Séminaire de pathologie infectieuse Namur, CHU, 27 septembre 2007
Nouveautés vaccinales
Dr Yves VAN LAETHEM Service des Maladies Infectieuses CHU Saint-Pierre, Bruxelles
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Human Papillomaviruses Circular double stranded DNA viruses Î Î
7000 - 8000 base pairs Non-enveloped capsid consisting of 72 pentavalent capsomeres
Up to 200 different genotypes Classified according to: Î
Tropism: Î
Î
Cutaneous or Mucosal
≈30–40 genotypes infect anogenital mucosa
Risk of neoplasia: Low risk or High risk Î
≈20 genotypes cause cervical cancer
Syrjänen and Syrjänen. Papillomavirus infections in human pathology in Wiley & Sons, Chichester; 2000. p.11–46.
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Clearly defined pathogenic HPV types and related diseases Classification
Examples Types Associated disease
Cutaneous Low Risk
1, 2, 3, 10, 27
Plantar and cutaneous warts
High Risk
5, 8
Epidermodysplasia verruciformis
Mucosal Low Risk
6, 11, 42, 43, 44, Condyloma acuminata 55 Recurrent Respiratory (Laryngeal) Papillomatosis (common types) (JORRP) 6-11 = 90% of genital warts2 Cervical lesions CIN 1 (4 to 25%)3-5
High Risk
16, 18, 31, 33, Flat warts, Bowen's disease 45, 35, 39, 51, Cervical dysplasia and carcinoma 52, 55, 56, 59, 66 16-18 = 70% of cervical cancer6 Carcinoma of penis, vulva, vagina, anus
1. Wieland et al. Papillomaviruses in human pathology: Epidemiology, pathogenesis and oncogenic role. In: Gross, Barasso Eds. Human papillomavirus infection: A clinical atlas. Ullstein-Mosby; 1997. p.1–18. 2. Von Krogh. Eur J Dermatol. 2001; 11:598–603 3. Clifford GM abstract 237 21st International Papillomavirus Conference 2004; 4. Feoli-Fonseca et al. J Med Virol. 2001;63:284–292; 5. Koutsky L The American Journal of Medicine;102,3-8, 1997; 6.Muñoz N. N Engl J Med (348) 2003: 518-27.
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Mechanisms of HPV transmission and acquisition Sexual contact Î Î Î Î
Through sexual intercourse1 Genital–genital, manual–genital, oral–genital2-4 Genital HPV infection in virgins is rare, but may result from nonpenetrative sexual contact2 Condom use may help reduce the risk, but it is not fully protective2
Nonsexual routes Î Î
Mother to newborn (vertical transmission; rare)5 Fomites (eg, undergarments, surgical gloves, biopsy forceps)6,7 - Hypothesized but not well documented
Very variable progression Î Î Î Î Î 1.
Not possible to determine who will develop disease 70 % of sexually active women will get a Papillomavirus infection during their lifetime* May take many years to appear Number of co-factors, identified and non-identified Cervical Cancer: rare and late complication of HPV infection
Kjaer SK, Chackerian B, van den Brule AJC, et al. Cancer Epidemiol Biomarkers Prev. 2001;10:101–106. 2. Winer RL, Lee S-K, Hughes JP, Adam DE, Kiviat NB, Koutsky LA. Am J Epidemiol. 2003;157:218–226. 3. Fairley CK, Gay NJ, Forbes A, Abramson M, Garland SM. Epidemiol Infect. 1995;115:169–176. 4. Herrero R, Castellsague X, Pawlita M, et al. J Natl Cancer Inst. 2003;95:1772–1783. 5. Smith EM, Ritchie JM, Yankowitz J, et al. Sex Transm Dis. 2004;31:57–62. 6. Ferenczy A, Bergeron C, Richart RM. Obstet Gynecol. 1989;74:950–954. 7. Roden RBS, Lowy DR, Schiller JT. J Infect Dis. 1997;176:1076–1079. *Koutsky. Am J Med 1997;102:3–8. 4
70% of people will get a HPV infection during lifetime
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Estimated prevalence of genital PapillomaVirus infection in a US population of men and women aged 15-49 years2,3
1% Genital warts 4% 10%
60%
Abnormal pap or colposcopy Subclinical infection, detected by DNA test
Prior infection, evidenced by antibodies
25% 1. Bosch F.X. Natl Cancer Inst Monogr 2003 31: 3-13 3. Koutsky, et al. Epidemiol Review, 1988,10:122-163.
