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Post-transplant vaccinations and immune reconstitution Lynne Strasfeld, MD September 13, 2013.

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Presentation on theme: "Post-transplant vaccinations and immune reconstitution Lynne Strasfeld, MD September 13, 2013."— Presentation transcript:

1 Post-transplant vaccinations and immune reconstitution Lynne Strasfeld, MD September 13, 2013

2 A none too infrequent story… 38 year old man with history of AML, s/p tBuCy MUD PBSCT – cGVHD (skin, mouth, eyes) – CMV reactivation – avascular necrosis of shoulder  off immune suppression as of 9 months post- transplant Presented 1 year post-transplant with fever, worsening sinusitis…..blood cultures with Streptococcus pneumoniae

3 Overview Post-transplant vaccinations – Vaccination schedules & strategies – Immunologic challenges of post-transplant vaccination – Close contacts of transplant recipients New vaccines

4 Worldwide, > 50,000 HSCTs performed each year Vaccine preventable diseases: influenza, pneumococcus, varicella, Bordetella pertussis  significant causes of morbidity, re-hospitalization and mortality after successful HSCT Invasive pneumococcal infections in 590/100,000 allogeneic & 199/100,000 autologous recipients per year, compared with 11.5/100,000 age-matched controls Kumar D, et al. Bone Marrow Transplant Lessons from 2009 H1N1

5 Loss of immunity post-transplant ~ 50% of patients with positive tetanus & polio titers at the time of allogeneic HSCT will become seronegative at 1 year, with most unprotected against both by 2 years Ljungman P, et al. J Infect Dis In the absence of revaccination, the majority of allogeneic patients will become susceptible to measles, mumps & rubella by 3-5 years post-HSCT Ljungman P, et al. Bone Marrow Transplant 2009.

6 Measles : median 60 cases reported to CDC annually 2011: 222 cases & 17 outbreaks (including 72 imported cases  total 200, or 90%, associated with importation from other countries) – 33/72 (46%) importations were from Europe (*France) & 19/72 (26%) from SE Asia (*India) – 34/46 (74%) were US residents Most (86%) were unvaccinated or had unknown vaccination status 2 year old boy with recent travel to Pakistan presented to an Oregon hospital with fever & rash, ultimately diagnosed with measles (measles IgM+). Scores of patients/staff exposed in the waiting area/ED. MMWR Morb Mortal Wkly Rep Apr;61:253-7.

7 1997 measles outbreak in São Paulo: 20,185 cases in 11 months Seroepidemiologic survey in 156 BMT recipients – 122 NOT vaccinated: 76 were < 2 years post-transplant, 8 on immunosuppression, 38 non-compliant 41 (34%) susceptible 43/47 (92%) 1 year post-transplant Persistence of host-derived humoral immunity for at least 6 months post-transplant – 32/34 vaccinated patients underwent serologic evaluation: 13/32 (41%) susceptible 16/22 (73%) 3 years post-vaccination * Significant loss of measles immunity 3 years post-vaccination – 8/54 susceptible patients (IgG <100mIU/mL): attack rate 14.8% 1 death from measles interstitial pneumonia Machado CM, et al. Blood 2002.

8 Bordatella pertussis “whooping cough” URI symptoms, with protracted cough (“coughing fits”) In 2012, 910 cases of pertussis reported in Oregon 4 infant deaths in Oregon since 2003 Oregon Public Health Division, Fact Sheet March 2012

9 Reported Pertussis Cases In The US: Then Routine pertussis immunization begins Cases (Thousands) Cases (Thousands) Year Year MMWR 2002;51:73-76

10 3.5 week old girl admitted with coughing episodes, admitted April 17 th (mother has cough)  apnea, bradycardia, and hypoxia….required ECMO support, with secondary bacterial pneumonia And now…….

11 VaccineCIBMTR (2009) Tdap, then Td x 2 dosesThree doses, 6-12 months IPVThree doses, 6-12 months Hib (conjugate)Three doses, 6-12 months PneumococcalConjugated PCV*, three monthly doses, 3-6 months Then, PPV23 after 3 doses of PCV HepBThree doses, 6-12 months (for those with risk factors) MMR24 months ‡ Inactivated influenza†Yearly, 4-6 months Live-attenuated varicella vaccine -Varivax ¤ - Zostavax 24 months ‡ (limited data) CDC (2000): NO, EBMT (2005): NO, CIBMTR (2009): selected patients * 13-valent (PCV-13), 2011 revision † no safety data on the live, cold-adapted vaccine for intranasal administration ‡ serologic testing to determine need for vaccination (CIII) ¤ limited experience with use post-transplant; CII recommendation if >24 months post-transplant, without active GVHD, off immune suppression Ljungman P, et al. Bone Marrow Transplant 2009; CIBMTR - EBMT, CDC, ASBMT, IDSA ????

