Goal and Objectives

Goal: . Provide the clinician with an overview of some recent developments in relevant to transplantation. Cheap Shots: Update on Vaccinations Objectives: . Discuss the mechanism and function of . Review some recently FDA approved vaccines: - Hepatitis B recombinant, adjuvanted (Heplisav-B)

David J. Quan, Pharm.D., BCPS - Meningococcal Group B Vaccine (Bexsero & Trumenba) Pharmacist Specialist-Solid Organ Transplant - Zoster vaccine recombinant, adjuvanted (Shingrix) UCSF Health Health Sciences Clinical Professor of Pharmacy . Review some useful resources available UCSF School of Pharmacy

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A Brief History of Vaccination

Date Event “ 400 BC Hippocrates describes mumps, diphtheria, and epidemic jaundice “An ounce of prevention is worth a 1100s Variolation with dried scab materials from smallpox patients 1798 publishes work vaccination against smallpox pound of cure.” 1879 creates first live (chicken cholera) 1893 Mass production of diphtheria antitoxin 1945 licensed in the United States -Benjamin Franklin 1977 Last case of naturally occurring smallpox 1981 Hepatitis B plasma-based vaccine developed 1968 Recombinant developed 1995 Live licensed 2014-5 Meningococcal serogroup B vaccines licensed 2017 Recombinant zoster vaccine

3 4 How Vaccines Work Different Types of Vaccines

Vaccine Type Vaccines Live, attenuated Measles, mumps, rubella (MMR) Pass virus through cell cultures to Varicella (Varivax) attenuate virus (unable to replicate) Influenza intranasal (FluMist) Inactivated Polio (IPV) “Killed” virus that retains immunogenicity Hepatitis A (Havrix, Vaqta) Tetanus, diphtheria (part of Tdap) Inactivated form of toxin Subunit / conjugate Hepatitis B (Engerix-B) Part of the pathogen used to provoke Pneumococcal (Pneumovax 23) immune response Meningococcal (Menactra)

Other Ingredients Action Preservatives Antimicrobial, single dose=no preservative Adjuvants Increases immune response

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How Vaccines Are Made Vaccines Eliminate Disease Elimination of Measles in the United States

MMWR 1995;43:1. https://www.cdc.gov/mmwr/preview/mmwrhtml/00039679.htm Vaccine Fact Book 2013. Pharmaceutical Manufacturers of America, September 2013. MMWR 2007; 54:2-92. https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5453a1.htm

7 Presentation Title 8 Presentation Title General Principles

. Before transplantation - Complete vaccine series (earlier the better) . Serologic monitoring to determine immunity - Document vaccinations in patient’s medical record Hepatitis B Vaccines . After transplantation - Optimal time to give vaccines post-transplant is not well defined . Wait at least 3-6 months after transplant to vaccinate . No evidence linking vaccinations to rejection episodes - Live vaccines should NOT be given post-transplant - Assess seroconversion (serologic monitoring)

Danziger-Isakov L. Am J Transplantation. 2013;13:311-317.

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Hepatitis B Vaccine Hepatitis B Vaccine New and Updated Recommendations Traditional

. Vaccination is the mainstay of hepatitis B virus prevention . Universal Hepatitis B vaccine within 24h of birth - Yeast-derived recombinant HBsAg . Testing HBsAg-positive pregnant women for HBV DNA - Decreased response: Smoking, obesity, diabetes, aging, chronic . Post-vaccination testing of infants whose mother’s HBsAg medical conditions, drug use, male, immune suppression status remains unknown . 3-dose vaccine series protective (anti-HBs ≥10mIU/mL) . Single-dose revaccination for infants born to HBsAg-positive - >90% adults <40 years old women not responding to initial vaccine series - 30-55% and 75% achieve anti-HBS ≥10mIU/mL after 1 & 2 doses . Removal of permissive language delaying birth dose until . Hepatitis B immune globulin (HBIG) after hospitalization - Plasma-derived (human donors) . Vaccination of persons with chronic liver disease - Passively acquired anti-HBs detected for 4-6 months - Post-exposure prophylaxis and liver transplantation

Schillie S, Vellozzi C, Reingold A, et al. MMWR Recomm Rep 2018;67(No. RR-1):1–31.