No prior/current infection
2. Koutsky. Am J Med 1997;102:3–8.
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1,2,3
Highly prevalent HPV encountered in adolescence - early adulthood1,2,3
Post-exposure
*
e Ag
Ag
Peak exposure
1 Ag 1 Ag e 1 e1 3 51 Ag 7 e 19 Ag e 2 Ag 1 e 23 Ag e 2 Ag 5 e 27 Ag e 2 Ag 9 e 31 Ag e 33 Ag e 3 Ag 5 e 37 Ag e 3 Ag 9 e 41 Ag e 4 Ag 3 e 45
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70% 60% 50% 40% 30% 20% 10% 0%
e
Proportion of individuals harbouring Human Papillomavirus
Preexposure
4
An estimated 70% of sexually active people will be exposed to the virus
at some point during their life1,2,3
[1] Koutsky LA. Am J Med 1997 [2] Koutsky LA et al. Epidemiology Rev 1988 [3] Syrjänen K et al. Sex Transm Dis 1990 [4] n=11,851 cervical smears of Danish women (15-93 yrs), Sanofi Pasteur MSD, data on file
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HPV and cervical mucosa – Normal Epithelium
7
Normal Cervix HPV enters through a break in the epithelium
*CIN = cervical intraepithelial neoplasia Adapted from Goodman A, Wilbur DC. N Engl J Med. 2003;349:1555–1564.
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HPV infection CIN 1
*CIN = cervical intraepithelial neoplasia Adapted from Goodman A, Wilbur DC. N Engl J Med. 2003;349:1555–1564.
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Cervical Cancer CIN 3
*CIN = cervical intraepithelial neoplasia Adapted from Goodman A, Wilbur DC. N Engl J Med. 2003;349:1555–1564.
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CIN 1 – 2/3
CIN 1 Image courtesy of the family of Dr Renso Barrasso (deceased)
CIN 3 Image courtesy of Prof J Monsonego
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Cervical cancer – Definition Cervical cancer results from malignant transformation of the cells which make up the lining of the uterine cervix Malignant change most often occurs at the transformation zone Malignant changes to the cells lining the uterine cervix produce: Squamous epithelium Squamous cell carcinoma (SCC) Columnar epithelium Adenocarcinoma Adenosquamous carcinoma
Invasive carcinoma of the cervix
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Place du cancer du col dans le monde 500.000 cancers par an
⇒ 250.000 morts/an
Lié à des virus hautement prévalents dans la majorité des populations
sexuellements actives dans le monde
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Cervical cancer is the second most common cause of death from cancer among young women in Europe* Other
Cancers**
Cervical Cancer
High mortality despite screening for early detection Breast Cancer
33,500 women diagnosed with Cervical
Cancer each year in Europe*,1 15,000 die (~45%)1
equivalent of 40/day or nearly 2/hour Female cancers (age 15–44 yrs) in the European Union (2002)1
* European Union (25 member states) plus Iceland, Norway and Switzerland ** Skin melanoma (7.5), Ovary (5.4), Thyroid (4.9), Colon/Rectum (4.4), Non-Hodgkin lymphoma (3.2), Hodgkin lymphoma (2.7), Lung (2.6), Corpus uteri (2.5), Brain-CNS (2.4), Leukaemia (2.3), Stomach (1.7), Kidney (1.3), Oral Cavity (0.7), Bladder (0.7), Pancreas (0.6), Liver (0.4), Other Pharynx (0.4), Multiple Myeloma (0.3), Larynx (0.2), Nasopharynx (0.2), Oesophagus (0.2)
[1] Ferlay et al, Globocan 2002: IARC Cancer Base No.5. Version 2.0 ARC Press, 2004 [2] Insinga et al. Am J Obstet Gynecol 2004
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Cervical Cancer Incidence – Belgium
Globocan 2002 – Belgium : 667 cases invasive cancer – 326 deaths (http://www-dep.iarc.fr)