12 Current post-transplant guidelines recommend immunization of all patient groups at fixed time points post-HSCT. – Limited data on efficacy of this approach, particularly for recipients of alternative donors & “atypical” recipients (eg., cord blood, T-cell depleted grafts, reduced intensity regimens, advanced patient age, presence of GVHD and/or recipients of immunomodulatory agents)

13 Lang PO, et al. J of Aging Research 2012

14 Bosch M, Khan FM, S J. Curr Opin Hematol Delayed recovery of adaptive immunity

15 Striking delay in recovery of lymphocyte compartment, the “machinery” of the adaptive immune system – Cellular immune response: initiated by antigen presenting cells (eg., dendritic cells) & requires the activation of functional T cells* – Humoral immune response: mediated by antibodies & requires functional B (plasma & memory cells) and T cells* *Functional thymus required for generation of a diverse naïve T cell receptor repertoire

16 Vaccine variables Timing Dosage Doses Route (IM, subcutaneous, intradermal) Conjugate Pathogen encountered as natural infection (VZV) vs. as vaccination pre-transplant (HBV) vs naïve (pneumococcus) Host (donor/recipient) variables Age Preexisting immunity (donor* & recipient) Graft type Time post-transplant Immune suppressive regimen (conditioning & immune suppression) Monoclonal antibodies GvHD * Vaccination of the donor has been shown to improve recipient post- transplant immunity in the case of tetanus toxoid, PCV7 and H. influenzae type b-conjugate vaccines.

17 What are the milestones of immune competence? 3 doses of IPV (219) & 3 doses of HepB (292) vaccine, if: – CD4 > 200/µl – In vitro T-cell response to phytohemagglutinin (PHA) at least 75% of the lower limit of normal – IgG > 500mg/dL – Off systemic immunosuppressive therapy, minimal/no GVHD Median age 24 (range ) at time of transplant Vaccinated median 23.4 months post-transplant 65% MRD, 9% MMRD, 25% MUD; 65% T-cell depleted  64% developed protective hepatitis B titers older age & prior chronic GvHD associated with vaccine nonreponse poorest response in MMRD subset  96% developed a > 4-fold response to all 3 polio serotypes, including recipients of an unrelated and/or T-cell depleted HCT Jaffe D, et al. Blood 2006.

18 38 pediatric patients immunized according to the Royal College of Paediatrics and Child Health guidelines for transplant recipients – 3 monthly doses of DTP, IPV & Hib vaccine at 12 months: autologous (n=10), HLA-matched sib (n=8) 18 months: unrelated (n=20)  92% achieved protected titers to all 3 serotypes of polio  4-fold rise in tetanus titers in 94%  4-fold rise to H. influenzae titers in 86% (NO in vivo correlates) Patel SR, et al. Clin Infect Dis 2007.

19 127 HSCT recipients, adults & children ( ) – median age 23, range – 53% MRD, 5.5% MMRD, 42% MUD; 56% T-cell depleted – Of 53 unmodified HSCTs, 26% developed cGVHD, 32% on IS at time of vaccination  PCV7 (127) & HIB (115) vaccination – median 1.1 years post-transplant; 81% vaccinated within 2 years 62% (79/127) responded to PCV7: 88% children vs. 44% adults (P<.001) 86% (99/115) responded to HIB: 96% children vs. 79% adults (P=.006) In patients > age 50, 58% (11/19) vaccinated AFTER reaching minimal milestones of immune competence (CD4 > 200/µL, IgG > 500mg/dL, PHA within 60% lower limit normal) responded to PCV7, vs. 0/8 vaccinated prior to milestones (P=.006) Higher numbers of circulating CD4 + CD45RA + T cells improved response to PCV7. Pao M, et al. Biol Blood Marrow Transpl 2008.

20 Influenza vaccination Influenza vaccination within the first 6 months following HSCT is associated with a poor serologic response to vaccine antigens. Engelhard D, et al. Bone Marrow Transplant Addition of GM-CSF to influenza vaccine resulted in a minor improvement in response to influenza B vaccine in HSCT recipients Pauksen K, et al. Clin Infect Dis In non-transplant patients with hematologic malignancy, 2 doses of influenza vaccine were not more effective than one. Ljungman P, et al. Br J Haematol 2005.

21 CLINICAL EFFICACY of influenza vaccination 177 transplant recipients (118 allo, 71%) followed for 1 year – 134 were < 6 months post-transplant (unvaccinated)  25 (18.6%) developed influenza – 43 eligible for vaccination (> 6 months post- transplant) 19 vaccinated: 2/19 (10.5%) developed influenza 24 unvaccinated: 12/24 (50%) developed influenza  vaccine efficacy 80% (VE¼((r0–r1):r0) Machado CM, et al. Bone Marrow Transplant 2005.