11 12 Hepatitis B Vaccine, Adjuvanted Hepatitis B Vaccines: Old and New Heplisav-B

. HBsAg from recombinant Engerix-B Recombivax- Heplisav-B Twinrix Hansenula polymorpha yeast HB . Cytosine phosphoguanine Doses 3 3 2 3-4 (CpG) 1018 adjuvant Viral antigens HBsAg HBsAg HBsAg HBsAg - 22-base mimicked HAVAg oligodeoxyribonucleotide: Adjuvant Aluminum Aluminum CpG 1018 Aluminum 5’-TGACTGTGAACGTTCGAGGATGA-3’ hydroxide hydroxide Toll-like 9 hydroxide - Toll-like 9 receptor agonist receptor . Bacterial/viral pathogen Derivation rDNA yeast rDNA yeast rDNA yeast rDNA yeast recognition source Adjuvant from - Increases magnitude and bacterial DNA quality of antibody response to Manufacturer GSK Merck Dynavax GSK antigen Cost $203 $224 $276 $358-478 Heyward WL. Vaccine. 2013;31:5300-5305.

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Patient Factors That Affect Response Seroprotection Rates Decrease With Age Hepatitis B, Adjuvanted Hepatitis B Vaccine, Adjuvanted

Hepatitis B Vaccine, Hepatitis B Vaccine Age Hepatitis B vaccine, Hepatitis B vaccine* Adjuvanted (Engerix-B) (years) Adjuvanted* (Engerix-B) (Heplisav-B) (Heplisav-B) Total trial population (N=6665) 95.4% 81.3% N SPR N SPR Patients with diabetes (N=961) 90.0% 65.1% 18-29 174 100% 99 93.9% Aged 40-70 (N=5434) 94.6% 78.7% 20-39 632 98.9% 326 92.0% Male (N=3353) 94.5% 78.8% 40-49 974 97.2% 518 84.2% Obesity (N=3241) 94.7% 75.4% 50-59 1439 95.2% 758 79.7% Smokers (N=2082) 95.9% 78.6% 60-70 1157 91.6% 588 72.6% *Heplisav-B week 24, Engerix-B week 28. SPR = Seroprotection Rate

Jackson S, et al. Vaccine. 2018;36:668-674. Dynavax Technologies Corporation. FDA Advisory Committee Briefing document. Heplisav-B prescribing information]. Berkeley, Ca: Dynavax Technologies Corporation; 2017.

15 16 Hepatitis B Vaccine Hepatitis B Vaccines Dosing

Reaction Hepatitis B Vaccine, Hepatitis B Vaccine Adjuvanted (Engerix-B) Vaccine Dose Day 0 Month 1 Month 2 Month 6 (Heplisav-B) Engerix-B 1mL (20mcg) IM XX X Dose 1 Dose 2 Dose 1 Dose 2 Dose 3 Engerix-B hemodialysis 2mL (40mcg) IM XXXX Local Recombivax HB 1mL (10mcg) IM XX X site pain 38.5% 34.8% 33.6% 24.7% 20.2% Recombivax HB hemodialysis 1mL (40mcg) IM XX X Injection site redness 4.1% 2.9% 0.5% 1.0% 0.7% Twinrix (hepatitis A & B) 1mL IM XX X Injection site swelling 2.3% 1.5% 0.7% 0.5% 0.5% Heplisav-B 0.5mL (20mcg) IM XX Systemic Fatigue 17.4% 13.8% 16.7% 11.9% 10.0% Headache 16.9% 12.8% 19.2% 12.3% 9.5% Malaise 9.2% 7.6% 8.9% 6.5% 6.4% Fever 1.1% 1.5% 1.8% 1.7% 1.8%

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Hepatitis B Vaccines Key Points

