uso dei vaccini nell adulto

3. Goal of vaccine interventions in infants and children Vaccines are often such a powerful tool that they can make elimination of a specific disease an achievable target. The required components of an effective recepy are: High effectiveness Extensive coverage Herd immunity effect Recepy vuol dire “ricetta”Recepy vuol dire “ricetta”

4. Herd immunity Successful vaccination protects immunised individuals from infection, thereby decreasing the percentage of susceptible persons within a population and reducing the possibility of infection transmission to others. At a definable prevalence of immunity, an infectious organism can no longer circulate freely among the remaining susceptibles

5. Smallpox: the only example of a successful eradication campaign(May 8th, 1980)

6. Other intermediate effects On the way of elimination, vaccines may deeply change the clinical history of a medical condition by decreasing the incidence of a specific agent or shifting the epidemiologic pattern of an infection from epidemic to endemic

7. Notified bacterial meningitis cases, Italy 1994 - 2008

8. Hib conjugate vaccine This vaccine both elicits durable immunity by the time maternal-derived antibodies dissipate, and reduces nasopharyngeal carriage thus diminishing the risk of transmission

9. Just by chance ? Effective vaccines are not available for: AIDS tuberculosis malaria the biggest health problems that we are facing today

10. Factors causing decreased acceptability of vaccines Awareness of disease threats is decreasing (as a consequence of vaccine efficacy !!!!): measles, polio, etc. Some segments of the public are unwilling to accept any risk of vaccine associated vaccination…. missing the need to make cost-benefit balances

11. CDC’s review of VAERS reports concerning Gardasil: As at June 30 2008, 9749 reports of adverse events after Gardasil administration over an estimate of at least 8 million women receiving the vaccine. 93% non serious: syncope, pain at the injection site, headcahe, nausea, and fever. Risk of fainting added to Gardasil prescribing information 7% serious: death, Guillain-Barré syndrome (GBS) and thromboembolic disorders.

12. CDC’s review of VAERS:Gardasil and GBS According to CDC and FDA analysis no evidence that Gardasil vaccinated women have an increase of the baseline 1 to 2 per 100,000 incidence of GBS in the general population No changes to any of the existing HPV recommendations Close to publication the data of the Vaccine Safety Datalink (VSD) project comparing a vaccinated (> 300,000 doses) and an unvaccinated population on the risk of 9 specific important outcomes including GBS

13. Polio vaccination in Italy Polio 1,2,3 live attenuated vaccine (OPV, Sabin) more immunogenic than inactivated vaccine (IPV, Salk) but rarely associated with polio-like disease After polio eradication in Italy, based on a risk / benefit analysis, IPV replaced OPV for infant and adult vaccination

14. Adult immunization strategies Rather than elimination, the aim is the reduction of morbidity/mortality in specific population groups Increased risk of morbidity Influenza, invasive pneumococcal disease for the elderly Cervical cancer in women Increased exposure Vaccine preventable diseases in travellers Influenza among health staff, etc.

15. Summary (1) Vaccines have a great potential among public heath prevention strategies Demonstrated remarkable achievements at very attractive costs The development of vaccines for the major endemic infectious diseases are a priority for current and future research

18. Professor zur Hausen, Nobel Prize winner in Medicine 2008 for his research on HPV

19. Il cancro della cervice è il secondo al mondo per frequenza, la mappa dimostra la concentrazioneIl cancro della cervice è il secondo al mondo per frequenza, la mappa dimostra la concentrazione

20. La figura mostra uno schema tridimensionale della superficie esterna del virione di HPV. La capsula o capsomero di 50-55 nm è interamente proteica, di forma icosaedrica, costituita da 72 pentameri. Ogni pentamero è costituito da cinque molecole di L1, al cui interno è incastonata una molecola di L2. In pratica, l’intera superficie esterna ed esposta di HPV è costituta da L1, verso cui (vedi in seguito) è misurabile la produzione naturale di una risposta immune di tipo umorale.La figura mostra uno schema tridimensionale della superficie esterna del virione di HPV. La capsula o capsomero di 50-55 nm è interamente proteica, di forma icosaedrica, costituita da 72 pentameri. Ogni pentamero è costituito da cinque molecole di L1, al cui interno è incastonata una molecola di L2. In pratica, l’intera superficie esterna ed esposta di HPV è costituta da L1, verso cui (vedi in seguito) è misurabile la produzione naturale di una risposta immune di tipo umorale.

