VACCINO ANTINFLUENZALE: TRA DUBBI E CERTEZZE

Transcript

1 VACCINO ANTINFLUENZALE: TRA DUBBI E CERTEZZE Susanna Esposito Unità di Pediatria ad Alta Intensità di Cura Università degli Studi di Milano Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico, Milano

2 AGENDA L'influenza è una malattia da prevenire nei primi anni di vita anche nel bambino sano? Ci sono dei metodi per incrementare l immunogenicità nei primi 2 anni di vita senza problemi di sicurezza e tollerabilità? Come può essere protetto dall influenza il bambino con meno di 6 mesi? Ci sono problemi di limitata efficacia e sicurezza nel bambino con patologia cronica? Il vaccino influenzale quadrivalente offre vantaggi rispetto al trivalente?

4 Hospitalisation during Influenza Season according to Age and Presence of Underlying Chronic Disease YEARS AGE HOSPIT./ 100,000 HR SUBJECTS HOSPIT./ 100,000 HEALTHY SUBJECTS mos mos 3 4 yrs 5 14 yrs 0 23 mos 2 4 yrs 5 17 yrs yrs yrs 65 yrs < 65 yrs 65 yrs (*) (*) (*) without a separation between high-risk (HR) and healthy subjects. Izurieta HS, et al. N Engl J Med 2000;342:232 9.

5 Mortality Rates due to Influenza and Pneumonia Age-associated rates of influenza-related deaths; data from British Columbia, Canada, influenza seasons < 6 months 6 23 months Sebastian R, et al. Vaccine 2008;26: years 5 9 years years Age group years years 65 years Provincial and national influenza surveillance reports from the British Columbia Centre for Disease Control, the Public Health Agency of Canada s FluWatch Program, and the Canada Communicable Disease Report (CCDR) were analysed from 1 Sep 1998 to 31 Aug 2004, to determine influenza-related deaths in British Columbia, Canada.

6 Effect of Age on Healthcare Burden Excess treatment events in otherwise healthy children under 15 years of age; data over 19 consecutive seasons (US) Outpatient visits Courses of antibiotics Neuzil KM, et al. N Engl J Med 2000;342: <6 months 6 12 months 1 <3 years 3 <5 years 5 <15 years Age

7 Role of Children in the Transmission of Influenza in Households and Schools Influenza attack rates are highest in children, average rate 20.3% ( %) 1 Children are the major pathway of influenza transmission within communities and households 2 Household & family members Influenza virus transmission School 1. Molinari NAM, et al. Vaccine 2007; 25: Weycker D, et al. Vaccine 2005;23:

8 Influenza vaccination recommendations WHO/Europe Recommend that member states vaccinate all individuals 6 months 1 EU Seven member states currently recommend paediatric vaccination; 2,3,4 recommendations vary by country: 6 months to <18 years of age: Austria, Estonia and Slovakia 6 35 months: Finland. Malta 6 24 months: Slovenia, Latvia 2-10 yrs: UK USA, Canada and PAHO countries US: All individuals 6 months of age 5 Canada: Children 6 24 months of age, and encourages all individuals 6 months of age to be vaccinated 6 Currently, 27 PAHO countries and territories recommend paediatric seasonal influenza vaccination 7* PAHO, Pan American Health Organization. * PAHO recommendations vary by country or territory. ESPID WHO Europe. 2010/11; 2. Blank & Szucs. Expert rev.vaccines 2009; 3. Mereckiene et al. Eurosurveillance 2010; 4. Finland Ministry of Social Affairs and Health. (accessed November, 2010); 5. US CDC 2010; 6. Canada Communicable Disease Report Ropero-Álvarez et al. BMC Public Health 2009; 8

9 Influenza vaccination in young children is cost effective The Finnish experience (assumed vaccine efficacy 60%) Age group and costs ( ) Without vaccination With vaccination Total savings 6 months to <3 years (N= ) Medical costs Vaccination program costs Health care costs Travel costs Total direct costs Productivity costs Societal costs ESPID 2013 Vaccination of young children is cost-saving, investing 1 million Assumed vaccine efficacy 60%. will save an estimated 2.8 million in societal costs Salo et al. Vaccine

10 Impact on the Community of Childhood Influenza Vaccination in Japan and the USA Vaccination of school children against influenza, Japan, 5-year moving average excess mortality due to influenza and pneumonia, all age groups Japan, all causes USA, all causes Japan, pneumonia and influenza USA, pneumonia and influenza Vaccination programme 2 0 Most schoolchildren Optional 0 Reichert TA, et al. N Engl J Med 2001;344:

12 Seroprotection rate (%) Immunogenicity of a single 0.5 ml dose of virosomal influenza vaccine Seroprotection rates at 4 weeks after vaccination Comparable high seroprotection rates after single dose administration and standard regimen p = p = p = % 99.0% 97.0% 99.0% 86.9% 92.9% EMA criterion for Seroprotection in adults Virosomal Influenza vaccine 1 x 0.5 ml Analysis performed per ITT population: 0.25 ml x 2: 98 subjects Virosomal Influenza vaccine 2 x 0.25 ml Analysis performed per ITT population: 0.5mL: 99 subjects ESPID 2013 Esposito et al. Vaccine 2012 Ritzwoller DP et al., Pediatrics 2005;116;

13 Safety evaluation at 4 weeks after vaccination Virosomal vaccine 0.5mL x 1 (99 subjects) Virosomal vaccine 0.25mL x 2 (98 subjects) Percentage of subjects with at least one adverse event (solicited and unsolicited, regardless of relationship) Total number of events Percentage of subjects with at least one solicited local adverse event first vaccination (%) (nr. of subjects), (nr. of events) Percentage of subjects with at least one solicited systemic adverse event first vaccination (%), (nr. of subjects), (nr. of events) after 1st vaccination after 2nd vaccination after 1st vaccination after 2nd vaccination after 1st vaccination after 2nd vaccination after 1st vaccination after 2nd vaccination 47% 50% NA 18.6% NA %, (17),(30) 22.4%, (22), (36) NA 17.2%, (16), (32) 20.2%, (20), (22) 16.3%, (16), (18) NA 17.2% (16), (19) Virosomal vaccine 0.25 ml x 2, 98 subjects returned diary at V1, 93 subjects at V2. Virosomal vaccine 0.50 ml x 1, 99 subjects returned diary at V1. ESPID 2013 Esposito et al. Vaccine 2012 Ritzwoller DP et al., Pediatrics 2005;116;

14 Subjects (% ± 95% CI) 100 Proportion of subjects with an HI titer 1:40 following two doses of vaccine FLUAD (n=104) H3N2 * 100 Non-adjuvanted split vaccine (n=118) H1N1 * 100 CHMP adult guideline threshold Influenza B * * FLUAD induced higher rates of seroprotection against all tested strains, including influenza B, than the non-adjuvanted vaccine * P=0.001 FLUAD vs. split Vesikari T, et al. Ped Infect Dis J 2009; 28: FLUAD is not licensed in US. FLUAD is recommended for active prophylaxis of influenza in the elderly. 0 Day post-first dose

15 Absolute vaccine efficacy (%) Vaccine efficacy in children against all circulating strains Comparative efficacy against PCR-confirmed influenza, all circulating strains, following vaccination with Fluad or conventional TIV Relative efficacy of Fluad vs. conventional TIV 75% 64% 86% 73% %* 79%* 92%* 77%* % 40% 45% 20 14% 0 * Statistically significant result. Post hoc analysis. 6 <72 6 <36 36 <72 6 <24 Vesikari et al., NEJM 2011;365: Age (months) Fluad Conventional TIV

16 Incidence of selected local/systemic reactions (%) Overall rates of local and systemic reactions following vaccination FLUAD (n=130) Local reactions Non-adjuvanted split vaccine (n=118) Systemic reactions * 0 Rates of reactions were comparable between FLUAD and the non-adjuvanted split vaccine * P=0.033 FLUAD vs. split Vesikari 16 T, et al. Ped Infect Dis J 2009; 28: FLUAD is not licensed in US. FLUAD is recommended for active prophylaxis of influenza in the elderly.

17 Word of caution While adjuvanted TIV has shown greater immunogenicity and efficacy than TIV against influenza in young children, the enthusiasm has suffered from the experience with H1N1 vaccine Pandemrix (GSK) being associated with narcolepsy Pandemrix contains AS03 adjuvant (DL-α-tocopherol + squalene) Countries reporting narcolepsy include Finland, Sweden, Norway, Iceland, Ireland, UK, and France EMA has determined (21 July 2011) that the connection is real No narcolepsy signal for MF59, the most widely used squalene adjuvant

18 Attack Rate (%) Comparative Efficacy Vs. Culture- Confirmed Modified CDC-ILI (P<0.001) TIV CAIV-T 88.8 (P<0.001) (P<0.001) 16.2 (P=NS) All Strains H1N1 H3 B Influenza Strain Belshe et al. N Engl J Med Feb 15;356(7): ATP Population Matched strains shown in solid bars (P<0.001) All Strains <24 Months

