Vaccination in Immunosuppressed Adults ASID Adult Immunisation Workshop 9 May 2018

Professor Katie Flanagan Types of Immunosuppression to Consider

• Cancer and haematological malignancies • Chronic infections – HIV • Chronic diseases – diabetes, COPD, autoimmune diseases • Asplenia • Physiological – pregnancy • Stem Cell / Solid organ / bone marrow transplant • Drug induced – Steroids – Other immunosuppressive drugs – methotrexate, azathioprine – Cancer and haematological malignancy treatments • – Monoclonal antibodies – Immune checkpoint inhibitors

General Rules

• Immune compromised persons are at increased risk of morbidity and mortality from many VPDs.

• Degree of immune compromise should be assessed to determine vaccination strategy

• Inactivated vaccines are generally safe in the immunocompromised adult but not always as immunogenic / efficacious

• Live vaccines are contraindicated in many immunocompromising situations due to risk of disseminated infection, in particular: – BCG is always contraindicated – Other live vaccines should not be given to those with severe immunocompromise

• Severe immunocompromise includes active leukaemia, lymphoma, generalised malignancy, recent chemo (last 3 months), aplastic anaemia, GVHD, BMT or solid organ transplant in last 2 years, transplant recipients still taking immunosuppressives, high-dose corticosteroids

General Rules

• Many vaccines can be given pre-emptively to people who anticipate immunocompromise in the future i.e. contemplating immunosuppressive therapy e.g. varicella zoster vaccine, pneumococcal vaccination

Influenza Vaccination • Annual seasonal vaccination recommended for all immune compromised adults • Should be given 2 doses at least 4 weeks apart the first time it is given • In a pandemic situation 2 doses of vaccine may be given any season

Cancer / Haematology Patients

Live vaccines • Contraindicated if on immunosuppressive therapy or have poorly controlled malignancy • Avoid when neutropaenic (<0.5x109/L) • Wait until 3 months after treatment and confirmed remission

Inactivated Vaccines • Give annual influenza (2 doses 1st time) • Give any required inactivated vaccines • Haematological malignancy patients (lymphoma, leukaemia, myeloma) should be given pneumococcal vaccination – 1 dose of 13 valent PCV then 2 doses of 23 valent PPV 8 weeks after PCV

Adult Cancer / Haematology Patients in Remission for >6 months

• Single dose dTpa • Single dose MMR / IPV / HepB (Check measles and rubella Abs 6-8 weeks after MMR and revaccinate if non- seroconverter) • Single dose 13vPCV then 2 doses 23vPPV • Single dose Hib

Solid Organ Transplant

Live vaccines contraindicated Inactivated vaccines safe but often delayed until 6 months post-Tx to maximise immunogenicity

Vaccine Pre-Transplant Post-Transplant (if not given before) dTpa Yes Yes IPV Yes Yes Hep A and B Yes (depends on serostatus) Yes (depends on serostatus) 13vPCV then Yes Yes 2 x 23vPPV MenACWY and Yes (if risk factors) Yes (if risk factors) MenB Annual influenza Yes MMR Yes No Haematopoietic Stem Cell Transplant

Protective immunity to VPDs partially or fully lost post HSCT, particularly first 6 months

AutologousVaccine HSCT patients recover immunity moreSchedule quickly & don’t get GVHD

13vPCV 3 doses 6, 8, 12m post HSCT 23vPPV 1 dose 24m post HSCT Hib / dTpa / IPV 3 doses 6, 8, 12m post HSCT HepB 3 doses 6, 8, 12m post HSCT High dose formulation or dose in each arm each visit 4vMenCV and MenB 2 doses 6 and 8m MMR * 24m - 1-2 doses (check Abs at 4wks) Varicella * 24m - 2 doses 4wks apart if seronegative

* Only if no ongoing GVHD and CMI has recovered There is a role for donor immunisation with Hib, PCV, hep B and tetanus vaccines prior to harvest but rarely done

Corticosteroids and Live Vaccines

Prednisolone Duration Timing of Equivalent Dose Vaccination <20mg / day Any Give any time ≥20mg / day < 14 days 1 month before or any time after cessation ≥20mg / day ≥14 days 1 month before or at least 1 month after cessation

20mg prednisolone is equivalent to:  16 mg methylprednisolone  16mg triamcinolone  3.2mg dexamethasone  80mg hydrocortisone Corticosteroids and DMARDS

• If on <20mg prednisolone equivalent daily and low dose DMARDS then can still receive live vaccines

• Low dose DMARDS: Drug Dose Dose in 70kg adult Methotrexate ≤0.4mg/kg/week 28mg Azathioprine ≤3mg/kg/day 210mg Mercaptopurine ≤1.5mg/kg/day 105mg

