Kenneth McCall, BSPharm, PharmD, BCGP Associate Professor | UNE Immunization Update 2017 Kenneth McCall, BSPharm, PharmD, BCGP Associate Professor | UNE

Objectives Discuss the gap between current rates and Healthy People 2020 goals for vaccinations. Categorize each of the CDC recommended flu vaccines based upon live/inactivated, route, prep., and storage. Discuss the influenza vaccines for 2017-18. Recognize the ACIP recommendations for pneumococcal vaccines. Compare the GSK zoster vaccine with Merck’s Zostavax. Apply ACIP recommendations and FDA approved indications for the CDC recommended vaccines. Recognize federal and state laws that regulate vaccine administration.

CDC ACIP 2017 Recommended Adult Immunization Schedule

Altered Immunocompetence: Inactivated Vaccines-Safety All inactivated vaccines can be administered safely to persons with altered immunocompetence. https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/immunocompetence.html

Altered Immunocompetence: Live Vaccines-Safety Severe complications have followed vaccination with certain live, attenuated viral and live, attenuated bacterial vaccines among persons with altered immunocompetence. Persons with most forms of altered immunocompetence should not receive live vaccines (MMR, varicella, MMRV, LAIV, zoster). Immunosuppressive steroid dose is considered to be daily receipt of 20 mg or more prednisone or equivalent for two or more weeks. Vaccination should be deferred for at least 1 month after discontinuation of immunosuppressive steroid therapy. https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/immunocompetence.html

Should Immunocompromised Patients or Those Who Will Undergo Immunosuppression Receive Herpes Zoster Vaccine? Zoster vaccine should be given to patients aged ≥60 years if it can be administered ≥4 weeks before beginning highly immunosuppressive therapy. Zoster vaccine should not be administered to highly immunocompromised patients. Zoster vaccine should be administered to patients aged ≥60 years who are receiving therapy considered to induce a low level of immunosuppression  IDSA Guidelines. Clin Infect Dis. 2014;58(3):e44-100.

Patients with high-level immuno-suppression include those: Primary immunodeficiency disorder (eg, severe combined immunodeficiency), receiving cancer chemotherapy, within 2 months after solid organ transplantation, with HIV infection with a CD4 T-lymphocyte count <200 cells/mm3 for adults and adolescents and percentage <15 for infants and children, receiving daily corticosteroid therapy with a dose ≥20 mg (or >2 mg/kg/day for patients who weigh <10 kg) of prednisone or equivalent for ≥14 days, and receiving certain biologic immune modulators, that is, a tumor necrosis factor-alpha (TNF-α) blocker or rituximab those receiving methotrexate (MTX) >0.4 mg/kg/week, azathioprine >3 mg/kg/day, or 6-mercaptopurine >1.5 mg/kg/day  Clin Infect Dis. 2014;58(3):e44-100.

Select the FALSE statement regarding vaccine use in immunocompromised patients. Inactivated vaccines are more likely to be unsafe Live vaccines are more likely to be unsafe Inactivated vaccines may be less effective in this population Live vaccines may be less effective in this population

Which medication would categorize a patient as high-level immunosuppression? Prednisone 20 mg QD x 10 days Low dose TNF-α blocker 0.2 mg/kg/wk MTX Azathioprine 1.5 mg/kg/day

Maine Pharmacist-Administered Immunization Regulations No Rx Required Rx Requireda Rx or Protocol Not permitted Adult (≥18 years) with PCPb Influenza ✓-RPh or Intern Other Vaccinesc Adult (≥18 years) without PCP Child < 18 years ✗ Child 7-17 years ✓-RPh only Child <7 years Sources: Maine H.P. 1267 L.D. 1715 and H.P. 836 L.D. 1218 Intern administration permitted as indicated under direct supervision of licensed pharmacist a Verbal/phone authorization acceptable b Primary care physician or existing relationship with a nurse practitioner or an authorized practitioner in Maine c All vaccines licensed by the US FDA recommended by the CDC ACIP