. Several hepatitis B vaccines are available . Hepatitis B vaccine, adjuvanted (Heplisav-B) - Higher seroprotection rates compared to conventional vaccine . Diabetes, obese, smokers, and aged 40-70 years . Seroprotection occurs earlier Meningococcal Vaccines . Efficacy based on surrogate marker (seroprotection) - 2-dose regimen . Interchangeability and dosing schedule - 2-dose vaccine applies only to Heplisav-B . When able, same manufacturer’s vaccine should be used for series . Series consisting of one Heplisav-B dose and vaccine from different manufacturer, should consist of 3 total doses (follow 3-dose schedule)* *Schillie S. Recommendations of the Advisory Committee on Practices for Use of a Hepatitis B Vaccine with a Novel Adjuvant. MMWR Morb Mortal Wkly Rep 2018;67:455–458. DOI: http://dx.doi.org/10.15585/mmwr.mm6715a5.

19 20 Meningococcal Vaccines Meningococcal Vaccines Serogroups A, C, Y, W-135 Serogroup B

. Neisseria meningitidis (meningococcus) can cause bacterial . Medical conditions at risk for meningococcal disease meningitis and sepsis, which can be fatal. - HIV - Five serogroups (groups A, B, C, Y, and W-135) cause a majority - Functional or anatomic asplenia of the invasive meningococcal disease. - Persistent complement deficiencies (e.g. C3, C5-9, factor H or D) - Most common in infants, teens and young adults . Patients taking eculizumab (Soliris) - Patients at risk: Asplenia, complement disorders, HIV-infection . Recombinant (serogroup B) vaccines: . Quadrivalent (serogroups A, C, Y, W-135) vaccines available: - Bexsero (recombinant Neisserial adhesin A (NadA), Neisserial - Menactra (diphtheria toxoid conjugate) Heparin Binding Antigen (NHBA), factor H binding protein (fHbp) . Ages 9 months through 55 years and Outer Membrane Vesicles (OMV), aluminum adjuvant) - Menveo (diphtheria oligosaccharide CRM197 protein conjugate) - Trumenba (recombinant lapidated factor H binding protein (fHbp) . Ages 2 months through 55 years from subfamilies A05 and B01). - Menomune (polysaccharide) discontinued in 2017

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Meningococcal Vaccines Meningococcal Serogroup B Vaccines Dosing Schedules Immunogenicity

Vaccine Dose Day 0 Month Month Month Cost Bexsero Bactericidal Age Age Trumenba Bactericidal Age Age 1 2 6 Antibody Response 18-24 11-17 Antibody Response 10-18 18-25 H44/76 (fHbp) 78% 98% ≥-4 fold increase dose 3 Meningococcal A/C/Y/W-135 5/99 (NadA) 94% 99% PMB90(A22) 86.2% 81.1% Menactra 0.5mL IM X $139 NZ98/254 (PorA P1.4) 67% 39% PMB2001 (A56) 92.0% 90.7% Menveo 0.5mL IM X $151 Composite endpoint: PMB2948 (B24) 81.9% 83.9% Meningococcal B 1 month post dose 2 88% 63% PMB2707 (B44) 88.3% 79.3% Bexsero 0.5mL IM XX $396 11 months post dose 2 66% Composite response 85.7% 82.7% Trumenba 0.5mL IM X X $319 NCT 01423084 LLOQ=1:16 for H44/76; 1:16 for 5/99, X X* X $478 NCT01830855, NCT01352845 1:8 for NZ98/254. Composite = hSBA ≥LLQ for LLOQ=1:16 for A22; 1:8 for A56, B24, and B44 all three strains. Composite = hSBA ≥ LLOQ for all primary strains

*3-dose vaccination regimen recommended when more accelerated immunity is desired (e.g. adolescent during outbreak

23 24 Meningococcal Serogroup B Vaccine Eculizumab Order Panel Safety Meningococcal Vaccines and Prophylaxis

