Influenza Vaccines Immunization Update: Maine Pharmacy Association April 1, 2017 Brooke Cowles, PharmD PGY-1 Pharmacy Resident & Clinical Instructor | UNE

ACIP Recommendations 2016-17 Influenza Season For 2016–17, U.S.-licensed trivalent influenza vaccines contain: A/California/7/2009 (H1N1)-like virus A/Hong Kong/4801/2014 (H3N2)- like virus B/Brisbane/60/2008-like (B/Victoria lineage) virus. This represents changes in the influenza A (H3N2) virus and the influenza B virus as compared with the 2015–16 season. Quadrivalent influenza vaccines will contain these vaccine viruses, and a B/Phuket/3073/2013-like (B/Yamagata lineage) virus. All persons aged ≥6 months should receive influenza vaccine annually. In light of concerns regarding low effectiveness against influenza A(H1N1)pdm09 in the United States during the 2013–14 and 2015–16 seasons, for the 2016–17 season, ACIP makes the interim recommendation that live attenuated influenza vaccine (LAIV4) should not be used. The current influenza vaccine has been 48% (95% confidence interval [CI], 37% - 57%) effective in preventing influenza-related medical visits in all age groups, the CDC reported on February 17. According to the report, the vaccine was 43% (95% CI, 29% - 54%) effective against influenza A (H3N2) viruses and 73% (95% CI, 54% - 84%) effective against influenza B–related illness. http://www.cdc.gov/mmwr/volumes/65/rr/rr6505a1.htm?s_cid=rr6505a1_e

ACIP Recommendations 2016-17 Influenza Season Persons with a History of Egg Allergy Those who only have hives after exposure to egg can receive any age- appropriate inactivated influenza virus (IIV) or recombinant influenza virus (RIV3) Those who report having other reactions besides hives (e.g. angioedema, respiratory distress, lightheadedness, or recurrent emesis) may receive any age-appropriate IIV or RIV3 vaccine as long as it is administered in an inpatient or outpatient medical setting Those who have had a previous severe allergic reaction to an influenza vaccine are contraindicated *Consider observing all patients for 15 minutes postvaccination* http://www.cdc.gov/mmwr/volumes/65/rr/rr6505a1.htm?s_cid=rr6505a1_e

Vaccinating Those with a History of Egg Allergy A VSD study with over 25.1 million doses of vaccine of various types (not just influenza vaccine) administered to children and adults revealed a total of 33 cases of reactions consistent to anaphylaxis In 8 cases, symptoms began within 30 minutes of vaccination In 21 cases, symptom onset was > 30 minutes postvaccination When 7.4 million doses of IIV3 were given, there were 10 cases of anaphylaxis 1.35 per 1 million doses of IIV31 Reviews of studies of experience with use of IIV and LAIV indicate that severe allergic reaction with egg allergy are unlikely In 2012, out of 4,172 egg-allergic patients (513 of those reporting history of severe allergic reaction) there were no noted occurrences of anaphylaxis, though there were milder reactions2 Mild reactions included 1 person with uticara, 2 vomiting, and 1 with eczema http://www.cdc.gov/mmwr/volumes/65/rr/rr6505a1.htm?s_cid=rr6505a1_e 1. McNeil MM et al. J Allergy Clin Immunol. 2016; 137:868-78. 2. Des Roches A et al. J Allergy Clin Immunol. 2012; 130:1213-16.

Select the TRUE statement: ACIP does not recommend LAIV for the 2016-2017 influenza season ACIP continues to recommend annual influenza vaccine for 6 mos and older LAIV is not recommended due to concerns regarding low effectiveness All statements are true

Adults with a history of egg allergy who have symptoms other than hives (e.g., angioedema, respiratory distress, lightheadedness, or recurrent emesis) may receive age appropriate inactivated influenza vaccine or recombinant influenza vaccine when administered in an inpatient or outpatient medical setting. True False

2017-2018 Influenza Vaccine The Vaccines and Related Biological Products Advisory Committee of the FDA selected the strains of influenza vaccine for the 2017-2018 season For the trivalent vaccine it will contain: A/Michigan/45/2015 (H1N1)pdm09-like virus A/Hong Kong/4801/2014 (H3N2)-like virus B/Brisbane/60/2008-like virus (B/Victoria lineage) For the quadrivalent vaccine it will also contain: B/Phuket/3073/2013-like virus (B/Yamagata) The only change is the H1N1 strain, however, this was the same strain recommended for the southern hemisphere in 2017 FDA Committee Selects 2017-2018 Influenza Vaccine Strains. Medscape. Mar 10, 2017.