Recent Blood Products / Immunoglobulins

Product Interval Before Live (MMR, MMRV, Varicella) Vaccination Blood transfusion / washed RBCs 0 months RBCs 3 months Packed RBCs 5 months Whole blood 6 months NHIG for ITP / Kawasaki 8-11 months NHIG for measles / hepA prophylaxis 3-6 months Plasma or platelets 7 months RhD Ig (anti-D) 0 months ZIG as varicella prophylaxis 5 months

BCG, Zoster and Yellow Fever vaccination can be given any time before or after blood products HIV Infection

Live vaccines • Contraindicated if CD4 <200/μL (<15%), history of AIDS-defining illness, symptomatic HIV infection • BCG is always contraindicated • Can give YF, MMR (if seronegative) and VZV (if seronegative) vaccines but NOT combined MMRV in asymptomatic HIV infection and those with CD4 ≥200/μL (15%) • Zoster vaccine if ≥ 50 years and VZV IgG+ and CD4 ≥350/μL (some say ≥200/μL safe)

Inactivated Vaccines • Annual influenza • Pneumococcal vaccination (1 x PCV13 + 2x PPV23) • 4vMenCV and MenB – 2 doses of each • HepA if non-immune • HepB 4 double doses at 0, 1, 2 and 6m more immunogenic, check anti-HBs and repeat doses if <10mIU/mL • 4vHPV – 3 doses @ 0, 2 and 6m. Females <45 yrs and males <26 yrs as per guidelines Asplenia

At risk of fulminant bacterial infection particularly invasive pneumococcal disease Go to Spleen Australia website for up-to-date advice https://spleen.org.au

Immunocompromised Travellers

• Yellow fever vaccine should be avoided in severe immunocompromise (travellers may need an exemption certificate)

• Do not give BCG

• Use the inactivated typhoid Vi polysaccharide vaccine not the live oral vaccine

Household Contacts

• Vaccinate household and close contacts of immunocompromised persons according to current recommendations – In particular annual influenza vaccination • Use of live vaccines in contacts is highly recommended • Consider need for VZV (if ≥50 years) and pertussis-containing vaccines • Small risk of rotavirus vaccine virus transmission to the immunocompromised

Immunotherapies

Name Target Name Target Type II activin Actoxumab + Bezlotoxumab C diff enterotoxin A recptors & B Alirocumab PCSK-9 β7 integrin subunit Bocociziumab PCSK9 CTLA4 MABp1, Xilonix IL-1α MM-302 HER2 IL-1β Patritumab HER3 IL-4Rα MEDI-4736 / RG7446, PD-L1 MPDL3280A IL-5 Elotuzumab CD2 IL-5R Inotuzumab ozogamicin / CD22 IL-6 Moxetumomeb pasudotoc /SA237 IL-6R subunit α Daratumumab CD38 / IL-13 Anti-complement C5 IL-17a Rituximab / CD20 IL-17R Alemtuzumab CD52 / IL-23 p19 subunit CD22 Rituximab

• Depletes B cells (anti-CD20) therefore prevents antibody responses • Different studies show differing effects but generally vaccine Ab responses (and CMI) impaired for up to 6 months post administration • Preferable to vaccinate prior to commencing therapy if possible

Eculizumab

• Prevents formation of the terminal complement complex C5b-9, by inhibiting the cleavage of C5-C5a • Indications: paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome • Worlds most expensive drug, 2010 (£340,000/dose) • Associated with increased susceptibility to serious Neisseria meningitidis infection with a rate of 1% (Australian average rate: 1/100,000) • Meningococcal vaccination recommended before starting treatment 4vMenV and MenBV 2 doses 8 weeks apart then check titres for response • Check Ab titres annually if ongoing therapy and revaccinate if titres fall • Antibiotic prophylaxis (PenV / erythromycn) also indicated

Immune Checkpoint Inhibitors & Flu Vaccination • (PD-1 inhibitor), (PD-1 inhibitor), (PD-L1 inhibitor), (CTLA4 inhibitor)

• Influenza vaccination has been associated with increased incidents of myocarditis and death in people on checkpoint inhibitors • One study showed PD-1/PD-L1 inhibs caused >50% immune related AEs (rash, arthritis, encephalitis, colitis) (>25% had severe irAEs) Can give if on single agent aPD-1 • Australian immunisation handbook says or aPD-L1 to consult your oncologist for advice Do not give flu vaccine within 6-8 • They are likely to ask the ID physician! wks of starting CTLA4 inhibs / combo therapy or 6-8 wks of • Trials are ongoing to investigate this stopping systematically

Thank You