Preventing Infections in the Era of Biologics

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2 Preventing Infections in the Era of Biologics Deepali Kumar MD MSc FRCPC Immunocompromised Infectious Diseases Program University Health Network Toronto

3 Disclosure Research Grants Roche, GSK Honoraria Sanofi, Pfizer Off-label use of vaccines

4 Objectives o ID Screening prior to immunosuppression o Inac2vated / Live Vaccines and their Timings o Changing landscape of shingles vaccina2on o Infec2ons to be aware of in immunosuppressed IBD pa2ents

5 ID Screening for IBD patients o Ac2ve Infec2on o Latent Infec2ons o TB (TB skin test or IGRA, Chest Xray) o Geographic infec2ons (eg, Strongyloides serology) o Endemic fungi: screening not sensi2ve o Serologic screening o HIV o HCV o Hepa22s B (HBsAg, an2- HBs, an2- HBc) o VZV o Measles, Mumps, Rubella (if born aoer 1970) o Past vaccina2on history

6 Yeung, Goodman, Fedorak, IBD 2012

7 Recommended Vaccines in IBD Inac2vated Vaccines TdaP booster (q10years) Pneumococcal (PCV13 and PPV23) Influenza HepB HPV (depends on age) Meningococcal (with risk factors) Live Vaccines MMR if seronega2ve and no documented vaccina2on Varicella (for VZV IgG nega2ve) Shingles (for VZV IgG posi2ve and over 50 years of age)

8 Inac%ve Vaccine Serology Popula%on Schedule Diphtheria/ Tetanus/Pertussis No All - Update if not given in last 10 yrs TdaP x 1 dose and Td booster q10yrs Pneumococcus No All PCV13 and PPV23 Influenza No All Annual Hepa22s B Yes All- If an2- HBs <10 IU/mL 3 doses at 0,1,6 months Hepa22s A Yes At risk liver disease, travellers, MSM* 2 doses at 0,6 months HPV No Males 9-26 and Females 9-45* 3 doses at 0,2,6 months Meningococcus No High risk (traveller, splenectomy) Two doses of quadrivalent conjugate vaccine *differs from ACG guidelines which follow ACIP (Farraye et al., Am J Gastro 2017)

9 Pneumococcal Vaccine Recommendations No prior pneumococcal vaccine Prevnar13- one dose Pneumovax23- one dose Pneumovax23 booster dose 8 weeks minimum 5 years Prior Pneumococcal vaccine (Pneumovax) 1 year minimum Prevnar13- one dose 8 weeks minimum Pneumovax23 one dose 5 years NACI 2012

10 Vaccine Seroprotection in IBD with Immunosuppression Vaccines include: influenza, pneumococcal, Hepatitis A/B Immunosuppression includes: Anti-TNF infliximab, adalimumab, certolizumab Immunomodulators MTX, 6-MP, AZA, Tac, MPA Prednisone >= 20mg/kg/d Nguyen et al., Dig Dis Sci, 2015

11 Vaccine Seroprotection in IBD with anti-tnf Nguyen et al., Dig Dis Sci, 2015

12 Timing of Inactivated Vaccines is important to achieve optimal vaccine response o It takes ~2 weeks for an2body and T- cell response to vaccine o Immunize at least 2 weeks prior to immunosuppression if possible o If already started on immunosuppression, inac2vated vaccines can be given at the nadir (midpoint) of immunosuppressive therapy o No need to interrupt therapy to administer inac2vated vaccines

13 Vedolizumab and HepB immunization o α 4 β 7 integrin inhibitor which may be gut selec2ve o RCT of Vedolizumab vs. placebo in which HepB vaccine (days 4, 32, 60) and oral cholera vaccine (days 4, 32) star2ng 4 days aoer Vedolizumab Wyant et al., Gut, 2015

14 Live-attenuated Vaccines Live Vaccine Considered immune Popula%on Serology Schedule Measles Mumps Rubella Two documented doses of vaccine Posi2ve serology Pts with unknown vaccine history Before immuno- Yes 2 doses one month apart Wait 4 weeks before star2ng immunosuppression Varicella Born before 1970 suppression Yes 2 doses one month starts apart Wait 4 weeks before star2ng immunosuppression Shingles Shingles in the last 1 year Age >= 50 Yes One dose 4 weeks before immunosuppression; consider in those on biologics Small case series of MMR, varicella, yellow fever vaccines on TNFi demonstrate safety

