitantly.. Siber G, Vaccine 2007

52 Pneumococcal antibody correlate of protection: open key-issues courtesy of G. Siber

53 Grazie per l attenzione!!!