21. La protezione è associata alla produzione di anticorpi neutralizzanti1 La protezione conferita dall’immunità umorale è dovuta all’effetto neutralizzante degli anticorpi di tipo IgG. Gli anticorpi neutralizzanti bloccano il legame di HPV con il recettore cellulare (1) e prevengono la liberazione del materiale nucleare dal capsomero (processo di uncoating) (2) Gli anticorpi neutralizzanti sono tipo-specifici (3) Chen XS, ei al. Mol Cell. 2000;5:557–567. Booy FP, et al. J Mol Biol. 1998;281:95–106. Roden RB, et al. J Virol. 1996;70:3298–3301.La protezione conferita dall’immunità umorale è dovuta all’effetto neutralizzante degli anticorpi di tipo IgG. Gli anticorpi neutralizzanti bloccano il legame di HPV con il recettore cellulare (1) e prevengono la liberazione del materiale nucleare dal capsomero (processo di uncoating) (2) Gli anticorpi neutralizzanti sono tipo-specifici (3) Chen XS, ei al. Mol Cell. 2000;5:557–567. Booy FP, et al. J Mol Biol. 1998;281:95–106. Roden RB, et al. J Virol. 1996;70:3298–3301.

22. The vaccine is produced in recombinant yeast, as is the hepatitis B vaccine It is adsorbed on the Merck & Co’s (MSD) proprietary aluminium adjuvant. Aluminium salts are used as adjuvant to increase vaccine immunogenicity, in vaccines as common as vaccines against tetanos, poliomyelitis (injectable)… The vaccine is produced in recombinant yeast, as is the hepatitis B vaccine It is adsorbed on the Merck & Co’s (MSD) proprietary aluminium adjuvant. Aluminium salts are used as adjuvant to increase vaccine immunogenicity, in vaccines as common as vaccines against tetanos, poliomyelitis (injectable)…

25. Determinants for the cost-effectiveness analysis of HPV vaccines Protective efficacy: virtually 100% on TARGET TYPES and provided that HAD NOT OCCURRED prior to vaccination Health benefits: delayed impact on cervical cancer, early impact on cervical dysplasia and genital warts Cost of the vaccine Duration of protection

26. Risposta B memory e durata della protezione vaccinica Dose booster a 60 mesi dopo ciclo iniziale: 1 settimana dopo il re-challenge titoli anticorpali simili 1 mese post primo ciclo Sierotitoli più elevati 1 mese dopo il rechallenge rispetto ad 1 mese post primo ciclo

27. Pneumococcal Disease: Pathogenesis

29. Conjugated and un-conjugated pneumococcal vaccines Conjugated vaccines (but not polisaccharide vaccines) induce mucosal immunity. These vaccines are effective in reducing bacterial colonisation and carrier state They exert a significant herd immunity effect which is not demonstrated for polisaccharide vaccines

33. Vaccino antipneumococcico e obiettivi di salute in Italia Obiettivo: ridurre morbidità da malattia pneumococcica nei < 5 anni Stimando incidenza 60 / 100k, efficacia 90%, copertura 90%, share tipi vaccinali 80% ? prevenzione 900 casi / anno Efficacia certa, ma costo-efficacia diversamente valutata dalle regioni (alti costi attuali del vaccino - attuale difficoltà in misurare morbidità)

34. Summary (2) Adult vaccination strategies aim at morbidity reduction rather than disease elimination Vaccine targets are derived by a thourough comprehension of disease impact in specific population groups The benefits of several effective adult vaccines (including HPV, pneumococcus, etc.) might be better exploited

35. Il vaccino per l’influenza stagionale Il Ministero della Salute sulla base dell’evidenza che la vaccinazione antiinfluenzale riduce la malattia in soggetti sani adulti del 70 – 90% e la mortalità per influenza nell’anziano del 40 – 75%, raccomanda la vaccinazione a: persone con età maggiore di 64 anni bambini di età > 6 mesi con comorbidità bambini in trattamento cronico con ASA adulti affetti da patologie croniche donne che saranno in 2-3 trimestre di gravidanza all’epoca del picco epidemico ospiti di lungodegenze personale sanitario persone a contatto con soggetti ad alto rischio di complicanze soggetti addetti a mansioni pubbliche di primario interesse soggetti a contatto con animali potenzialmente affetti da ceppi aviari