Influenza Vaccines

Influenza A and B are the two types of influenza viruses that cause epidemic human disease. Since 1977, influenza A (H1N1 and H3N2) viruses and influenza B viruses have circulated globally.1 The influenza A virus is composed of a viral genome covered by a protein shell, the capsid. A lipid bi-layer envelops the capsid, as shown in the figure.2 Influenza A viruses are categorized into subtypes on the basis of two surface antigens: hemagglutinin and neuraminidase.1 Within the envelope is the influenza genome, which is organized into 8 pieces of single-stranded RNA.2 1. Centers for Disease Control and Prevention. MMWR Recomm Rep. 2010;59(RR-8):1–62. 2. Molecular Expressions: Cell Biology and Microscopy Structure and Function of Cells and Viruses. http://micro.magnet.fsu.edu/cells/viruses/influenzavirus.html. Accessed April 15, 2012. 13

ACIP Recommendations 2017-18 Influenza Season For 2017–18, U.S.-licensed trivalent influenza vaccines contain: A/Michigan/45/2015 (H1N1)pdm09-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 (H1N1) virus as compared with the 2016–17 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. Afluria may be used in persons ≥5 years old. Pregnant women may receive any licensed, recommended, age-appropriate vaccine. Live attenuated influenza vaccine (LAIV4) should still 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. https://www.cdc.gov/flu/professionals/acip/index.htm

Age Indication for Influenza Vaccines: United States, 2017-2018 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 Afluria is now approved for 5 years and up “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+).

New Influenza Vaccines: Fluad ® (Seqirus) Adjuvanted trivalent inactivated vaccine FDA approved November, 2015 People ages 65 and older Flucelvax® (Novartis)– quadrivalent inactivated vaccine grown in mammalian cells. FDA approved May, 2016| Adults 4 years and older Flublok® (Protein Sciences Corp.) – inactivated, trivalent, recombinant vaccine. FDA approved March 2013 People ages 18 years and older Doesn’t list “severe allergic reaction to egg protein” in the contraindications

Which of the following is the predominant flu strain of 2017-18? Type B strain in trivalent vaccine Type B strain not in trivalent vaccine Type A H1N1 strain Type A H3N2 strain

Adjuvanted Trivalent Inactivated Influenza Vaccine Fluad®

New Influenza Vaccines: Fluad ® (Seqirus) – Adjuvanted, inactivated, trivalent vaccine FLUAD also contains MF59C.1 adjuvant (MF59®), a squalene based oil-in-water emulsion. FDA approved November 2015 People ages 65 years and older

% of adults >65 years with local adverse reactions in days 1-7

% of adults >65 years with systemic adverse reactions in days 1-7

Seroconversion Rates at Day 22

Difference in seroconversion rate (95% CI) at day 22

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

Influenza Positive Specimens Reported by USPH Labs, Cumulative, 2016-2017 Season The flu vaccine's effectiveness may vary depending on age, health, and immune status and how well scientists identity circulating viruses. In 2014-15, vaccine effectiveness was under 20%.

Administration Fluarix Quadrivalent®: 0.5-mL dose IM - deltoid 1 inch, 25 gauge needle

Quadrivalent Influenza Vaccines contain which of the following? Four type A strains Two type A strains, 1 type B, & 1 type C Two type A strains & 2 type B strains Four type B strains

Inactivated, Trivalent Recombinant Vaccine Flublok®

New Influenza Vaccines: Flublok® (Protein Sciences Corporation)– trivalent inactivated vaccine grown in insect cells rather than chicken embryo cells. FDA approved November, 2013 Adults 18 years and older (new indication as of April 2015; previously 18-49 years). Doesn’t list “severe allergic reaction to egg protein” in the contraindications* *Flublok contains no egg proteins, antibiotics, or preservatives. The stoppers used for the single-dose vials are not made with natural rubber latex.

Vaccine Efficacy against Culture-Confirmed Influenza in Healthy Adults 18-49 years

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

ACIP Recommendations for flu vaccination of person who report egg allergy.

Administration Flublok®: 0.5-mL dose IM - deltoid 1 inch, 25 gauge needle

Select an influenza vaccine for a healthy 37-year-old woman with severe egg allergy. Flublok Flumist Fluzone Fluarix

Influenza Vaccines: Summary

Age Indication for Influenza Vaccines: United States, 2017-2018 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, 2017-18 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 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, 2017-18 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 *Generally, less than 7 years old.