‡ ‡ ‡ Bexsero* Bexsero* Trumenba Trumenba Trumenba . Eculizumab increases risk Dose 1 Dose 2 Dose 1 Dose 2 Dose 3 of meningococcal disease Pain (any) 90% 83% 86.7% 77.7% 76% . Eculizumab Order Panel Erythema 50% 45% 16.2% 12.5% 13.9% - Dosing guidance Fever 1% 5% 6.4% 2% 2.7% . Meningococcal vaccines Myalgia 49% 48% 24.2% 17.8% 17.6% - Meningococcal A/C/Y/W Arthralgia 13% 16% 21.9% 16.7% 16% and Fatigue 37% 35% 54% 38.3% 35.9% - Meningococcal B Headache 33% 34% 51.8% 37.8% 35.4% . Antimicrobial prophylaxis

*Ages 10 through 25 years. National (NCT) Identifier NCT01272180. - Ciprofloxacin ‡Ages 18 to 25. National Clinical Trial (NCT) Identifier NCT01352845. or - Penicillin VK

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Meningococcal Vaccination Key Points

. Two types of meningococcal vaccines: (ACWY) and B - Meningococcal conjugate (ACWY) . All preteens & teens with booster and children/adults at risk - Serogroup B vaccine (Zoster) Vaccines . People >10 years at increased risk for meningococcal disease . Two serogroup B vaccines available - Same vaccine should be used to complete the series - Efficacy in the short-term (antibodies wane with time) . Patients on eculizumab at high risk (despite vaccination) - Vaccinate at least 2 weeks prior to administration - Consider antimicrobial prophylaxis for duration of therapy

https://www.cdc.gov/vaccines/vpd/mening/hcp/adolescent-vaccine.html (accessed 9/3/2018) McNamara LA. High Risk for Invasive Meningococcal MMWR Morb Mortal Wkly Rep 2017;66:734-737.

27 28 Varicella Zoster Virus Live Vaccines

. Varicella zoster virus is from the herpesvirus family that . Live attenuated microorganisms (vaccine) provide continual causes in children and young adults. antigenic stimulation . Reactivation later in life causes a painful rash (Shingles) - Memory cell production . Risk of shingles increases with age - Robust immune response . People at high risk of shingles: . Varivax (Varicella virus vaccine live) - / - Prevent varicella (chickenpox) in children and adolescents - HIV infection . Zostavax (Zoster vaccine live) - - Prevent shingles in adults >50 years old . Several different vaccines available . Do NOT give live vaccines to immunocompromised patients - Potential for disseminated disease

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Zoster Vaccine Recombinant, Adjuvanted Zoster Vaccine Recombinant, Adjuvanted Shingrix Shingrix

Age group (years) of zoster per Efficacy . Recombinant zoster virus surface glycoprotein E (gE) antigen 1000 person-years - gE is the predominant surface protein on zoster virus Overall (≥50) 0.3 97.2% 50-59 0.3 96.6% . AS01B adjuvant (liposomal formulation) - Monophosphoryl lipid A (MPL) from Minnesota 60-69 0.3 97.4% - QS-21 from Quillaja saponaria Molina ≥70 0.3 97.9% NCT01165177 (subjects ≥ 50 yrs)

Age group (years) Incidence rate of post Efficacy herpetic neuralgia per 1000 person-years Overall (≥70) 0.1 88.8% 70-79 0.1 93.0% ≥80 0.3 71.2% Pooled data from study NCT01165177 (subjects ≥ 50 yrs) & NCT01165229 (subjects ≥70 yrs)

31 32 Zoster Vaccine Recombinant, Adjuvanted Zoster Vaccine Recombinant Adjuvantesd Phase I/II Study in Autologous Hematopoietic Cell Transplant (HCT) Immunogenicity and Safety in Adults Post Renal Transplant (Zoster 041 trial)