36. Target di copertura vaccinale in Italia Target minimo 70%, ottimale 100%

38. . How will we know when we are in a pandemic? The World Health Organization (WHO) has developed guidelines to identify phases of a pandemic based on the spread of disease. We expect that official declaration of a pandemic will be made by the WHO. Currently, we are in Phase 3, meaning that a significant flu virus – H5N1 - is circulating among birds which could - in the future - mutate to become a pandemic strain of the flu. But currently we have only seen very limited human-to-human transmission. In total, since 2003, 265 people have been infected with H5N1, and 159 have died. These are the reported and confirmed cases. We don’t know how many others may have gone unreported. Of the 116 cases of H5N1 infection in humans reported during 2006, 80 died. That’s greater than a 50% death rate. Almost half (56) of those cases were in Indonesia, and there the death rate was even higher: 46 out of 56. (source: WHO) At the point where evidence shows increased human-to-human transmission, we will enter Phase 4. This will be an indication that the circulating flu has mutated so that humans are more widely susceptible. During this phase, efforts will likely be made to contain the virus before it spreads to humans in other locations, since the virus will be localized and highly inefficient. Moving from Phase 3 to 4 could take weeks, months or years. Scientists do not know when a pandemic might occur – only that eventually, it will. At the point where there is evidence of significant human-to-human transmission, we enter Phase 5. It is likely that the virus will be still be localized, though capable of infecting a wider circle of people than in Phase 4. When the virus has mutated sufficiently to become efficient in its ability to move from human-to-human and spread outside local areas, we enter Phase 6, and WHO will declare a pandemic. How will we know when we are in a pandemic? The World Health Organization (WHO) has developed guidelines to identify phases of a pandemic based on the spread of disease. We expect that official declaration of a pandemic will be made by the WHO. Currently, we are in Phase 3, meaning that a significant flu virus – H5N1 - is circulating among birds which could - in the future - mutate to become a pandemic strain of the flu. But currently we have only seen very limited human-to-human transmission. In total, since 2003, 265 people have been infected with H5N1, and 159 have died. These are the reported and confirmed cases. We don’t know how many others may have gone unreported. Of the 116 cases of H5N1 infection in humans reported during 2006, 80 died. That’s greater than a 50% death rate. Almost half (56) of those cases were in Indonesia, and there the death rate was even higher: 46 out of 56. (source: WHO) At the point where evidence shows increased human-to-human transmission, we will enter Phase 4. This will be an indication that the circulating flu has mutated so that humans are more widely susceptible. During this phase, efforts will likely be made to contain the virus before it spreads to humans in other locations, since the virus will be localized and highly inefficient. Moving from Phase 3 to 4 could take weeks, months or years. Scientists do not know when a pandemic might occur – only that eventually, it will. At the point where there is evidence of significant human-to-human transmission, we enter Phase 5. It is likely that the virus will be still be localized, though capable of infecting a wider circle of people than in Phase 4. When the virus has mutated sufficiently to become efficient in its ability to move from human-to-human and spread outside local areas, we enter Phase 6, and WHO will declare a pandemic.

39. Influenza vaccines Vaccines are the mainstay for prevention of seasonal flu since half a century A pandemic vaccine will be developed, but impact on the pandemic low because of delayed availability Pre-pandemic vaccines developed to gain time. New adjuvants and new production techniques been developed (antigen sparing). Assumptions Low efficacy ~30% (mismatch, one dose) New adjuvants allow broaden efficacy on drifted strains Priming may be done with one or two doses

40. Development of the vaccine strategy

41. Case fatality rate > 60% in human cases of avian influenza 2% in 1918 pandemic 0.2% in 1957 pandemic < 0.1% in seasonal flu

42. Ruolo del vaccino nel piano pandemico italiano Nella fase 3, caratterizzata da presenza di un nuovo sottotipo virale, ma assenza di trasmissione interumana, è necessario identificare le categorie prioritarie a cui offrire la vaccinazione pandemica. Il presente Piano identifica 6 categorie, elencate in ordine di priorità: 1. Personale sanitario e di assistenza (ospedali, …) 2. Personale addetto ai servizi essenziali alla sicurezza e alla emergenza (polizia, …) 3. Personale addetto ai servizi di pubblica utilità (esercito….) 4. Persone ad elevato rischio di complicanze severe o fatali a causa dell’influenza 5. Bambini e adolescenti sani di età compresa tra 2 e 18 anni 6. Adulti sani