CONSIDERATIONS Vaccine Patient Group Quadrivalent (Fluzone Quad, Fluarix, Flulaval) Everyone age appropriate ≤64 years old Trivalent (Fluad, Fluvirin) Age appropriate 6 months to 64 year olds and no supply or insurance coverage of quadrivalent Flublok Severe egg allergy Fluzone HD, Fluad Adjuvated ≥ 65 years old Fluzone Intradermal, Afluria Age appropriate and fear of needles Flumist Not recommended *Any age-appropriate flu shot is the best flu shot

Who should get the flu shot? You All of the above

Universal Flu Vaccine on the Horizon Will be the first in the world to fight all types of the virus Uses proteins found on the core of the virus, rather than the surface These proteins do not change as often; vaccine may provide protection for years Stimulates the immune system to boost T-cells, rather than antibodies

Universal Flu Vaccine on the Horizon Developed by Oxford University’s Jenner Institute and Vaccitech Two-year clinical trial is just beginning 500 patients in UK this season 1500 more next year

Pneumococcal Vaccine PPSV23 / Pneumovax® PCV13 / Pnevnar®

Pneumococcal Disease Complex immunization recommendation for adults Pneumococcal disease is caused the bacterium Streptococcus pneumoniae Clinical Features Pneumonia Otitis media Sinus infections Bacteremia Meningitis Risk Factors Asplenia Chronic heart, pulmonary, liver, or renal disease Cigarette smoking Cerebrospinal fluid leak Age less than 2 years, or 65 years and older Complex immunization recommendation for adults There are different types of pneumococcal disease, such as lung infections (pneumococcal pneumonia), blood infections (bacteremia), infections of the covering of the brain and spinal cord (pneumococcal meningitis), and middle ear infections (otitis media). Pneumococcal disease is a leading cause of vaccine-preventable illness and death in the United States. Pneumonia is the most common presentation of pneumococcal disease among adults – incubation of pneumonia is 1-3 days – it is characterized by abrupt onset of fever, rigors, chills, pleuritic chest pain, productive cough, dyspnea, tachypnea, hypoxia and diagnosed by x-ray imaging and symptoms However, calling the pneumococcal vaccine the “pneumonia vaccine” can be misleading – one of the greatest benefits of receiving the pneumococcal vaccine is the protection against invasive pneumococcal disease, or “IPD” such as bacteremia or meningitis. The term “invasive” refers to infection of an area of the body that is normally bacteria free – such as the blood stream or the cerebrospinal fluid http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM201669.pdf https://www.merck.com/product/usa/pi_circulars/p/pneumovax_23/pneumovax_pi.pdf

Pneumococcal Vaccines Pneumovax 23® (PPSV23, pneumococcal polysaccharide vaccine) Prevnar 13® (PCV13, pneumococcal conjugate vaccine) Pneumococcal polysaccharide vaccine is composed of purified preparations of pneumococcal capsular polysaccharide. The first polysaccharide pneumococcal vaccine was licensed in the United States in 1977. It contained purified capsular polysaccharide antigen from 14 different types of pneumococcal bacteria. In 1983, a 23-valent polysaccharide vaccine (PPSV23) was licensed and replaced the 14-valent vaccine, which is no longer produced. PPSV23 contains polysaccharide antigen from 23 types of pneumococcal bacteria that cause 88% of bacteremic pneumococcal disease. In addition, cross-reactivity occurs for several capsular types that account for an additional 8% of bacteremic disease. The polysaccharide vaccine currently available in the United States (Pneumovax 23, Merck) contains 25 mcg of each antigen per dose and contains 0.25% phenol as a preservative. The vaccine is available in a single-dose vial or syringe, and in a 5-dose vial. Pneumococcal vaccine is given by injection and may be administered either intramuscularly or subcutaneously. The first pneumococcal conjugate vaccine (PCV7) was licensed in the United States in 2000. It includes purified capsular polysaccharide of seven serotypes of S. pneumoniae (4, 9V, 14, 19F, 23F, 18C, and 6B) conjugated to a nontoxic variant of diphtheria toxin known as CRM197. In 2010 a 13-valent pneumococcal conjugate vaccine (PCV13) was licensed in the United States. It contains the 7 serotypes of S pneumonia as PCV7 plus serotypes 1, 3, 5, 6A, 7F and 19A which are also conjugated to CRM197. A 0.5-mL PCV13 dose contains approximately 2.2 µg of polysaccharide from each of 12 serotypes and approximately 4.4 μg of polysaccharide from serotype 6B; the total concentration of CRM197 is approximately 34 µg. The vaccine contains 0.02% polysorbate 80 (P80), 0.125 mg of aluminum as aluminum phosphate (AlPO4) adjuvant, 5mL of succinate buffer, and no thimerosal preservative. Except for the addition of six serotypes, P80, and succinate buffer, the formulation of PCV13 is the same as that of PCV7. ABCs data indicate that in 2008, a total of 61% of invasive pneumococcal disease cases among children younger than 5 years were attributable to the serotypes included in PCV13, with serotype 19A accounting for 43% of cases; PCV7 serotypes caused less than 2% of cases.