22 The “over/under approach” to influenza vaccination No study has reported an increased risk for GVHD in association with influenza vaccination Data are limited, largely from heterogeneous groups of patients following traditional myeloablative conditioning Common practice: – Vaccinate yearly, beginning > 4-6 months post-transplant – Consider vaccination between 3-6 months post-transplant, in the context of widespread community activity, with a 2 nd dose at 6 months post-transplant Ensure vaccination of family members/close contacts of transplant recipients & healthcare workers (cocooning)

23 Influenza vaccine formulations Trivalent vaccines Inactivated vaccines – IM, all age >6 months – intradermal (licensed in 2011 for ages 18-64, uses 1/5 th the usual amount of vaccine antigens) – high-dose vaccine – licensed in 2009 for individuals > 65 (based on increased immunogenicity) Intranasal (LAIV) – master attenuated cold-adapted donor virus from which reassortments are generated with H & N antigens matching circulating strains – approved for ages 2-49 (healthy) – perhaps more effective than inactivated vaccine in children, equivalent in adults – contraindicated: immunocompromised patients, chronic illness (cardiac, pulmonary, DM, renal insufficiency), pregnant women, household members & providers with close contact with severely immunocompromised persons In 2012, the FDA approved a trivalent inactivated influenza vaccine produced in cultured mammalian cells (Flucelvax) for age > 18 AND quadrivalent formulations of inactivated and live-attenuated influenza vaccines

24 Pneumococcal vaccination in SCT recipients Superiority of conjugate vaccine – 64 donor/recipient pairs, randomized to PPV23 or PCV7 – Pre-transplant vaccination of donor & 6-month post- transplant vaccination of recipient Kumar D, et al. Clin Infect Dis % vs 38.6% 55.6% vs 90.9%, P=.02

25 Pneumococcal vaccination….is earlier better? 158 patients, 13 EBMT centers  PCV7 x 3 months or 9 months post-transplant Primary endpoint: antibody level > 0.15µg/mL for each serotype at 1 month after 3 rd dose of PCV7 Noninferiority margin 20%  early vaccination: 79%  late vaccination: 82% (P=0.64) % with positive titers to all 7 serotypes at 24 months post- transplant  early vaccination: 59%  late vaccination: 85% (P=0.013) cGVHD & older donor age associated with poor response 2011 update: – PCV13 as replacement for PCV7 Ljungman P, et al. Bone Marrow Transplant – Prospective open-label study underway WHO threshold for response: >0.35 µg/mL Cordonnier C, et al. Clin Infect Dis 2009.

26 Pneumococcal vaccine updates: “prime – boost” MMWR October 12, For patients who have previously received one or more doses of PPSV23, a single dose of PCV13 should be given one or more years after the last PPSV23 dose was received. For patients who require additional doses of PPSV23, the first such dose should be given no sooner than eight weeks after PCV13 and at least five years after the most recent dose of PPSV23.

27 Varicella zoster virus Studies of live attenuated varicella vaccine (LAVV) in children post-HSCT Chou JF, et al. Biol Blood Marrow Transplant Kussmaul SC, et al. Bone Marrow Transplant Sauerbrei A, et al. Bone Marrow Transplant  CIBMTR: LAVV can be used in “select patient populations”

28 Herpes zoster 20-59% of allogeneic recipients develop shingles within 5 years post-transplant Patient populationZoster incidence (per 1000 person-years) Older adults (>60)7-11 HSCT recipient200 (typically within 24 months) Hodgkin’s disease50-70 NHL25-50 Leukemia55-50 Multiple myeloma40-60 HIV/AIDS25-50 Solid tumor on chemotherapy 19 RA10-15 In 2006, Zostavax® was licensed for prevention of herpes zoster in healthy, immunocompetent adults > % fewer episodes of HZ 66.5% less PHN

29 Pilot study of Varilrix™ vaccination in 9 VZV-seropositive autologous HSCT recipients – 3-4 months post-transplant – 2/9 with vesicle formation at injection site – no systemic side effects – “overall strengthening in antigen-specific immune response post-vaccination”, as studied by lymphocyte proliferation (NO statistical difference) – 1/9 developed herpes zoster in follow-up (? 6 months) Ljungman P, et al. Support Care Cancer 2003.

30 67 year old man with DLBCL, s/p BuMelT- conditioned autologous SCT 2006, relapse in 2009, on replacement hydrocortisone for adrenal insufficiency VZV IgG+ pre-transplant Varivax in March 2010 (with MMR, HepB, and HepA vaccinations) June 2010  recurrent herpes zoster November 2010: cutaneous dissemination, pancytopenia with HPS, hepatitis (CD4 53 cells/mm 3 ) BM & liver biopsy with granulomas, skin biopsy grew VZV (vOka strain)  multiorgan system failure & death Bhalla P, et al. manuscript in preparation Kraft JN, Shaw JC. Varicella infection caused by Oka strain vaccine in a heart transplant recipient. Arch Dermatol 2006.