Recently Licensed Influenza Vaccine Products

Adjuvanted Trivalent Inactivated Influenza Vaccine Fluad®

Adjuvanted Trivalent Vaccine FDA approved November 2015 for people ages 65 and older Adjuvanted, inactivated, trivalent vaccine (Seqirus) Fluad also contains MF59C.1 (MF59®), a squalene based oil-in-water emulsion First adjuvanted influenza vaccine in the United States To date, there have been no randomized studies to compare Fluad with Fluzone High Dose http://www.cdc.gov/mmwr/volumes/65/rr/rr6505a1.htm?s_cid=rr6505a1_e

S.E. Frey et al. Vaccine. 32 (2014) 5027–5034. In 2010-2011, subjects (N=7082) were randomized to receive one dose of aTIV or TIV Primary Objectives: Assess lot-to-lot consistency of aTIV, non-inferiority, superiority, and immunogenicity 22 days after vaccination Results: Immunological equivalence was established and aTIV was found to be non-inferior to TIV S.E. Frey et al. Vaccine. 32 (2014) 5027–5034.

S.E. Frey et al. Vaccine. 32 (2014) 5027–5034. Fig. 2. Geometric mean ratio (GMR), percentage of subjects showing seroconversion and percentage of subjects seroprotected (±95% CI) for all (A) homologous and (B)heterologous strains at Day 22 post-vaccination. Lines represent the relevant CHMP criterion for each measure. Data presented are for the full analysis set. S.E. Frey et al. Vaccine. 32 (2014) 5027–5034.

% of adults >65 years with local adverse reactions in days 1-7 S.E. Frey et al. Vaccine. 32 (2014) 5027–5034.

% of adults >65 years with systemic adverse reactions in days 1-7 S.E. Frey et al. Vaccine. 32 (2014) 5027–5034.

Administration Dose: 0.5 mL Inject: IM into deltoid with 1 inch, 25 gauge needle Storage: Store Fluad® at 2°C - 8°C (36 - 46°F) Gently shake each syringe Fluad Package Insert

Vaccine Products: 2016 – 2017 Season

Inactivated, Trivalent Recombinant Vaccine Flublok® (Protein Sciences)

Trivalent Recombinant Vaccine FDA approved November, 2013 for adults 18 years and older Trivalent inactivated vaccine grown in insect cells rather than chicken embryo cells Doesn’t list “severe allergic reaction to egg protein” in the contraindications Does not contain egg proteins, antibiotics, or preservatives http://www.cdc.gov/mmwr/volumes/65/rr/rr6505a1.htm?s_cid=rr6505a1_e

Frequency of Local and Systemic Reactions within 7 days of Flublok or Placebo in Adults 18-49 years

Administration Dose: 0.5 mL Inject: IM into the deltoid with 1 inch, 25 gauge needle Storage: Store Flublok® at 2°C - 8°C (36 - 46°F) Gently shake before administering

High-Dose Inactivated Influenza Trivalent Vaccine (IIV) Fluzone HD® (Sanofi Pasteur)

High Dose Trivalent Vaccine FDA approved in 2009 for adults 65 years of age and older Contains more hemagglutinin per vaccine virus strain compared to a standard inactivated influenza vaccine 60 µg per strain vs. 15 µg per strain At this point, there is no preferential recommendation between aIIV3, standard-dose IIV, or high-dose IIV3 for those aged ≥ 65 years