15 Timing of Live Vaccines is important for safety and optimal vaccine response o Give prior to immunosuppression, at least 4 weeks o Avoid live vaccines during immunosuppression (excep2on re: live shingles vaccine) o AOer immunosuppression is discon2nued, consider the half- life of immunosuppression and wait at least 3-5 half- lives to administer live vaccine

16 Zoster Vaccine (Zostavax) o Live, apenuated VZV o Single dose (0.65mL) subcu o Contains at least 14- fold more virus than Varicella vaccine (secondary vaccina2on) o For age 60 yrs, 51% effec2ve in preven2on of shingles and 67% effec2ve in preven2on of PHN o Can be given to age yrs

17 Zoster Risk in patients with inflammatory diseases on anti-tnf agents is elevated concomitant prednisone use >10mg/d was associated with much higher rates of zoster (~2- fold higher) Strangfeld JAMA 2009

18 Zoster Risk in IBD: IMS Lifelink Database Long et al., AP&T, 2012

19 Zoster Risk in IBD: IMS Lifelink Database Long et al., AP&T, 2012

20 >460,000 person retrospec2ve Medicare cohort of pa2ents >60 yrs with autoimmune condi2ons 4% received HZ vaccine and f/u 2 yrs 11.6 vs. 7.8 per 1000 py in unvaccinated vs. vaccinated Zhang et al., JAMA 2012

21 Biologics and Zoster vaccine safety 633 were on an%- TNF/biologics who were vaccinated (no cases of HZ in 6 wks post- vaccine) Those vaccinated (while receiving biologics +/- steroids) had a lower incidence of shingles Zhang et al., JAMA 2012

22 VA Study o 56,417 persons with IBD in the VA database from o 59 received HZ vaccine while on an2- TNF and had no adverse events out to 6 wks Khan et al., AP&T, 2017

23 Canadian Recommendations for Live Herpes Zoster Vaccine (2014) o Herpes zoster vaccine is not indicated for persons with immune compromise including o Cor2costeroids > 2mg/kg daily or >20mg/d o Chemotherapies o Transplanta2on o HIV o HZ vaccine can be given to o Persons on low dose MTX / AZA / 6- MP for inflammatory condi2ons o HZ vaccine can be considered for o Persons on biologics on a case- by- case basis Update on HZ vaccine, PHAC 2014

24 VERVE (ongoing study) o N=1000 pa2ents on TNFi therapy will receive shingles vaccine vs. placebo o Age 50 years o Primary outcome: 6 week immunogenicity and safety o Trial comple2on: Sept

25 Adjuvanted Non-live Shingles Vaccine o Subunit inactivated vaccine based on ge glycoprotein of VZV o >16,000 patients (age>50) in RCT (prior shingles excluded) o Efficacy 97.2% for an endpoint of confirmed herpes zoster o At ACIP meeting in Oct 2017, this vaccine was preferred over live shingles vaccine for age > 50 (Canadian recommendations pending) o No data in patients on biologics but immunogenic in chemotherapy and transplantation

26 Immunization of Household Contacts of IBD patients on Immunosuppression o HH contacts can receive all age appropriate vaccines o MMR, varicella, zostavax, rotavirus, live apenuated flu vaccine can be administered to HH contacts (excep2ons smallpox or oral polio) o Varicella transmission is rare and usually when rash is present o Wash hands aoer changing infant diaper Rubin et al., CID 2013 ACIP general recommendations MMWR. 2011; 60(RR02):1-60.

27 Infections of particular concern during TNFi therapy o Bacterial infec2ons o Pneumonia HR 1.54 (95%CI ) o TB reac2va2on risk on TNFi is fold, may be lower in IBD pa2ents due to? younger age o Nocardia case series in pa2ents on TNFi o Fungal infec2ons o Histoplasmosis (specific risk in pa2ents on TNFi) o Pneumocys2s (has been described in pa2ents on biologics, high- dose steroids) o Viral infec2ons o VZV o CMV coli2s especially in severe steroid- refractory UC o JC virus causing PML in pa2ents on natalizumab o Parasi2c: Strongyloides treat if posi2ve serology Long et al., Am J Gastro, 2013; Seminerio et al., Dig Dis Sci, 2013; Dave et al., IBD, 2014

28 Thank you!