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HPV : Necessary cause for cervical cancer Papillomavirus is necessary to develop cervical cancer Î Virtually 100% attributable to Papillomavirus - Primary research Bosch (JNCI 1995): prevalence 93 % HPV DNA (>1000 biopsies from 22
countries) - Re-analysis Walboomers (J Pathol 1999): HPV DNA in 99.7 % - Delvenne (Vaccine 2001) HPV causes cancer in organotypic culture models Î
Environmental and other co-factors
HPV Infection and Cancer Risk RR
> 500
HPV 18 & and adenocarcinoma a HPV 16 & cervical cancer HPV & cervical cancer
100
Hepatitis B & liver cancer (South-East Asia)
50
Hepatitis B & liver cancer (Greece)
20
Hepatitis C & liver cancer (Italy)
10
Cigarettes & lung cancer
Bosch FX et al. J Clin Pathol 2002
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CIN - Current model of genital carcinogenic HPV on disease progression
Variable period ~2 years
HPV infection
High grade dysplasia CIN 3
High grade dysplasia CIN 2/3
Invasive cervical cancer
Endpoint recommended by WHO** & FDA***
Low grade dysplasia CIN 1 Normal cytology Transient infection Variable can occur in 38.9°C (oral temperature) within 5 days post-vaccination visit was
reported in 1.5% of the GARDASIL® -vaccinated population (n=6,040) compared to 1.1% in the placebo group (n=3,981)
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Serum cLIA GMT with 95% CI, mMU/mL
Children - adolescents higher immune response than adults 1600 1500
Immunogenicity Bridge
Efficacy Program
1300 1100 900 700
500
9 Age n
10 11 12 13 14 15 16 17 18 19 20 21 22 23 Age at Enrollment (Years)
9 68
Nolan T et al. 2005, Block et al. Pediatrics 2006
Number of Subjects Evaluable (n) 10 11 12 13 14 15 16 17 18 19 20 21 22 23 129 166 141 166 148 109 85 137 440 511 624 576 564 400
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Proportion of females harbouring Human Papillomavirus (any type) [%]
Human Papillomavirus vaccination should start with those who would benefit most (comparable to the US CDC’s ACIP* recommendation + recent VVOG*** guidelines)
Age (years)
70 60
Routine
Catch up
9-12
13-26
Pre-exposure
Peak exposure
Could be considered later on 27-45 70% life time infection risk**,2,3,4
50 40 30 Cannot screen adolescents
20 10 0
15 18 19 20 21 22 23 24 25
30
35
40
45
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[1] Cervical smears of Danish women aged 15-93 (n=11,865) collected in 2005, Krüger Kjaer S et al. EUROGIN. 23-26 April 2006. Paris, France [2] Koutsky LA. Am J Med 1997 [3] Koutsky LA et al. Epidemiology Rev 1988 [4] Syrjänen K et al. Sex Transm Dis 1990
* United States’ Centers for Diseases Control and Prevention’s Advisory Committee on Immunization Practices *** Vlaamse Vereniging Obstetrie Gynaecologie ** for sexually active people
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1
Long Term Follow-Up Study Through Nordic Registries Denmark
Finland
Sweden
Iceland
Norway
Phase III Study Registry-Based Follow-Up Study population 3.5 yr New subjects 2003
2004
2005
2006
2007
6 yr
8 yr
10 yr
2 yr
4 yr
6 yr
2008
2009
2010
2011
2012
2013
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Cervarix (GSK) Vaccin bivalent 16-18, sur culture cellulaire d’insecte Adjuvant différent : Î Sanofi: Hydroxyde d’aluminium Î GSK: idem +ASO4 Revendique taux Ac plus élevé/plus longtemps,
MAIS techniques ELISA différentes … ⇒ étude comparative des 2 vaccins va commencer < immunogénicité sur 18-26 ans (+ autres sous groupes)
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Cervarix Protection croisée (sur PCR des sérotypes) après 6 mois montrée pour
type 45 (95 %) et 31 (54 %) et 52 Données en attente chez Sanofi