Methods: Retrospective cohort study HD vaccine (60 mcg of hemagglutinin per strain): N= 929,730 SD vaccine (15 mcg of hemagglutinin per strain): : N= 1,615,545 US Medicare beneficiaries 65 years and older who received influenza vaccine in a community pharmacy Primary outcome: probable episode of influenza-related illness defined by a community medical encounter with the provision of a rapid influenza test followed by dispensing of oseltamivir within a 2-day period Lancet Infect Dis 2015;15:293-300 Lancet Infect Dis 2015;15:293-300

Efficacy of HD Vaccine versus SD Vaccine Against Influenza-Related Illness Similar results to Diazgranados et al. Those who received IIV-HD 22% less likely to have influenza-associated illness and 22% less likely to be admitted to the hospital for influenza Each plot displays the rate of influenza per 10 000 person-weeks. Data was smoothed using a weighted average, placing a weight of 0・5 on the current week and a weight of 0・25 on the previous and following weeks. (A) Rapid infl uenza test followed by treatment with oseltamivir. (B) Inpatient hospital admissions or emergency department visits with an infl uenza International Classifi cation of Diseases, ninth revision, Clinical Modifi cation code. RIT=rapid infl uenza diagnostic test. Lancet Infect Dis 2015;15:293-300

Administration Dose: 0.5 mL Inject: IM into the deltoid with 1 inch, 25 gauge needle Storage: Store Fluzone HD® at 2°C - 8°C (36 - 46°F) Gently shake before administering

Inactivated Influenza Vaccine (IIV) Quadrivalent Fluarix®, FluLaval®, Fluzone®, Fluzone Intradermal®

IIV Quadrivalent Fluarix® (GlaxoSmithKline) FDA approved December 2012 People ages 3 years and older Fluzone Quadrivalent® (Sanofi Pasteur) FDA approved March 2013 People ages 6 months and older Flulaval® (GlaxoSmithKline) FDA approved in 2013 http://www.cdc.gov/mmwr/volumes/65/rr/rr6505a1.htm?s_cid=rr6505a1_e

Administration Dose: 0.5 mL Inject: IM into the deltoid with 1 inch, 25 gauge needle Storage: Store at 2°C - 8°C (36 - 46°F) Flulaval multi-dose vial must be discarded 28 days once entered Gently shake before administering Afluria also has the same discard date once entered

Intradermal Influenza Vaccine FDA approved in 2014 for persons 18 through 64 years of age Associated with higher rates of injection site reactions (erythema, induration, swelling, and pruritus, but not pain) than the IM inactivated influenza vaccines Erythema (>75%) Induration (>50%) Swelling (>50%) Pain (>50%) Pruritus (>40%)

Comparison of local side effects to ID and IM influenza vaccine Percent Human Vaccines. 2010;6:346-54.

Intradermal Injection Technique Remove needle cap Hold microinjection system between thumb and middle finger Do not place fingers on the windows Insert needle rapidly perpendicular to the skin Inject using the index finger Remove needle from the skin and activate the needle shield by pushing firmly on the plunger Fluzone Intradermal Package Insert

Which side effect is more common with the intradermal influenza vaccine than the IM influenza vaccine? Headache Fever Injection site swelling Malaise

Live Attenuated Influenza Vaccine (LAIV) Quadrivalent Flumist® (MedImmune)

Live Attenuated Influenza Vaccine FDA approved in March 2012 for healthy people ages 2 through 49 years Is not recommended in children 6 – 23 months of age due to increased risk of hospitalization and wheezing Live attenuated vaccine which contains two type A and two type B strains Flumist Package Insert http://www.cdc.gov/mmwr/volumes/65/rr/rr6505a1.htm?s_cid=rr6505a1_e

Live Attenuated Influenza Vaccine Contraindications Precautions History of severe allergy to any component of the vaccine (including eggs) Concomitant aspirin or salicylate-containing therapy in children & adolscents Children aged 2-4 years who received a diagnosis of asthma or has had wheezing episode in past 12 months Children & adults who are immunosuppressed Close contacts & caregivers of severely immunocompromised persons Pregnancy Received antiviral medication within past 48 hours Moderate to severe illness with or without fever History of Guillain-Barre syndrome within 6 weeks of receipt of influenza vaccine Asthma in persons aged ≥ 5 years Other underlying medical conditions that might predispose to complications after wild-type influenza infection (COPD, CVD, renal, hepatic, or metabolic disorders)

