Influenza Vaccines: The Good, The Bad, The Controversies

Transcription

1 Influenza Vaccines: The Good, The Bad, The Controversies Janet A. Englund, M.D. Dept. Of Pediatrics, Seattle Children s Hospital, University of Washington Fred Hutchinson Cancer Research Center Sept. 25, 2014

2 FINANCIAL DISCLOSURES AND CONFLICTS OF INTEREST My institution has received research support for clinical studies from Gilead and Chimerix. I have served as a consultant for GSK POTENTIAL CONFLICTS OF INTEREST: I support my institution s efforts to immunize HCW with flu vaccine. Institutions I have worked for have received pharmaceutical, government and foundation funding for the evaluation of influenza vaccines in children and pregnant women over the past 20 yrs. My mother receives flu vaccine, for free, from Medicare. My husband and children receive flu vaccine because they are miserable when sick.

3 INFLUENZA VACCINE: Challenges of influenza Epidemiology Prevention Do flu vaccines work? Which vaccine for children? Do health care workers need flu shots?

4 THE BURDEN OF FLU Average Annual Influenza Morbidity and Mortality ARD hospitalizations 12 per 10,000 Deaths 1 per 10,000 Medically attended illnesses 12 per 100 Acute respiratory illness 26 per 100 Influenza virus infections 33 per 100 Glezen. Epidemiol Rev. 1982;4:25; Glezen et al. J. Infect Dis. 1987;155:119; Glezen et al. Pediatr Infect Dis J. 1997;16:1065.

5 2014: US P&I Mortality by week, 122 Cities Mortality Reporting System, United States, * % of deaths exceeding epidemic threshold for pneumonia and influenza Excess Mortality Excess Mortality

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7 Children are highest risk group for hospitalization due to Influenza (Hong Kong) * CHILDREN ARD: Acute Respiratory Disease; P&I: Pneumonia and Influenza-like illness, CV- Cardiovascular; IHD- Ischemic heart disease; DM- Diabetes Mellitus Wong CM et al, PLoS Med April; 3(4): e121

8 2014: What influenza viruses are circulating? who.int/influenza/surveillance_monitoring/updates/ 2014_08_14_influenza_global_circulation.pdf

9 Influenza morbidity may be greater in developing countries and aboriginal populations Higher incidence of infection: longer period of circulating influenza in most tropical areas Higher rate of preterm and underweight births High environmental exposures such as indoor air pollution High rates of pneumococcal carriage Decreased access to preventive medicine and therapy

10 Prevention of Influenza: Vaccine The only practical and proven approach to prevent influenza is influenza vaccine. Currently available influenza vaccine has variable effectiveness depending on match to circulating strain, and health status and age of recipient Influenza virus changes are unpredictable -rates of infection, morbidity and mortality also vary widely

11 PREVENTION OF INFLUENZA: Other solutions? - Darwin Market, Northern Territory, Australia-

12 Prevention of Influenza: Vaccine Issues with influenza vaccine: Requires annual administration Timing and distribution of vaccine uncertain Pediatric immunization is complicated Multiple types of vaccine available (inactivated, live) but no vaccine for babies < 6 months (who are at highest risk of hospitalization) Changes in public perception over time

13 Chronic disease Pregnancy Elderly 1

14 Influenza Vaccine Influenza vaccine is the cornerstone of influenza prevention Influenza vaccine is very safe and relatively inexpensive Influenza vaccine effectiveness is only ONE of many considerations in making policy decisions Burden of disease is critical Absolute vs relative prevention can be considered Practical considerations are important The landscape of influenza vaccine is rapidly evolving and healthcare providers, policymakers and healthcare analysts need to be responsive and flexible

15 2005 ACIP Influenza Vaccine Recommendations : TARGET GROUPS FOR VACCINATION Persons at Increased Risk for Complications Vaccination with inactivated influenza vaccine is recommended for the following persons who are at increased risk for complications from influenza: persons aged >65 years; residents of nursing homes and other chronic-care facilities that house persons of any age who have chronic medical conditions; adults and children who have chronic disorders of the pulmonary or cardiovascular systems, including asthma (hypertension is not considered a high-risk condition); adults and children who have required regular medical follow-up or hospitalization during the preceding year TOO COMPLICATED because of chronic metabolic diseases (including diabetes mellitus), renal dysfunction, hemoglobinopathies, or immunosuppression (including immunosuppression caused by medications or by human immunodeficiency virus [HIV]); adults and children who have any condition (e.g., cognitive dysfunction, spinal cord injuries, seizure disorders, or other neuromuscular disorders) that can compromise respiratory function or the handling of respiratory secretions or that can increase the risk for aspiration; children and adolescents (aged 6 months 18 years) who are receiving long-term aspirin therapy and, therefore, might be at risk for experiencing Reye syndrome after influenza infection; women who will be pregnant during the influenza season; and children aged 6 23 months.