19 Number of Subjects CAIV-T Safety issues Excess wheezing, bronchiolitis in infants aged < 24 months 20 TIV CAIV-T Weeks Post Vaccination Excess hospitalization in infants aged < 12 months for respiratory and non-respiratory causes

21 Immune Responses to IIV3 Vaccine in HIV-Uninfected Pregnant Women and Transplacental Transfer of Antibodies to Newborns Madhi SA et al. N Engl J Med 2014;371:

22 Kaplan Meier Estimates of Percentages of Confirmed Cases of Influenza According to Cohort and Study Group Madhi SA et al. N Engl J Med 2014;371:

23 SAFETY AND TOLERABILITY OF CAIV-T IN INFANTS YOUNGER THAN 6 MONTHS OF AGE (Vesikari et al., Pediatrics 2008) 59 healthy infants aged 6-16 weeks and 61 aged weeks were randomized to receive CAIV-T or placebo In the 6-16 week cohort, more influenza vaccine recipients experienced irritability (66.7% vs 35.7%) and runny nose or nasal congestion (63.3% vs 33.3%) after dose 1 CAIV-T was generally well tolerated in infants 6-24 weeks of age

25 CHILDREN AT HIGHER RISK FOR INFLUENZA COMPLICATIONS THOSE WHO HAVE CHRONIC PULMONARY (INCLUDING ASTHMA), OR CARDIOVASCULAR, RENAL, HEPATIC, HEMATOLOGICAL OR METABOLIC DISORDERS (INCLUDING DIABETES MELLITUS) THOSE WHO ARE IMMUNOSUPPRESSED THOSE WHO HAVE ANY CONDITION THAT CAN COMPROMISE RESPIRATORY FUNCTION OR THE HANDLING OF RESPIRATORY SECRETIONS OR THAT CAN INCREASE THE RISK FOR ASPIRATION THOSE WHO ARE RECEIVING LONG-TERM ASPIRIN THERAPY WHO THEREFORE MIGHT BE AT RISK FOR EXPERIENCING REYE SYNDROME AFTER INFLUENZA INFECTION

26 Influenza vaccination coverage in children with underlying medical conditions (From Esposito S et al., Vaccine 2006)

27 Am Lung Ass Asthma Clin Res Centers, N Engl J Med 2001

28 CARDIORESPIRATORY PARAMETERS AND ADVERSE EVENTS IN THE 4 H AFTER INFLUENZA VACCINATION (Esposito S et al., Vaccine 2008) No significant between-group difference

29 IMMUNOGENICITY OF MF59-ADJUVANTED SEASONAL INFLUENZA VACCINE IN CHILDREN WITH JIA TREATED WITH DIFFERENT DRUGS (Dell Era et al., Vaccine 2012)

30 SAFETY OF MF-59 ADJUVANTED INFLUENZA VACCINE IN PEDIATRIC PATIENTS WITH JIA (Dell Era et al., Vaccine 2012)

31 VACCINATED HIGH-RISK CHILDREN (No.=72) Why is your child vaccinated against influenza? ANSWER Pediatrician s recommendation FREQUENCY 63 (87.5%) Protection of parents 6 (8.3%) Protection of an elderly family members Previous serious influenza-like illness 2 (2.8%) 1 (1.4%) Esposito S et al., Vaccine 2006

32 UNVACCINATED HIGH-RISK CHILDREN (No.=202) Why is your child not vaccinated against influenza? ANSWER FREQUENCY Lack of awareness 173 (85.6%) Inconvenience 11 (5.5%) Concern about side effects 18 (8.9%) Esposito S et al. Vaccine 2006

33

34 KNOWLEDGE AND OPINION OF ITALIAN HCWs ON INFLUENZA (From Esposito S et al., Vaccine 2007)

35 After three decades of official recommendations that all HCWs be vaccinated against influenza, vaccination rates generally remain below 30% in Europe Experiences in the USA have shown that mandatory policies achieve a compliance rate of nearly 100% Given the available evidence concerning the benefits, burdens and risks of HCWs influenza vaccination and the limited effectiveness of voluntary policies, is it time to consider mandatory vaccination policies for HCWs in Europe?