Cell Mediated Immune Response . Within 50-70 days of HCT . 4-18 mos. after renal tx VRR(%) HZ/su Placebo . Cell-mediated immunity . 2-doses 1-2 months apart Humoral immune 80.2% 4.2% (CD4(2+) T-cell frequency response . Humoral and cell-mediated - 3- and 2-dose groups greater Cell-mediated 71.4% 0% immune response than saline response > placebo . Safety . Combined humoral and cell Adverse Events HZ/su Placebo mediated response - Local AEs more common Local 87% 7.6% - 3-dose > 2-dose group - General AEs similar General 68.7% 55.3% . Safety - No biopsy-confirmed MAEs 25.8% 22% - 2 cases of zoster (3-dose) rejection (1st month) Bx proven rej. <1mo.* 0% 0% - 2 cases of zoster (saline) Vink P. ID Week 2017, Abstract #1348. - Pain at injection site VRR=Vaccine Response Rate, HZ/Su=Herpes Rejection Mos. 2-13* 4/132 7/132 Zoster Subunit Adjuvanted Vaccine. MAE = AEs Stadtmauer EA. Blood. 2014;124:2921-2929 - Myalgias with medically attended visits.* Month(s) after vaccination, https://clinicaltrials.gov/ct2/show/NCT02058589

33 34 *Month(s) after vaccination.

Varicella Vaccines Varicella Zoster Vaccines Dose Schedule Key Points

Vaccine / Indication Dose Schedule Cost . Different vaccines for different indications Varivax 0.5mL Age 12-15 Age 4-6 yrs Age 7-18 yrs $289 - Varivax (live) to prevent chickenpox Varicella virus vaccine live SQ mos Dose 2 Catch-up 2nd Prevent varicella >12 Dose 1 dose* - Zostavax (live), Shingrix (recombinant) to prevent shingles months old . Current ACIP guidance recommends Shingrix (recombinant) Zostavax 0.65mL Single dose $255 over Zostavax (live) for prevention of shingles Zoster vaccine live SQ Prevent shingles > 50 yrs - NO recommendation for use in transplant recipients old . Shingrix has been studied in renal transplant recipients Shingrix 0.5mL Day 0 2-6 months later $336 Zoster vaccine SQ Dose 1 Dose 1 - Preliminary data looks promising (results yet to be published) recombinant, adjuvanted - ACIP guidance forthcoming based on data Prevent shingles >50 yrs old *Centers for Disease Control and Prevention (CDC). Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007;56(RR-4):1–40.

35 36 Thimerosal in Vaccines Useful Vaccine Resources Mercury Exposure

• Thimerosal is a mercury-containing compound used as a preservative • 25mcg mercury in 0.5mL flu vaccine . Advisory Committee on Immunization Practices (ACIP) • ~50mcg mercury in 6oz of albacore tuna* • No good evidence that thimerosal in vaccines is associated with autism‡ - https://www.cdc.gov/vaccines/acip/index.html . IDSA Guidelines Vaccination of Immunocompromised Host • Public Health Services (PHS) recommends July 9, 1999 removal of Thimerosal from childhood vaccines - Clinical Infectious Diseases 2014;58:e44-100 • Manufacturers begin to phase out thimerosal in . California Immunization Registry (CAIR) 1999 childhood vaccines - www.cairweb.org 2001 • Manufacturing of childhood vaccines containing thimerosal cease . HealthMap Vaccine Finder • All childhood vaccines containing thimerosal are - https://vaccinefinder.org 2003 no longer available . Reporting System (VAERS) 2004 • Only multiple-dose vials of influenza vaccine contain thimerosal. - http://vaers.hhs.gov/ *http://safinacenter.org/documents/2016/09/mercury-seafood-guide-consumers-web.pdf/. ‡ Institute of Medicine. 2004. Immunization Safety Review: . Washington, DC: The National Academies Press.

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Where to Get Vaccinated? Tab in ApeX Easy as zip code, vaccine, and click search

. Administration history (from ApeX) . Immunization Registry (CAIRS) . “Recommended Immunizations” due date . Immunizations report

https://vaccinefinder.org (accessed 9/3/2018)

39 40 Conclusions

. Advances in vaccine technology: - More effective and safe vaccines . New vaccines complement and extend current vaccines - Hepatitis B vaccine (recombinant), adjuvanted - Meningococcal group B vaccines - Zoster vaccine (recombinant), adjuvanted . Success stories in medicine - Vaccination - Transplantation

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