Vaccine Update March 28, 2018

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1 Vaccine Update March 28, 2018 Paul A. Offit, MD Division of Infectious Diseases Vaccine Education Center Children s Hospital of Philadelphia Perelman School of Medicine The University of Pennsylvania

2 Topics FluMist: Influenza: Heplisav B: HPV vaccine: MenB: It s back A seasonal update ACIP recommendations Update on safety Risk to college students

3 FluMist: It s back

4 What is FluMist?

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7 LAIV Made using two influenza viruses (A/Ann Arbor/6/60 and B/Ann Arbor/1/66) that were cold-temperature adapted in the 1960s. HA and NA of circulating strains to be included in the vaccine are reassorted into these two viruses. 7

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10 Why did the ACIP give LAIV a preferential recommendation in 2014?

11 LAIV vs IIV LAIV vs IIV efficacy for lab-confirmed influenza regardless of match between vaccine and circulating strains. Incidence of influenza: LAIV IIV Study 1 3.9% 8.6% Study 2 2.8% 5.8% Study 3 4.5% 6.6%

12 LAIV vs IIV Study 1: Belshe, NEJM (2007); 356: Study 2: Ashkenazi, Ped Infect Dis J (2006); 25:870-9 Study 3: Fleming, Ped Infect Dis J (2006); 25:860-9

13 LAIV vs IIV Before June 2014, ACIP had not expressed a preference for LAIV over IIV. But other countries and some US states had already expressed a preference for LAIV: Canada 2-17 years United Kingdom 2-17 years Israel 2-17 years Germany 2-6 years US-Oregon 2-5 years US-Washington 2-7 years

14 ACIP, June 2014 If LAIV is available, it should be used for healthy children aged 2 through 8 years who have no contraindications or precautions. If LAIV is not immediately available, IIV should be used. Vaccination should not be delayed in order to procure LAIV.

15 So what happened?

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17 H1N1 didn t replicate well enough to induce a protective immune response

18 On February 24, 2016, the ACIP withdrew its recommendation

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22 ACIP, February 2018 Although the effectiveness of the new formulation of LAIV4 against H1N1pdm09 viruses is not yet known, available data suggests that the new LAIV4 containing A/Slovenia may provide protection more comparable to that observed with pre-2009 influenza vaccines.

23 ACIP, February 2018 For the season, LAIV4 is an option for influenza vaccination for persons for whom it is otherwise appropriate.

24 Influenza: A seasonal update

25 All geographic regions affected

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27 Predominantly H3N2

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29 Relative increase in out-patient visits

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31 Relative increase in hospitalizations

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33 Relative increase in mortality

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36 Vaccine effectiveness

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41 Why such poor vaccine effectiveness against H3N2 strains?

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43 The hemagglutinin (HA) mutates HA mutates from year to year. Therefore, the CDC requires a yearly vaccine for everyone more than 6 months of age. HA occasionally mutates while traveling up from South to North America. This accounted for poor vaccine efficacy (13 percent) in H3N2 can mutate during manufacture in eggs. 43

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47 We need a better influenza vaccine

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49 Heplisav B: ACIP recommendations

50 Hepatitis B: The disease

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54 The first hepatitis B vaccine

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56 Electron micrograph from a patient infected with hepatitis B virus

57 The first hepatitis B vaccine Maurice Hilleman took plasma from people infected with hepatitis B virus and purified hepatitis B surface antigen particles. Preparation was subjected to treatment with pepsin, urea, and formaldehyde. Used in U.S. between 1981 and 1986 and targeted to high-risk groups. Enthusiasm limited by source of HBsAg in the vaccine (human blood).

58 The second hepatitis B vaccine

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60 The second hepatitis B vaccine In 1991, recommended for all newborns in the United States as a three-dose vaccine to be given at birth, 1-2 months, and 6-15 months. Adherence to this schedule has virtually eliminated hepatitis B virus infections in children. But problems remain: (1) about 5 percent of recipients don t respond; (2) the vaccine is less effective in certain high-risk groups (diabetes, renal disease, immunosuppressed, obese, elderly, smokers).

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63 The third hepatitis B vaccine

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65 The third hepatitis B vaccine Contains 20 micrograms of recombinantderived hepatitis B surface antigen combined with 3 milligrams of a novel CpGoligonucleotide adjuvant. CpG are short, single-stranded, synthetic, DNA molecules containing cytosine (C) and guanine (G) linked by a phosphodiester (p). Given as a 2-dose instead of 3-dose vaccine. Licensed on November 9, 2017 as a 2-dose vaccine for adults over 18 years of age.

66 Adults recommended to receive hepatitis B vaccine Household and sexual contacts of HBsAg-positive people. Injection drug users. Healthcare and public safety personnel. Hemodialysis patients. International travelers to regions with high or intermediate endemicity. Persons with chronic liver disease. Persons with HIV infection. Adults with type-1 diabetes.

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68 CpG-oligonucleotide adjuvants CpG motifs are considered to be pathogenassociated molecular patterns (PAMPs) due to their abundance in microbial genomes but rarity in vertebrate genomes. The CpG PAMP is recognized by our innate immune system through toll-like receptors (TLRs) on B cells and dendritic cells. TLRs recognize structurally conserved molecules from microbes.

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72 Heplisav-B studies Studied in about 14,000 adults vs. Engerix. Protective efficacy predicted by antibody responses 10 miu/ml of HBsAb. Overall seroprotection rate was 95% for Heplisav-B and 81.2% for Engerix at week 28 and 90.1% vs. 70.8% at week 32. In patients with type 2 diabetes, seroprotection rate was 90% for Heplisav-B and 65.1% for Engerix.

73 Heplisav-B vs. Engerix seroprotection Years Heplisav-B Engerix % 93.9% % 92% % 84.2% % 79.7% % 72.6%

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75 Heplisav-B vs. Engerix safety Local Heplisav-B Engerix Pain 41.7% 40.8% Redness 3.7% 1.1% Swelling 2.4% 1.3%

76 Heplisav-B vs. Engerix safety Systemic Heplisav-B Engerix Fatigue 21.4% 25.1% Headache 20.1% 25.3% Malaise 13.8% 16% Fever 38.0 o C 1.7% 3.4% Acute MI 0.17% 0.05% Prostate cancer 0.04% 0.18%

77 ACIP Working group summary Heplisav-B results in high levels of seroprotection. Heplisav-B two dose series administered at 0 and 1 month will likely improve series completion. Most safety outcomes similar between Heplisav-B and Engerix. Acute MI was reported to be higher in Heplisav-B group; safety will be monitored in post-marketing studies.

78 ACIP: Preferential recommendations High-dose vs. standard-dose influenza vaccine for older adults (No) HPV-4 vs. HPV-2 (No). Live attenuated influenza vaccine (FluMist) versus inactivated influenza vaccine for children (Yes). IPV versus OPV (Yes). DTaP versus DTP (Yes). Shingrix versus Zostavax (Yes). 78

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80 HPV Vaccine: Update on safety

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85 VAERS

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87 Vaccine Safety DataLink (VSD)

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89 HPV9 VAERS Signals detected for syncope, injection-site reactions, allergic reactions, pancreatitis, and appendicitis. Syncope and injection-site reactions were expected no plans for follow-up. Signals for allergic reactions, pancreatitis, and appendicitis were not confirmed upon further evaluation.

90 MenB: Risk to college students

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101 Additional Resources ACIP meetings on-line - Vaccine Education Center at CHOP Centers for Disease Control and Prevention Immunization Action Coalition Every Child By Two

102 To obtain continuing education credits, go to:

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