43. Pandemic severity index In principles, we cannot say today what the response to the next pandemic will be because we do not know how hard the pandemic will hit. Even for same values of attack rate the impact of the pandemic will vary hugely in terms of clinical burden according to the severity index. Therefore, extreme response measures will be acceptable to face a devastiting pandemic, but will not be aceptable to contain a mild one. In principles, we cannot say today what the response to the next pandemic will be because we do not know how hard the pandemic will hit. Even for same values of attack rate the impact of the pandemic will vary hugely in terms of clinical burden according to the severity index. Therefore, extreme response measures will be acceptable to face a devastiting pandemic, but will not be aceptable to contain a mild one.

44. Summary (4) We keep on waiting the next influenza pandemic Models predict that its severity might be substantial, and, mostly, unpredictable beforehand A comprehensive vaccination strategy, which include the use of seasonal influenza, pre-pandemic and pandemic vaccines, will be a mainstay of health system response.

48. I colori ci sono ma sono molto estesiI colori ci sono ma sono molto estesi

50. TwinrixTM Update Hepatitis A Inactivated & Hepatitis B (Recombinant) Vaccine Accelerated dosing schedule of 0, 7, 21-30 days and a booster dose at 12 months FDA approved March 28, 2007 - Hep B vaccine if required (HPV likely not to be useful) - Hep B vaccine if required (HPV likely not to be useful)

56. Il vaccino WC/rBS (whole cell-recombinant B-subunit) ha individuato come strategia quella di indurre la produzione di anticorpi contro:- il corpo batterico- la subunità B della tossina colerica con l’obiettivo di bloccare il suo attacco alle cellule intestinali e, quindi, alla subunità A (parte attiva della tossina) di rendersi intracellulare ed esplicare la propria azione patogena

57. Similitudine antigenica tra le subunità B delle tossine di Vibrio cholerae e di Escherichia coli enterotossigena (ETEC),

60. Meningococcal conjugate polysaccharide vaccine Chemical conjugation to a protein carrier ? monovalent (C) in Italy ? quadrivalent (A+C+Y+W-135) in US In Italy: Age: > 12 months 1 dose, intramuscolar Duration of protection: unknown (no clear boosting requirements defined)

61. What vaccine for international travellers ? Priority should be given to the need to protect from all potential meningococcal strains ? Quadrivalent polysaccharide

63. Is vaccination effective ? Since the introduction of the quadrivalent meningococcal (A, C, Y, W135) vaccine as Hajj visa requirement in the year 2002, no further outbreaks have occurred.

64. Summary (3) Vaccines are a mainstay of travel medicine preventive interventions The selection of vaccine recommandations is based on destination as well as traveller characteristics Research for the development of vaccines for malaria and dengue are the first priorities in this area

66. Dimostra l’outbreak di casi di morbillo nel 2008, a carico prevalentemente di locali infettati in USA da soggetti infettatisi all’esteroDimostra l’outbreak di casi di morbillo nel 2008, a carico prevalentemente di locali infettati in USA da soggetti infettatisi all’estero

67. Indicazioni all’impiego di BCG

68. Dimostra che gli americani che nel 2008 hanno preso il morbillo e non erano vaccinati, avevano deciso di non vaccinarsi per motivi filosofici Dimostra che gli americani che nel 2008 hanno preso il morbillo e non erano vaccinati, avevano deciso di non vaccinarsi per motivi filosofici