31 Heat-inactivated, live attenuated varicella-zoster vaccine Phase II study 111 autologous VZV- seropositive HSCT recipients – Vaccinated within 30 days pre- transplant, then at 30, 60, and 90 days post-transplant – Zoster in 7/53 vaccinated (13%) vs 19/58 unvaccinated (33%), P=0.01 – In vitro CD4 T-cell proliferation response to VZV was greater in vaccine recipients & correlated with protection from zoster Hata A, et al. N Engl J Med A Phase III, Double-Blind, Randomized, Placebo- Controlled, Multicenter Clinical Trial to Study the Safety, Tolerability, Efficacy, and Immunogenicity of V212 in Recipients of Autologous Hematopoietic Cell Transplants (HCTs), Merck V Vaccination prior to & at 1, 2, and 3 months post-transplant, 1:1 randomization, patients with history of primary varicella and/or VZV IgG enrolled, 83 confirmed cases of herpes zoster

32 Vaccines NOT recommended for the transplant recipient BCG (Bacillus Calmette-Guérin) (live) Oral poliovirus vaccine (live) Intranasal influenza vaccine (live) Cholera Typhoid, oral (live) Rotavirus (live, not licensed for adult use) Zostavax (live) Yellow fever vaccination contraindicated IF < 24 months, active GVHD, and/or on immunosuppression

33 Time Post-TransplantVaccineComments 3 monthsPCV13 6 monthsPCV13 12 monthsPCV13 HPVFemales and males age ≤ 26 years Hep A** IPV HBV Tdap HiB Meningococcal conjugate 14 monthsHep AOmit this dose for patients who did not receive initial dose at 12 months IPV HBV Td HiB 18 monthsPPSV23If cGvHD or ineligible by criteria £, substitute PCV13 Hep A IPV HBVCheck HBsAb 1-2 months after last HBV injection. If negative, repeat series with doses at 1, 2 and 6 months; consider double dose formulation Td HiB 24 monthsMMRPatient must meet dosing criteria to receive this immunization § AnnuallyInactivated influenza vaccine Vaccines to AvoidZostavax ® Live vaccine with high viral load Varivax ® Safety data not established Recommendations for Autologous and Allogeneic Transplant Recipients* *Vaccines should be given at indicated time points to all autologous and allogeneic transplant recipients except those with active stage III – IV GvHD; with active infections; or those receiving chemotherapy for relapse, AIHA, etc. **For recipients who are HepB or HepC positive or those with cGvHD of the liver, NASH, hemochromatosis, or other chronic liver disease, check Hepatitis A antibody titers at 12 months post-transplant. If negative, proceed with Hepatitis A vaccine £ Patient must meet all dosing criteria to receive PPSV23: IgG > 500, CD4 > 200 AND no to minimal immune activation as documented by immune reconstitution panel § Patient may receive this vaccine if off all immune suppression for at least one year, > 5 months since last IVIG infusion, IgG > 500, CD4 > 200 AND minimal to no immune activation as documented by immune reconstitution panel DRAFT: OHSU post-transplant vaccination schedule

34 What to do with the family? Vaccines to AVOID Intranasal influenza vaccine Oral poliovirus vaccine Vaccines that are okay, but…. Rotavirus vaccine – transplant recipient should avoid changing diapers for 2-4 weeks after vaccination Varivax™ – transplant recipients should avoid vaccinee if a rash develops within 3-6 weeks of vaccination Zostavax™ – transplant recipients should avoid vaccinee if a rash develops within 3-6 weeks of vaccination MMR Yellow fever vaccine

35 New vaccines on the horizon Heat-inactivated varicella-zoster virus vaccine CMV vaccine

36 CMV vaccine study CMV DNA vaccine (TransVax; Vical) before conditioning and at 1, 3, & 6 months post-transplant – Plasmids encoding glycoprotein B & pp65 CMV R+ 16 US transplant centers, NOT T-cell depleted 94 HSCT recipients & 14 paired donors Efficacy evaluation in 74 unpaired recipients 19/40 (48%) of vaccine recipients required CMV-specific antiviral therapy, vs. 21/34 (62%) controls, P = Kharfan-Dabaja MA, et al. Lancet Infect Dis 2012.

37 The future Optimization of post- transplant vaccination algorithms – Parallel assessments of in vitro parameters of immune reconstitution – Prospective study of immunization at fixed time points vs. as guided by immunologic milestones More, and more effective vaccines

38 Recent reviews of note Thom KA, et al. Infection prevention in the cancer center. Clin Infect Dis 2013;57: Baden LR, et al. Prevention and treatment of cancer-related infections. J Natl Compr Canc Netw 2012;10:


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