Administration Dose: 0.1 mL into each nostril Administed: Intranasally while patient is in the upright position Storage: Store at 2°C - 8°C (36 - 46°F) Keep in carton to protect from light

Influenza Vaccine Summary

Age Indication for Influenza Vaccines: United States, 2016-2017 0.5-2 years 2 years 3 4-8 9-17 18-49 years 50-64 years 65+ Fluzone / Fluzone Quad ✓ Flumist Quad Fluarix Quad FluLaval Quad Fluvirin Afluria1 +- Flucelvax Quad Flublok2 Fluzone Intradermal Quad Fluzone High-Dose Fluad Adjuvated Trivalent “A licensed, age-appropriate vaccine should be used.” Age indication via needle/syringe is >5 years and by Pharmjet needle-free injection is 18-64 years. FDA labeled age indication expanded in 2015 to 18 years and older (now including adults 65+).

Characteristics of Influenza Vaccines: United States, 2016-17 Live Mercury Egg Protein Latex Fluzone / Fluzone Quad ✓1 ✓ Flumist Quad Fluarix Quad FluLaval Quad Fluvirin ✓3 Afluria Flucelvax Quad ✓2 Flublok Fluzone Intradermal Quad Fluzone High-Dose Fluad Adjuvanted Trivalent Multi-dose vials contain mercury. Single-dose prefilled syringes are mercury-free. Estimated to contain <50 femtograms (5x10-8 mcg) of total egg protein per 0.5 ml dose. Syringe tip may contain natural rubber latex.

Route of Admin. for Influenza Vaccines: United States, 2016-17 Young Children* Older Children Adults Fluzone / Fluzone Quad IM Thigh IM Deltoid Flumist Quad Intranasal Fluarix Quad FluLaval Quad Fluvirin Afluria Flucelvax Quad Flublok Fluzone Intradermal Quad ID Deltoid Fluzone High-Dose Fluad Adjuvanted Trivalent *Generally, less than 7 years old.

Select an influenza vaccine for a health 37-year old woman with severe egg allergy: Flublok Fluad Fluzone Fluarix

Select the multi-dose vial influenza vaccine that must be discarded 28 days after the stopper has been pierced: Fluarix Afluria Flucelvax Fluzone

Tips for an Ouch-Free Flu Shot Do not prepare the vaccine in front of the patient. Use a prefilled syringe or change the needle. Make sure the alcohol is dry before injecting. Ensure the patient’s arm is relaxed. Inject into the deltoid at least 3 finger widths below the crest of the shoulder. Distract kids; ask them to pretend they are blowing out candles on a birthday cake or blow on a pinwheel.

Questions & Discussion

References 1. Robinson CL, Romero JR, Kempe A et al. “Advisory Committee on Immunization Practices Recommended Immunization Schedule for Adults Aged 19 Years or Older – United States, 2017. MMWR. 2017 Feb; 66(5):136-37. 2. Grohskopf LA, Sokolow LZ, Broder KR, et al. “Prevention and Control of Seasonal Influenza with Vaccines Recommendations of the Advisory Committee on Immunization Practices – United States, 2016-17 Influenza Season. MMWR. 2016 Aug; 65(5):1-36. 3. Des Roches, A, Paradis L, Gagnon R, et al. “Egg-allergic patients can be safely vaccinated against influenza.” J Allergy Clin Immunol. 2012; 130:1213-16. 4. McNeil MM, Weintraub ES, Duffy J, et al. “Risk of anaphylaxis after vaccination in children and adults.” J Allergy Clin Immunol. 2016; 137:868-78. 5. Frey SE, Aplasca-De Los Reyes MR, Reynales H et al. “Comparison of the safety and immunogenicity of an MF59®-adjuvanted with a non-adjuvanted seasonal influenza vaccine in elderly subjects. Vaccine. 32 (2014) 5027–5034.