69. Il diagramma riassume il processo costitutivo delle VLPs. Il primo passaggio consiste nell’isolamento del DNA del tipo di HPV e nell’inserzione del gene codificante per la proteina capsidica L1 all’interno di un plasmide. Il plasmide carrier del gene virale è quindi inserito all’interno di una cellula eucariotica, che provvede alla trascrizione di RNA messaggero per L1 e alla traduzione del messagger nella proteina L1. Le proteine L1 prodotte hanno la capacità intrinseca di assemblarsi prima in pentameri per poi costituire l’intero capsomero che costituisce l’involucro di HPV. Poichè l’unica componenete nucleica inserita nella cellula eucariotica era il gene di L1 non vi è alcuna produzione di genoma virale da parte del sistema ed i capsomeri prodotti risultano vuoti. Quindi, le VLPs, pur essendo antigenicamente indistinguibili dal virus naturale, sono intrinsecamente prive di ogni capacità infettante ed oncogenica. Le VLPs prodotte vengono in seguito purificate ed utilizzate a scopo vaccinale. Il diagramma riassume il processo costitutivo delle VLPs. Il primo passaggio consiste nell’isolamento del DNA del tipo di HPV e nell’inserzione del gene codificante per la proteina capsidica L1 all’interno di un plasmide. Il plasmide carrier del gene virale è quindi inserito all’interno di una cellula eucariotica, che provvede alla trascrizione di RNA messaggero per L1 e alla traduzione del messagger nella proteina L1. Le proteine L1 prodotte hanno la capacità intrinseca di assemblarsi prima in pentameri per poi costituire l’intero capsomero che costituisce l’involucro di HPV. Poichè l’unica componenete nucleica inserita nella cellula eucariotica era il gene di L1 non vi è alcuna produzione di genoma virale da parte del sistema ed i capsomeri prodotti risultano vuoti. Quindi, le VLPs, pur essendo antigenicamente indistinguibili dal virus naturale, sono intrinsecamente prive di ogni capacità infettante ed oncogenica. Le VLPs prodotte vengono in seguito purificate ed utilizzate a scopo vaccinale.

70. Meccanismi proposti per la risposta immune ad HPV1–5 Key Point It has been proposed that HPV L1 VLP stimulates an adaptive immune response in humans, resulting in the generation of type-specific neutralizing anti-HPV antibodies. Key Point It has been proposed that HPV L1 VLP stimulates an adaptive immune response in humans, resulting in the generation of type-specific neutralizing anti-HPV antibodies.

71. La risposta B memory Importanza della risposta B memory: Permette una risposta vigorosa se re-challenge dell’antigene Permette una risposta molto più rapida che nel corso del challenge iniziale

72. Extending recommandations for HPV vaccines Ongoig trials will soon shed light on efficacy and safety among: Women 26 to 54 years of age Boys and men The true challenge will be to extend the coverage among pre-adolescent girls

73. Vaccinazione per S.pneumoniae in Italia Vaccino glico-coniugato eptavalente Registrato in Italia nel 2001 81% dei casi di meningite in Italia imputabile a ceppi vaccinali (dati ISS) Incluso nel calendario vaccinazione solo per bambini a rischio di età < 5 anni Tre dosi nel primo anno di vita (immunogeno nell’infanzia, a differenza di 23-valente)

76. Politiche regionali sul vaccino antipneumococcico Offerta gratuita a tutti < 5 anni ad alto rischio Disponibilità vaccino gratuito o a spesa compartecipata sulla base delle strategie regionali

82. Meningococcal polysaccharide vaccines Purified capsular polysaccharide ? monovalent (A, C) and bivalent (A/C) ? quadrivalent (A+C+Y+W-135) 1 dose, subcutaneous Age: > 2 years Duration of protection: 3 years A substantial proportion of cases are caused by “type B” meningococcus, for which no vaccine is licensed or available

83. Advantages of conjugate vaccines Usefulness of the Polysaccharide vaccine is limited because it does not confer long-lasting immunity and does not cause a sustainable reduction of nasopharyngeal carriage of N. meningitidis, and therefore does not interrupt transmission sufficiently to elicit herd immunity. Conjugate vaccines exert enhanced immunogenicity due to the protein component, which elicit a T-cell dependant antibody response: immunogenic in infants longer duration of protection reduction of nasopharyngeal carriage

84. Vaccino pandemico e prepandemico Vaccino pandemico Poiché il tipo virale della prossima pandemia è attualmente ignoto, il vaccino pandemico attualmente non esiste. Tuttavia, sono in atto procedure accelerate per rendere la preparazione, sperimentazione, registrazione e disseminazione del vaccino la più rapida possibile dopo l’insorgenza della prossima pandemia. Vaccino pre-pandemico Vi sono indizi che il prossimo ceppo pandemico sia un ceppo aviario H5 (più probabilmente) oppure H7 o H9. Sulla base di questa previsione sono in fase avanzata di registrazione vaccini diretti verso i corrispettivi virus aviari, definiti vaccini pre-pandemici. Vaccino per l’influenza stagionale La vaccinazione per l’influenza stagionale può conferire una sorta di priming che renda la vaccinazione pandemica più efficace una volta disponibile.

85. Pre-pandemic vaccines Pre-pandemic vaccines need strategies for: Priming of the population Stock-piling

86. What will determine the priority governments will give to the pandemic response ?