16 PREVENTION 2010 USA: Universal flu vaccine for all persons > 6 M

17 Populations to Consider Elderly: Healthy vs frail; underlying medical conditions or not Community living vs nursing home; younger elderly vs older elderly: Pregnant women: High risk for mortality Infants and Children: Infants < 6 months & toddlers 6-23 M: Highest risk of hospitalization Children 2-5 yrs; School age children: Highest risk of disease; disease spreaders Health Care Workers: critical workforce, contact with vulnerable patients

18 When should pregnant women get their flu shots? People magazine, 2013; Mar 11, p. 29

19 Children: High Risk for Influenza Complications MORBIDITY MORTALITY Seizures and encephalopathy in a young girl with influenza A oads/slides-jun-2012/02-influenza-finelli.pdf

20 Assessment of Influenza Vaccine Effectiveness in Children Many factors are important when assessing vaccine effectiveness for children: Good match of vaccine to circulating strains required Studies require timely administration of TWO doses for children < 9 years and high enough attack rate to judge efficacy Heterogeneity in case definitions and endpoints confusing Underlying conditions such as asthma must be considered AGE GROUPS ARE CRUCIAL FOR ANALYSIS 6M to 2 Yr; 2-5 Yr, 5-9 Yr, > 10 years

21 THE GOOD Influenza vaccine works

22 New Studies Show Effectiveness against severe influenza disesase JID 2014;210:675-83

23 Influenza vaccine efficacy in children: Selected Randomized Controlled Trials of TIV* Author/Year/ Journal Neuzil (2001) Clover (1991) Hoberman (2003) Loeb (2010) Vesikari (2011) Study Study Age Vaccine Lab VE (%) 95% CI Year location range Type Confirmation USA <16 y TIV Cx, HI 91 64, USA <16 y TIV Cx, HI 77 20, USA 3-18 y TIV Cx, HI 62 P< USA 6-24 m TIV Cx 66 34, USA 6 m - 24 m TIV CX , Canada 36 m- 15 y TIV RT-PCR 61% 8, Germany, TIV-Adj 86 74, m RT-PCR Finland TIV 43 15, 61 Range of VE point estimates: 0% - 91% *Not 6/8 study-years statistically significant. with significant protection [VE of 43-91%] **2 study years with no measurable effect (low AR in control group) 23 * Lafond et al JPIDS 2013

24 Examples of LAIV VE studies in children <7 yrs old: Randomized Clinical Trials (adapted, Osterholm et al. Lancet ID; 2011) Author (Year) Study Year No. subjects Age range VE (95% CI) Belshe (1998) m 93 (88,96) Belshe (2000) m 87 (78,93) Vesikari (2006) m 84 (74,90) Vesikari (2006) m 85 (78,90) Bracco Neto (2009) m 72 (62,80) Tam (2007) m 68 (59,75) Tam (2007) m 57 (30,74) Lum (2010) m 64 (40,79) Summary VE 83 (69-91)

25 Indirect Effects of LAIV in a School-Based Immunization Program in Texas* School-based influenza vaccine delivery increased vaccine uptake Including all schools, indirect benefit increased to 29% and 23% of total medically-attended acute respiratory Infections (MAARI) during the intense epidemic phase. Important factors: % coverage, vaccine match, timing. This indirect protection increased the estimates for influenza-attributable MAARI. LAIV provides almost immediate protection and can be administered during the epidemic LAIV provides transient non-specific protection and longlasting specific protection *Glezen, Piedra, & Gaglani JID 2010; 202:

26 The Bad.

27 Multiple choices of flu vaccine.. (13 different kinds) Trivalent inactivated influenza vaccine: two A s and 1 B Quadrivalent inactivated influenza vaccine: Already two A s and now two B s Thimerosal-free inactivated vaccine- pediatric formulation Live attenuated quadrivalent influenza vaccine Cell-based (egg-free) vaccine: limited supplies Increased evidence of safety of inactivated flu vaccine in people who can eat eggs; new vaccine not licensed in children High dose inactivated vaccine (double dose) Improved efficacy for elderly in recent controlled clinical trial of high dose vs std dose trivalent inactivated vaccine (DiazGranados NEJM 2014; 371: 635) Intradermal vaccine for the needle phobic

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29 LIMITATIONS OF LICENSED VACCINES Unpredictable effectiveness Lower immunogenicity/efficacy in certain vulnerable populations with little data in many of these groups Difficulty predicting what will emerge each season (antigenic drift, new B lineages) Production timelines/regulatory issues Requirement for annual immunization Many vaccines are available, but better vaccines are still needed!

30 Vaccine least effective in the elderlywith highest risk of mortality from flu! Studies in nursing homes: VE against medically-attended acute respiratory illness and pneumonia: 20-50% VE against influenza-related death: 27-70% Lower when drifted strains Effective in both persons with/without high-risk condition Studies in community dwelling elderly: Effective against P&I hospitalization Reduces P&I deaths Ecologic studies: Lack of effect on reducing P&I deaths with increased vaccine coverage (2 studies) but positive association in one study.

31 THE CONTROVERSIAL: Which vaccine? How early in the year? How to get health care providers immunized?

32 Influenza Vaccine for Children: 2 choices Trivalent inactivated Injection Indicated for: >6 months Anyone Need 2 doses first year for children <9 Live attenuated Nasal Indicated for: 2-55 yrs of age Generally healthy Need 2 doses first time for children <9

33 Vaccine effectiveness: LAIV vs. TIV by age group LAIV better TIV Better LAIV generally more effective than TIV in children - Neuzil (2001) notable exception - No obvious VE trend by age <18 yrs TIV more effective or equally effective in persons >18 yrs. - LAIV more effective in one study of military recruits One study in elderly failed to show VE because of low incidence Ambrose, et al. Infl Resp Vir 2010; 5: 67-75

34 ACIP Policy Question: Should LAIV be preferentially given to children?

35 Preferential use of LAIV in Children: ACIP, June 2014

36 What to do for children with a history of wheezing? Review MMWR 2014: Wheezing is a precaution, not a contraindication to LAIV If history of wheezing illness requiring treatment in past 12 months: should receive IIV (inactivated flu vaccine) If a remote history of wheeze or asthma is well controlled, consider advising family of risk of wheezing after LAIV and review management

37 How to get Health Care Providers (HCP) Immunized In general, HCP are a healthier population that responds well to vaccine Demonstrated effectiveness of TIV and LAIV against influenza in healthy adults used as proxy for effectiveness in HCP Increased risk of exposure for HCP working in primary care BUT: Limited prospective controlled data demonstrating effect of influenza vaccine in preventing laboratoryconfirmed influenza disease in HCP Can flu vaccine be mandatory?

38 Rationale for Healthcare Provider Flu Vaccination* Prevent transmission of influenza to patients Transmission of influenza in healthcare settings occurs; vaccination of patients and providers reduces risk Vulnerable populations have suboptimal response to vaccine yet have most serious consequences from infection Reduce risk of infection of health care personnel Maintain a critical workforce Set an example for the importance of vaccination for every person *Infect Control Hosp Epi 2010;10:987

39 What More Is Needed? Efficacy: More data still needed Improvements needed for vaccines in special populations: Better demonstration of effectiveness in prospective controlled clinical trials Need for more trials sponsored by government or non-profit agencies: EXAMPLES: Maternal immunization 3 studies worldwide sponsored by Bill & Melinda Gates Fndn (Mali, S. Africa, Nepal) CDC and Gates-sponsored studies Improved supply and distribution some progress has been made Good PR work Continue emphasis on vaccine uptake in HCW! School administration of vaccines, Seattle WA

40 Have you had your flu shot yet?

41 ACKNOWLEDGEMENTS Special Thanks to: Seattle - LOTS OF PEOPLE, and K. Neuzil, J. Ortiz, J. Kuypers, D. Zerr Baylor College of Medicine W. P. Glezen, W. Keitel, F. Munoz, P. Piedra, CDC J. Bresee, T. Uyeki, L. Grohskopf