ACIP Recommendations on Pneumococcal Vaccinations in Adults

Pneumococcal Vaccine Recommendations for Adults with Immunocompromising Conditions https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6140a4.htm

Pneumococcal vaccine-naïve persons aged > 65 years *minimum interval between sequential administration of PCV13 and PPSV23 is 8 weeks; PPSV23 can be given later than 6-12 months after PCV13 if this window is missed.

Persons who previously received PPSV23 at age > 65 years *minimum interval between sequential administration of PCV13 and PPSV23 is 8 weeks; PPSV23 can be given later than 6-12 months after PCV13 if this window is missed.

Persons who previously received PPSV23 before age 65 years who are now aged > 65 years

A 65-year-old man who is pneumonia vaccine naïve A 65-year-old man who is pneumonia vaccine naïve. What pneumonia vaccine(s) is/are recommended? Pneumovax only Prevnar only Both; Pneumovax prior to Prevnar Both; Prevnar prior to Pneumovax

A 56 yo woman takes TNF alpha blocker therapy for RA A 56 yo woman takes TNF alpha blocker therapy for RA. Which of the vaccines is NOT recommended? Inactivated influenza annually Prevnar Pneumovax at least 8 weeks after Prevnar Zostavax zostavax

Questions and Discussion

Add zoster slides

Preventing Shingles: Zostavax or Shingrix? Kenneth McCall, BSPharm, PharmD Associate Professor | UNE Maine Pharmacy Association Think of creative title

Clinical Presentation of Herpes Zoster1–3 Herpes Zoster Rash Follows a Dermatomal Distribution © Phototake. © Phototake. © Dr. P. Marazzi / Photo Researchers, Inc. Prodrome Acute HZ Rash Evolution of Rash Complications? Abnormal Skin Sensations Headache Photophobia Malaise Unilateral Dermatomal Rash Maculopapules/Vesicles Altered Sensitivity to Touch Unbearable Itching Cessation of New Vesicles Pustulation Scabbing Cutaneous Healing Neurologic Cutaneous Ophthalmic Visceral (rare) Clinical Presentation of Herpes Zoster The presentation and subsequent resolution of zoster may not always be straightforward. The zoster rash is often preceded by several days of a prodromal phase that is characterized by pain that may range from tingling and burning to severe sharp, stabbing, or lancinating. Headache, photophobia, and malaise may also occur.1,2 The zoster rash, itself, is generally limited to 1 unilateral dermatome. Frequently reported symptoms include altered sensitivity to touch, pain provoked by slight stimuli, and unbearable itching.1,2 Lesions usually last 7 to 10 days and the rash fully heals within 2 to 4 weeks.1 Complications of zoster may include postherpetic neuralgia (PHN), scarring, bacterial superinfection, cranial and motor neuron palsies, visual impairment, and hearing loss.1,3 Although most complications will resolve over time, some patients are refractory to treatments and may suffer permanent impairment.1,2,4 1. Weaver BA. J Am Osteopath Assoc. 2009;109(6 suppl 2):S2–S6. 2. Harpaz R et al. MMWR. 2008;57(RR–5):1–30. 3. Oxman MN. Varicella-Zoster Virus: Virology and Clinical Management. Cambridge University Press; 2000:246–275. 4.Watson CPN et al. Pain. 1991;46:195–199. Pain (varying severity) “Aching”, “burning”, “stabbing”, “shock-like” Oxman MN. In: Arvin AM et al, eds. Varicella-Zoster Virus: Virology and Clinical Management. Cambridge, UK: Cambridge University Press; 2000:246–275. Weaver BA. J Am Osteopath Assoc. 2007;107(suppl 1):S2–S7. 3. Harpaz R et al. MMWR Morb Mortal Wkly Rep. 2008;57(RR-5):1–30.

