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
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?
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?
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 1973 1993 1992 1997 1968 1973 0 11 mos 12 24 mos 3 4 yrs 5 14 yrs 0 23 mos 2 4 yrs 5 17 yrs 15 44 yrs 45 64 yrs 65 yrs 1969 1995 < 65 yrs 65 yrs 1900 800 320 92 56 110 392 635 399 518 496 1038 186 86 41 144 187 0 25 8 12 23 25 13 23 20 42 (*) 125 228 (*) (*) without a separation between high-risk (HR) and healthy subjects. Izurieta HS, et al. N Engl J Med 2000;342:232 9.
Mortality Rates due to Influenza and Pneumonia Age-associated rates of influenza-related deaths; data from British Columbia, Canada, 1998 2004 influenza seasons 0.10 0.08 0.06 0.04 0.02 0 < 6 months 6 23 months Sebastian R, et al. Vaccine 2008;26:1397 1403. 2 4 years 5 9 years 10 19 years Age group 20 49 years 50 64 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.
Effect of Age on Healthcare Burden Excess treatment events in otherwise healthy children under 15 years of age; data over 19 consecutive seasons (US) 16 14 Outpatient visits Courses of antibiotics Neuzil KM, et al. N Engl J Med 2000;342:225 31. 12 10 8 6 4 2 0 <6 months 6 12 months 1 <3 years 3 <5 years 5 <15 years Age
Role of Children in the Transmission of Influenza in Households and Schools Influenza attack rates are highest in children, average rate 20.3% (7.5 25.8%) 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; 25:5086 96. 2. Weycker D, et al. Vaccine 2005;23:1284 93.
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 2013 1. 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. 20105. 7. Ropero-Álvarez et al. BMC Public Health 2009; 8
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=140 000) Medical costs 3 473 091 694 521 2 778 571 Vaccination program costs 0 1 057 916-1 057 916 Health care costs 3 473 091 1 752 437 1 720 654 Travel costs 247 972 889 016-641 043 Total direct costs 3 721 064 2 641 453 1 079 611 Productivity costs 3 355 692 1 631 008 1 724 684 Societal costs 7 076 756 4 272 461 2 804 295 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 2006 9
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 70 14 60 12 50 10 40 8 30 6 20 4 10 Vaccination programme 2 0 Most schoolchildren Optional 0 Reichert TA, et al. N Engl J Med 2001;344:889 96.
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?
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 = 0.567 p = 0.317 p = 0.164 98.0% 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;153-159 12
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% 47 51 NA 19 17.2%, (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;153-159 13
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 * 80 80 80 60 60 * 60 40 40 40 20 20 20 0 0 28 49 0 28 49 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; 28:563 571. FLUAD is not licensed in US. FLUAD is recommended for active prophylaxis of influenza in the elderly. 0 Day post-first dose 0 0 28 49
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% 100 80 86%* 79%* 92%* 77%* 60 40 43% 40% 45% 20 14% 0 * Statistically significant result. Post hoc analysis. 6 <72 6 <36 36 <72 6 <24 Vesikari et al., NEJM 2011;365:1406-1416 Age (months) Fluad Conventional TIV
Incidence of selected local/systemic reactions (%) Overall rates of local and systemic reactions following vaccination 100 80 FLUAD (n=130) Local reactions Non-adjuvanted split vaccine (n=118) Systemic reactions 60 40 20 * 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; 28:563 571. FLUAD is not licensed in US. FLUAD is recommended for active prophylaxis of influenza in the elderly.
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
Attack Rate (%) Comparative Efficacy Vs. Culture- Confirmed Modified CDC-ILI 9 8 7 6 5 4 3 2 1 0 8.6 54.7 (P<0.001) 3.9 0.7 TIV CAIV-T 88.8 (P<0.001) 0.1 4.5 79.1 (P<0.001) 16.2 (P=NS) All Strains H1N1 H3 B Influenza Strain Belshe et al. N Engl J Med. 2007 Feb 15;356(7):685-96. ATP Population 1.0 3.5 Matched strains shown in solid bars 7.2 55.6 (P<0.001) 3.0 3.2 All Strains <24 Months
Number of Subjects CAIV-T Safety issues Excess wheezing, bronchiolitis in infants aged < 24 months 20 TIV CAIV-T 18 16 14 12 10 8 6 4 2 0 1 2 3 4 5 6 Weeks Post Vaccination Excess hospitalization in infants aged < 12 months for respiratory and non-respiratory causes
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?
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;371:918-931
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;371:918-931.
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 16-24 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
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?
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
Influenza vaccination coverage in children with underlying medical conditions (From Esposito S et al., Vaccine 2006)
Am Lung Ass Asthma Clin Res Centers, N Engl J Med 2001
CARDIORESPIRATORY PARAMETERS AND ADVERSE EVENTS IN THE 4 H AFTER INFLUENZA VACCINATION (Esposito S et al., Vaccine 2008) No significant between-group difference
IMMUNOGENICITY OF MF59-ADJUVANTED SEASONAL INFLUENZA VACCINE IN CHILDREN WITH JIA TREATED WITH DIFFERENT DRUGS (Dell Era et al., Vaccine 2012)
SAFETY OF MF-59 ADJUVANTED INFLUENZA VACCINE IN PEDIATRIC PATIENTS WITH JIA (Dell Era et al., Vaccine 2012)
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
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
KNOWLEDGE AND OPINION OF ITALIAN HCWs ON INFLUENZA (From Esposito S et al., Vaccine 2007)
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?
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?
Distribuzione dei virus influenzali A e B identificati in Italia (2002-2003/2014-2015) 100 90 80 70 60 50 40 30 20 10 0 * 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
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 2007 2008 e 2008 09 100 80 60 40 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.
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 2007 2008 e 2008 2009 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 ± 3.4 7.6 ± 4.4 4.6 ± 2.6 Assenza da scuola, giorni medi ± SD 6.1 ± 4.9 7.6 ± 4.4 6.4 ± 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.
Lineage Influenza B circolante B-mismatch in Europa (Stagioni 2003/2004-2012/2013) 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.
GMTs (95% CI) Studio D-QIV-003 (Bambini 3 17 anni) Titoli anticorpi anti-emoagglutinina (HI) 700 Flu-D-QIV TIV1 (Vic) TIV2 (Yam) 600 500 400 300 200 100 0 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: 1878 1887
Symptoms post-dose 1 (% of subjects) Safety: reattogenicità nei bambini (3 17 anni) Studio D-QIV-003 100 Fu-D-QIV TIV1 (Vic) TIV2 (Yam) 80 60 Durante i 7 giorni post-vaccinazione 40 20 0 All Grade 3 All Grade 3 All Grade 3 Any symptoms General symptoms Local symptoms 1. Domachowske J et al. J Infect Dis 2013; 207:1878 1887; 2. GSK Data on File 2013, Clinical Study Report 113275 (FLU D-QIV-003)
Jain VK et al. NEJM 2013; 369 (26): 2481-2491 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
648 casi gravi, 163 decessi I vaccini non salvano vita, Le vaccinazioni si!
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