Effficacité sur prévention infection persistante et prévention des lésions
précancéreuses provoquées par 16 et 18 : 100 % (si on prend en compte virus dans lésion et échantillons antérieurs) ou 90% si sur >18.000 femmes de 15 à 25 ans de 14 pays de 4 continents Lancet juin 2007 NB:Recul de plus de 5 ans ausssi quant au maintien efficacité Meilleure immunogénicité chez 10-14 ans aussi (taux x2)
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Papillomavirus vaccination and screening: A strong interaction in the future Vaccination: little impact on pap smears for first 5–10 years
Vaccine recipients still need screening
• Long natural history of disease
• Vaccines targeted to cover 70% oncogenic HPV infections • Screening = opportunity for vaccination
Screening target population will benefit from introduction of vaccination
• Increased HPV-cancer awareness Î Ç screening • Screening not 100% effective (coverage, sensitivity) 47
Risque « virologique »? Shift possible vers sérotypes cancérigènes non vaccinaux
MAIS : 16 et 18 induisent le plus haut risque de dysplasie (suivi de 10 ans) ! Screening reste nécessaire !
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Rotavirus
Prévention de la gastroentérite à rotavirus des petits enfants
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Rotavirus Agents les plus fréquents de gastroentérite aigue(GE) de par le monde
chez nourrisson et jeune enfant Chaque année : 125.105 cas et 500.000 décès (> 80 % dans PVD) Chez nous : léthalité très faible mais cause 15-50 % des GE → 1ère cause hospit et 2ème consultation chez les < 5 ans Rotavirus : virus ARN avec triple enveloppe protéique
réassortiment assurant diversité++ des virus circulant MAIS 4 génotypes prédominants (> 90 % des hospit.) G1, G2, G3, G4, et émergeance du G9 récente
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Epidémiologie
Incidence sous estimée ? 15.200/100.000 enfants de < 5 ans en Europe Mortalité 1/54.000
! Aspect infection nosocomiale USA : ¼ des diagnostics ! cf. étude européenne : 90% GE nosoco sont virales transmission par personnel à partir environnement (dose infectante faible/ excrétion virale++) Belgique : 6-7.000 hospit/an
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Epidemiologie Essentiellement entre 6 et 24 mois Î 95% infectés > 1 fois à l’âge de 5 ans Î avant 3 mois: asymptomatique car Ac maternels / allaitement / immaturité intestinale Î infection symptomatique très rares après 5 ans car immunité s’accroît à chaque épisode Avec impact essentiellement sur qualité de vie des enfants / parents
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Paediatric Rotavirus Gastroenteritis can lead to severe consequences Severe dehydration
Hits when infants are particularly vulnerable (6-24 months)1 No known risk factors1 Unpredictable evolution of symptoms & severity1,2,3 Î
Overnight, a seemingly mild PRG can become life-threatening
>20 diarrhoea or vomiting episodes in 24 h not uncommon3 Severe dehydration may require hospitalisation Source: MOLL, Thieme 1983
[1] Raebel MS, Ou BS, Pharmacotherapy,1999 [2] Clark HF, Offit PA.Ped Ann 2004 [3] Matson D.O. In: Long SS Ed. Principles and Practice of Paediatric Infectious Diseases 2003
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Rotavirus is a leading cause of infant hospitalisation1,2 Virtually all children will be infected at least once by the age of 2 to 3
231 deaths 1 / 54
87,000 hospitalisations
240 / day
700,000 office visits
Rotavirus represents 50-60% of emergency room visits & hospitalisations for paediatric gastroenteritis6
Cases of Acute Gastroenteritis
In Europe* per year in children
