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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


PIETRE MILIARI NELLA STORIA DEI VACCINI ANTI-

ST. PNEUMONIAE

PRIMA GENERAZIONE

• 1911-14 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


CDC's Active Bacterial Core surveillance (ABCs), a population- and laboratory-based system.

The total population aged


The overall incidence of IPD among children aged


Direct and Indirect Effects of Routine Vaccination of Children with 7-

Valent Pneumococcal Conjugate Vaccine on Incidence of Invasive

Pneumococcal Disease United States, 1998--2003

For persons >5 years, total IPD declined by 29% (CI=25-33)

and V-IPD decresead by 62% (CI=50-66) from 1998-99 to 2003,

with the absolute rate reduction in people >65 years.

MMWR, 2005/54(36);893-897


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);893-897


Rates of IPD among adults aged >18 years in US,

1998/99-2006 (PCV-7 serotypes)


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


TARGET

POPULATION

RECOMMENDATION SCHEDULE

Infants born in 2003 Free of charge 3 doses at

3-5-11 months

Children aged

12-23 months

Children aged

! 24 months

Children in specific

risk-categories

(Resolution by the Ministry of Health

n°11 – 19th Nov. 2001)

LIGURIA REGION

Department of Health and Social Services

Regional Council Resolution n°563 - 23 rd May 2003

Co-payment:

Euro 20,66 per dose

Co-payment:

Euro 20,66 per dose

Free of charge

2 doses

1 dose

According to age


LIGURIA REGION

Department of Health and Social Services

Regional Immunization Plan 2005-2007

Regional Council Resolution n°1268 - 28 th October 2005

Regional Council Resolution n°1471 - 18 th November 2005

Regional Council Resolution n° 165 - 27 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

3-5-11 months

Children aged

12-23 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


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


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 11-12

Months of Age

Local Public Health

Unit of Genoa

Infectious Diseases Unit, IRCCS

Gaslini Paediatric Hospital, Genoa


Study period (enrollment, blood sampling and lab analyses)

2006-2008 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.


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


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): 3653-62

Tichmann-Schumann I et al. Pediatr Infect Dis J 2005; 24(1): 70-7

Esposito S et al, Vaccine 2005; 23(14): 1703-8

Käyhty H et al Pediatr Infect Dis J 2005; 24(2): 108-14

Knuf M et al. Vaccine 2006;24:4727-4736

Goldblatt D et al. Pediatr Infect Dis J 2006;25:312-319)


Immunogenicity of DTaP-HBV-IPV-Hib vaccine and PCV7

administered at age 3, 5 and 11-12 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


J Prev Med Hyg 2008;49:34-46


DOCUMENTO GRUPPO

VACCINI SItI 2009


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


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, 2000-2002, (n=33946)

and after, 2003-2005, (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 (480-487.0)

- pneumococcal pneumonia (481) (lobar pneumonia, organism unspecified)

- acute otitis media (382, 382.0, 382.9)

- bacterial meningitis, non-specified meningitis (320-322-322.9)

- septicemia (038)

- urinary tract infections (599.0)


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

-15.2%

-36.4%

P value< 0.05

P value< 0.01

-70.5%

P value< 0.05

P value= NS


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


Data from Nationwide Inpatient Sample (Agency for Health Care),

representing 20% of all US admissions (nearly 35.000.000 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

(2001-2004) were compaared with expected rates calculated from pre-

PCV years (1997-1999).

The year of vaccine introduction (2000) was excluded.

Rates of admission for dehydration were assessed for comparison.

The Lancet, April 2007


Year 2004

Grijalva CG, The Lancet 2007

Trends in monthly US

admission rates (1997-2004)

for all-cause and pnpneumonia,

before and after

routine immunization of

children with 7-PCV.

This annual decline in all-cause pneumonia admissions of 506 per 100000 children younger than

2 years represented about 41000 pneumonia admissions prevented in 2004.

This decline represented about 17 fewer admissions per 100000 children in 2004.

Year 2004

During the 8 study years, 10659 (2%) children


“…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…


Italian Network for the Special Surveillance of bacterial

meningitis and sepsis: results in children aged < 5 yrs from

Liguria (2000-2008 years)

by St. pneumoniae

by unidentified agents overall

START UP OF THE 7-PCV IMMUNIZATION


Consensus Conference sulla vaccinazione universale antipneumococcica dei nuovi nati.

Roma, 27-27 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):1553-8.

Saukkoriipi A, et al., Mol Cell Probes. 2004;18(3):147-53.

Poulter MD, Scand J Infect Dis. 2005;37(5):391-2.

Yang S, J. Clin. Microbiol. 2005;43(7):3221-6.

Suzuki N, J Med Microbiol. 2006;55(Pt 6):709-14.

Kais M, Diagn Microbiol Infect Dis. 2006;55(3):169-78.

Morozumi M, J Clin Microbiol. 2006;44(4):1440-6.

Bayram A, et al., J Microbiol Immunol Infect. 2006;39(6):452-7.

WHO. Position paper. 23 march 2007,82nd year No.12, 2007, 82, 93–104.

Carvalho MD, et al., J Clin Microbiol. 2007; 45(8):2460-6.


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


Vaccini antipneumococcici

coniugati in commercio* o in prossima

commercializzazione in Italia


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


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.


39 laboratori partecipanti alla rete per la

sorveglianza dell’antibiotico-resistenza (AR-ISS)

Pantosti A et al, SANIT, Roma, Maggio 2008


Nella popolazione generale i sierotipi più frequenti sono

risultati: 14 (12%), 3 (10,4%), 1 (9,7%) e 19A (9,4%)

Nei bambini


Pantosti A et al, SANIT, Roma, Maggio 2008


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.


Distribuzione dei sierotipi di pneumococco e malattie invasive

associate nella popolazione generale in Liguria

Nov 2006 - Feb 2009 (N=46)


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 2006 - Feb 2009)


Rates of IPD among children aged


Changes in incidence of NVT in

children


The serotype distribuition within all age population of penicillinresistant

S. pneumoniae, causing respiratory and invasive

diseases, which had a highly significant change (p


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……


The proportion of Penicillin Non Susceptible-isolates (27%)

decreased from 32% to 19% in 1998-2003 (p=0.01) but increased from

19 to 30% in 2003-2005 (p=0.03).

SUMMARY:

VS: -73% (p


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.) etc.)

have been isolated and some

of them have shown a significant increase, increase,

with 19A

being the most prevalent. prevalent

• The addition of new serotypes in the PCV could increase

the percentage of the vaccine-preventable IPD cases in

the next future.


Department of Health Sciences

Section of Hygiene and Preventive Medicine

University of Genoa


Criteria for the evaluation and targeting

of PCV candidates

courtesy of G. Siber


A WHO working group has proposed a protective concentration for PCVs in

infants:

The relevant role of antibody-response for PCV:

a correlate of protection exists…

World Health Organization

WHO Technical Report Series n.927 2005.

Recommendations for the production and control of pneumococcal conjugate vaccines

A concentration of IgG anticapsular polysaccharide antibodies measured by

ELISA≥0.35 µg/ml /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).


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


Pneumococcal antibody correlate of

protection: open key-issues

courtesy of G. Siber


Grazie per l’attenzione!!!

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