What s New in Flu? An Update on Influenza Prevention and Treatment

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1 What s New in Flu? An Update on Influenza Prevention and Treatment Kathryn M. Edwards MD Sarah H. Sell and Cornelius Vanderbilt Professor of Pediatrics Vanderbilt University Nashville, TN, USA

2 Disclosures I have no relevant financial relationships with the manufacturer(s) of any commercial product(s) discussed in this CME activity I do not intend to discuss an unapproved investigative use of a commercial product/device in my presentation.

3 Objectives To provide an update on influenza disease burden in the U.S. To understand current influenza vaccine recommendations. To review the characteristics of currently available influenza vaccines. To understand antivirals directed to influenza and their recommended use. To review future influenza vaccine approaches Page 3 5/13/2 013

4 Influenza A Virus Hemagglutinin (H) 17 subtypes (attachment, penetration) Neuraminidase (N) 10 subtypes (release) 8 viral genes (assembly, replication) M2 Protein (replication) Source: AS Fauci Page 4 5/13/2013

5 Clinical Manifestations of Influenza Acute febrile respiratory illness - Many influenza-like illness definitions - Fever or feverish - Cough and/or sore throat, otitis - More serious manifestations - Primary or secondary pneumonia, croup, bronchiolitis - Non-specific febrile illness, particularly in infants - Extra-pulmonary manifestations - Neurologic Encephalitis, seizures Page 5 - Myositis - Cardiac 5/13/2013

6 Hospitalizations per months 6-23 months months Total <5 years Age Poehling, KA et al. NEJM 2006;355:31-40

7 Discharge Diagnoses For Children <5 years With Influenza 0-5 months 6-59 months 30% 20% 10% 0% Poehling, KA et al. NEJM 2006;355:31-40

8 Influenza Outpatient Visit Rates Per 1000 Children < 6mos 6-23 mos 2-4 yrs 5-12 yrs Poehling, KA et al. NEJM 2006;355:31-40

9 Culture-confirmed Influenza over 25 years in Primary Care Clinic at Vanderbilt University Ill visits AOM LRI Rate per 1000 children <1 1- <2 2-<5 Age (years) Neuzil et al. J Infect Dis 2002;185:147-52

10 Influenza Burden in U.S. Infection rates are highest among children, with complications and hospitalizations from seasonal influenza being greatest among persons aged 65 years, children aged <2 years, and persons of any age who have medical conditions that confer increased risk for complications from influenza. Highly variable from year-to-year. Approximately 100 pediatric deaths reported yearly. Approximately 55,000 to 431,000 hospitalizations per year, with a mean of 226,000. Page 10

11 Was a Bad Influenza Year MMWR / June 8, 2018 / Vol. 67 / No. 22

12 High Number of Hospitalizations Noted MMWR / June 8, 2018 / Vol. 67 / No. 22

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14 Shang M, Blanton L, Brammer L, et al. Influenza Associated Pediatric Deaths in the United States, Pediatrics.2018;141(4):e

15 US ACIP Influenza Vaccine Recommendations Historically recommended for all high-risk children 6 months. Two doses recommended. In 2005 recommended for all children aged 6-23 months to prevent hospitalizations and deaths In 2006 recommended for all children aged months to prevent outpatient visits and indirect costs In 2008 recommended for all persons 6 months In 2014 preferential recommendation for LAIV for healthy children (2-17 years of age) since LAIV consistently more effective than trivalent IIV in this population in comparative trials

16 NEJM 2007;356:685-96

17 Pediatric Trial of LAIV vs IIV Randomized, double-blind trial in 8,492 children (6-59 months of age) from 249 sites in 3 continents Primary endpoint: culture-confirmed influenza illness, most strains were H3N2 and influenza B LAIV IIV p-value Confirmed influenza 3.9% 8.6% < LAIV associated with 55% reduction in culture confirmed influenza compared to IIV NEJM 2007;356:

18 Summary of comparative studies *Observational Study, Challenge Study, others randomized controlled trials Influenza Other Respi Viruses 2011;5:67-75.

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21 US ACIP Influenza Vaccine Recommendations In 2015 preferential recommendation for LAIV removed LAIV4 not recommended in the US for and seasons Studies in other areas of the world were ongoing 21

22 What were the reasons for the poor H1N1 effectiveness in the US? Chance, methodology, programmatic issues Poor replicative fitness of H1N1 Viral interference between four LAIV strains Repeat immunization leading to a more restricted adult-type response

23 The Way Forward: Modifications Made to LAIV-Ann Arbor Backbone Strain

24 Presented at the ACIP February 2018

25 Presented at the ACIP February 2018

26 Presented at the ACIP February 2018

27 Presented at the ACIP February 2018

28 Presented at the ACIP February 2018

29 Presented at the ACIP February 2018

30 Presented at the ACIP February 2018

31 ACIP Recommendations On February 21, 2018, the ACIP voted in favor of a reinstated recommendation for LAIV4. For the season, immunization providers may choose to administer any licensed, age appropriate influenza vaccine including Live Attenuated Influenza Vaccine (LAIV) and Injectable Influenza Vaccine (IIV). The recommendation follows the presentation of positive results from a US study in children between the ages of 2 to <4 years evaluating the shedding and antibody responses of the H1N1 strain in LAIV4. Study demonstrated new H1N1 LAIV post-pandemic strain (A/Slovenia) performed significantly better than the H1N1 LAIV post-pandemic strain (A/Bolivia). The antibody response induced with the new H1N1 LAIV strain was comparable to earlier data seen with the highly effective H1N1 LAIV strain included in the vaccine before the 2009 influenza pandemic.

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41 Antiviral Use in Hospitalized Patients is Low 45% Received Oseltamivir

42 Recommended Use of Antiviral Agents in Influenza

43 Proportions of High-risk outpatients prescribed antivirals

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52 Infections in Children website

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54 Kaplan Meier Curves of the Time to Alleviation of Influenza Symptoms with Baloxavir versus Placebo in the Phase 3 Trial. FG Hayden et al. N Engl J Med 2018;379:

55 Kaplan Meier Curves for Alleviation of Symptoms in RCT FG Hayden et al. N Engl J Med 2018;379:

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62 New Approaches to Influenza Vaccine

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65 Summary Influenza is a common respiratory illness accounting for substantial morbidity and some mortality annually Influenza vaccines are safe and effective Absolute efficacy varies by year and influenced by circulating virus, vaccine administered, host characteristics and previous influenza experience Antivirals are indicated in hospitalized patients and those with co-morbidities Antivirals are uncommonly used in children New antivirals are under development 12/18/2018 Page 65