Herpes Zoster is the reactivation of which virus? Measles Mumps Rubella Varicella 4

What is the most common longterm complication of herpes zoster? Bell’s palsy Postherpetic neuralgia Vision loss Myocarditis 2

Prevention of Zoster and Postherpetic Neuralgia ZOSTAVAX® (Zoster Vaccine Live)

Zoster Vaccine Indication ACIP recommends routine vaccination of all persons aged >60 years with 1 dose of zoster vaccine. NEW FDA LABELING: “ZOSTAVAX is a live attenuated virus vaccine indicated for prevention of herpes zoster (shingles) in individuals 50 years of age and older.” Persons who report a previous episode of zoster and persons with chronic medical conditions can be vaccinated unless those conditions are contraindications or precautions. Zoster vaccination is not indicated to treat acute zoster. Zostavax® [package insert]. Whitehouse Station, NJ: Merck; April 2011. Recommendations of the Advisory Committee on Immunization Practices (ACIP) http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5705a1.htm?s_cid=rr5705a1_e

Vaccine Contraindications Allergy to neomycin or any vaccine component Pregnancy Immunocompromised status AIDS or other clinical manifestations of HIV, including persons with CD4+ T-lymphocyte values <200 per mm3 malignant neoplasms affecting the bone marrow chemotherapy or radiation within the last 3 months Persons on immunosuppressive therapy, including high-dose corticosteroids (>20 mg/day of prednisone or equivalent) lasting two or more weeks

Storage and Handling Zoster vaccine must be stored frozen The vaccine must be discarded if not used within 30 minutes after reconstitution. New labeling: Zostavax may be stored and/or transported at fridge temp for up to 72 hours prior to reconstitution. Any unused vaccine at fridge temp should be discarded. Zostavax® [package insert]. Whitehouse Station, NJ: Merck; April 2011.

Administration Zostavax: SINGLE 0.65-mL dose (reconstituted) SQ – upper, outer tricep 5/8 inch, 25 gauge needle

What is the maximum length of time between reconstitution and administration of Zostavax? 10 minutes 30 minutes 1 hour 1 day 2

Prevention of Zoster and Postherpetic Neuralgia Shingrix® (Herpes Zoster Adjuvanted Subunit Vaccine)

Coming soon: Shingrix® Inactivated, recombinant zoster subunit vaccine Manufactured by GlaxoSmithKline ADD: table comparing zostavax and shingrix (storage, administration, formulation) Combines glycoprotein E with an adjuvant system suspension Adjuvant is bacterial, from salmonella minesota Also found effective against postherpatic neuralgia (PHN) Mention: Will likely be an option for immunocomprimised patients and patients ≥50 year olds, Better efficacy and lasting protection compared to Zostavax

Storage and Administration Stored in the refrigerator at 4o C Suspension that must be reconstituted with adjuvant suspension upon administration IM injection 2 dose series, given 2-6 months apart

Coming soon: Shingrix® Trials: ZOE-50: Shingrix reduced risk of herpes zoster by 97.2% in patients 50-59 year olds (Zostavax had only 70% efficacy for the same population group) ZOE-70: Shingrix reduced risk of herpes zoster by 90% in patients ≥70 years old (Zostavax had only 38% efficacy for the same population group) Zoster-048: Shingrix demonstrates appropriate immunogeneicity and safety data in all approved populations regardless of if the patient has received a previous Zostavax vaccine Should patients wait for Shingrix to be approved to get vaccinated? Patients previously vaccinated with Zostavax may be indicated for a Shingrix booster shot? Better efficacy → 90-97% depending on age Offers lasting protection → does not wane over at least 4 years, possibly 9 years Administration to immunocompromised will be labeled indication

Coming soon: Shingrix® Status: Recommended for approval by the FDA panel (11-0 vote) Now up for approval by the FDA at the end of October Will then be considered at ACIP meeting on Oct. 25 for current guidelines

Summary Zostavax Shingrix Formulation Powder for reconstitution Suspension for reconstitution Storage Freezer Refrigerator Administration SQ Single Dose IM 2 doses Efficacy 38-70% 90-97% Type LIVE INACTIVATED Comparison table

Questions and Discussion