37 Distribuzione dei virus influenzali A e B identificati in Italia ( / ) * 20% 16% 26% 28% 48% 58% Virus B Virus A Dati della sorveglianza virologica di InfluNet, dal sito del Ministero della Salute; *Dati Istituto Superiore di Sanità

38 Percentage La presentazione clinica dell influenza A e B è simile nei bambini Presentazione clinica dei bambini di età <15 anni con infezione da virus influenzale confermata in Italia durante le stagioni e I bambini con influenza A/H3N2 hanno avuto LRTI, sibili e polmonite con frequenza significativamente superiore rispetto ai bambini con A/H1N1 o B (all p < 0.05) Influenza A/H1N1 (n = 143) Influenza A/H3N2 (n = 519) Influenza B (n = 239) 20 0 LRTI, lower respiratory tract infection. Esposito S, et al. BMC Infect Dis 2011; 11: 271.

39 L influenza B causa un elevato tasso di ospedalizzazioni e assenteismo da scuola Outcomes clinici in bambini di età <15 years con infezione da virus influenzale confermata in Italia durante le stagioni e Outcome clinico Influenza A/H1N1 (n = 143) Influenza A/H3N2 (n = 519) Influenza B (n = 239) Tasso di ospedalizzazione, numero (%) 6.0 (4.2) 87 (16.8)* 30 (12.5) Durata dell ospedalizzazione, Nessuna differenza statisticamente Tasso di ospedalizzazione più basso nei bambini con Compared with influenza significativa A/H3N2, children nei tassi with di influenza A/H1N1 rispetto a quelli con influenza influenza A/H1N1 or B had a significantly ospedalizzazione shorter tra stay l influenza A/H3N2 o B (p < 0.05) hospital and missed fewer days A/H3N2 at school e (both l influenza p < 0.05) B 1 giorni medi ± SD 5.2 ± ± ± 2.6 Assenza da scuola, giorni medi ± SD 6.1 ± ± ± 5.0 *Influenza A/H3N2 vs influenza A/H1N1, p < 0.05; influenza A/H3N2 vs influenza A/H1N1 e influenza B, p < 0.05; SD, standard deviation. Periodo significativamente (p < 0.05)più breve di permanenza in ospedale e meno giorni di scuola persi nei bambini con influenza A/H1N1 o B in confronto a quelli con influenza A/H3N2 Esposito S, et al. BMC Infect Dis 2011; 11: 271.

40 Lineage Influenza B circolante B-mismatch in Europa (Stagioni 2003/ /2013) Yamagata Victoria 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Dati non disponibili * * * * VIC YM YM VIC VIC YM VIC VIC VIC YM Lineage vaccinale *Mismatch vaccinale: >60% mismatch; Mismatch vaccinale parziale:<80% matching 1. Ambrose CS, et al. Hum Vaccin Immunother 2012; 8: 81-8; 2. ECDC. Annual epidemiological report on communicable diseases in Europe.

41 GMTs (95% CI) Studio D-QIV-003 (Bambini 3 17 anni) Titoli anticorpi anti-emoagglutinina (HI) 700 Flu-D-QIV TIV1 (Vic) TIV2 (Yam) PRE POST PRE POST PRE POST PRE POST H1N1 H3N2 B-Victoria B-Yamagata Coorte Per protocol per l immunogenicità: Flu-D-QIV n=791, TIV1 (Vic) n=819, TIV2 (Yam) n=801 PRE=Giorno 0 e POST (Giorno 28) Elaborazione grafica da Tab.2 di: Domachowske J et al. J Infect Dis 2013; 207:

42 Symptoms post-dose 1 (% of subjects) Safety: reattogenicità nei bambini (3 17 anni) Studio D-QIV Fu-D-QIV TIV1 (Vic) TIV2 (Yam) Durante i 7 giorni post-vaccinazione All Grade 3 All Grade 3 All Grade 3 Any symptoms General symptoms Local symptoms 1. Domachowske J et al. J Infect Dis 2013; 207: ; 2. GSK Data on File 2013, Clinical Study Report (FLU D-QIV-003)

43 Jain VK et al. NEJM 2013; 369 (26): Studio di efficacia nei bambini 3-8 anni (Q-QIV-006) Immunogenicità - PP cohort Titoli anticorpali HI vs ciascun sottotipo A e lineage B al basale, 1 mese, e 6-8 mesi dopo la vaccinazione 6-8 mesi dopo la vaccinazione, il tasso di sieroprotezione era >90% vs A/H3N2 e B/Yamagata e >80% vs A/H1N1 e B/Victoria

44

45 648 casi gravi, 163 decessi I vaccini non salvano vita, Le vaccinazioni si!

46 SEE YOU IN MILAN!