2 A none too infrequent story… 38 year old man with history of AML, s/p tBuCy MUD PBSCTcGVHD (skin, mouth, eyes)CMV reactivationavascular necrosis of shoulder off immune suppression as of 9 months post-transplantPresented 1 year post-transplant with fever, worsening sinusitis…..blood cultures with Streptococcus pneumoniae
3 Overview Post-transplant vaccinations New vaccines Vaccination schedules & strategiesImmunologic challenges of post-transplant vaccinationClose contacts of transplant recipientsNew 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 HSCTInvasive pneumococcal infections in 590/100,000 allogeneic & 199/100,000 autologous recipients per year, compared with 11.5/100,000 age-matched controlsKumar D, et al. Bone Marrow Transplant 2008.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 yearsLjungman P, et al. J Infect Dis 1990.In the absence of revaccination, the majority of allogeneic patients will become susceptible to measles, mumps & rubella by 3-5 years post-HSCTLjungman P, et al. Bone Marrow Transplant 2009.
6 Measles 2001-2010: 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 residentsMost (86%) were unvaccinated or had unknown vaccination status2 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 Seroepidemiologic survey in 156 BMT recipients 1997 measles outbreak in São Paulo: 20,185 cases in 11 monthsSeroepidemiologic survey in 156 BMT recipients122 NOT vaccinated: 76 were < 2 years post-transplant, 8 on immunosuppression, 38 non-compliant41 (34%) susceptible43/47 (92%) < 1 year post-transplant were immune, vs. 37/75 (51%) > 1 year post-transplantPersistence of host-derived humoral immunity for at least 6 months post-transplant32/34 vaccinated patients underwent serologic evaluation: 13/32 (41%) susceptible16/22 (73%) < 3 years post-vaccination were immune, vs. 3/10 (30%) > 3 years post-vaccination* Significant loss of measles immunity 3 years post-vaccination8/54 susceptible patients (IgG <100mIU/mL): attack rate 14.8%1 death from measles interstitial pneumoniaMachado 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 Oregon4 infant deaths in Oregon since 2003Oregon Public Health Division, Fact SheetMarch 2012
9 Reported Pertussis Cases In The US: Then 300Routine pertussis immunization begins250200Cases (Thousands)15010050192219301940195019601970198019902000YearMMWR 2002;51:73-76
10 And now…….3.5 week old girl admitted with coughing episodes, admitted April 17th (mother has cough) apnea, bradycardia, and hypoxia….required ECMO support, with secondary bacterial pneumonia
11 ???? Vaccine CIBMTR (2009) Tdap, then Td x 2 doses Three doses, 6-12 monthsIPVHib (conjugate)PneumococcalConjugated PCV*, three monthly doses, 3-6 monthsThen, PPV23 after 3 doses of PCVHepBThree doses, 6-12 months (for those with risk factors)MMR24 months‡Inactivated influenza†Yearly, 4-6 monthsLive-attenuated varicella vaccineVarivax¤Zostavax24 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 suppressionLjungman 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)
14 Delayed recovery of adaptive immunity Bosch M, Khan FM, S J. Curr Opin Hematol 2012.
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 Preexisting immunity (donor* & recipient) Graft type Vaccine variablesHost (donor/recipient) variablesAgePreexisting immunity (donor* & recipient)Graft typeTime post-transplantImmune suppressive regimen (conditioning & immune suppression)Monoclonal antibodiesGvHDTimingDosageDosesRoute (IM, subcutaneous, intradermal)ConjugatePathogen encountered as natural infection (VZV) vs. as vaccination pre-transplant (HBV) vs naïve (pneumococcus)* 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/µlIn vitro T-cell response to phytohemagglutinin (PHA) at least 75% of the lower limit of normalIgG > 500mg/dLOff systemic immunosuppressive therapy, minimal/no GVHDMedian age 24 (range ) at time of transplantVaccinated median 23.4 months post-transplant65% MRD, 9% MMRD, 25% MUD; 65% T-cell depleted 64% developed protective hepatitis B titersolder age & prior chronic GvHD associated with vaccine nonreponsepoorest 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 HCTJaffe D, et al. Blood 2006.
18 38 pediatric patients immunized according to the Royal College of Paediatrics and Child Health guidelines for transplant recipients3 monthly doses of DTP, IPV & Hib vaccine at12 months: autologous (n=10), HLA-matched sib (n=8)18 months: unrelated (n=20)92% achieved protected titers to all 3 serotypes of polio4-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 (2002-2005) median age 23, range53% MRD, 5.5% MMRD, 42% MUD; 56% T-cell depletedOf 53 unmodified HSCTs, 26% developed cGVHD, 32% on IS at time of vaccination PCV7 (127) & HIB (115) vaccinationmedian 1.1 years post-transplant; 81% vaccinated within 2 years62% (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 1993.Addition of GM-CSF to influenza vaccine resulted in a minor improvement in response to influenza B vaccine in HSCT recipientsPauksen K, et al. Clin Infect Dis 2000.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 year134 were < 6 months post-transplant (unvaccinated) (18.6%) developed influenza43 eligible for vaccination (> 6 months post-transplant)19 vaccinated: 2/19 (10.5%) developed influenza24 unvaccinated: 12/24 (50%) developed influenzavaccine 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 vaccinationData are limited, largely from heterogeneous groups of patients following traditional myeloablative conditioningCommon practice:Vaccinate yearly, beginning > 4-6 months post-transplantConsider vaccination between 3-6 months post-transplant, in the context of widespread community activity, with a 2nd dose at 6 months post-transplantEnsure vaccination of family members/close contacts of transplant recipients & healthcare workers (cocooning)
23 Influenza vaccine formulations Trivalent vaccinesInactivated vaccinesIM, all age >6 monthsintradermal (licensed in 2011 for ages 18-64, uses 1/5th 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 strainsapproved for ages 2-49 (healthy)perhaps more effective than inactivated vaccine in children, equivalent in adultscontraindicated: immunocompromised patients, chronic illness (cardiac, pulmonary, DM, renal insufficiency), pregnant women, household members & providers with close contact with severely immunocompromised personsIn 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 vaccine64 donor/recipient pairs, randomized to PPV23 or PCV7Pre-transplant vaccination of donor & 6-month post-transplant vaccination of recipientKumar D, et al. Clin Infect Dis 2007.0% 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-transplantPrimary endpoint: antibody level > 0.15µg/mL for each serotype at 1 month after 3rd dose of PCV7Noninferiority 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 responseWHO threshold for response: >0.35 µg/mL2011 update:PCV13 as replacement for PCV7Ljungman P, et al. Bone Marrow Transplant 2011.Prospective open-label study underwayCordonnier C, et al. Clin Infect Dis 2009.
26 Pneumococcal vaccine updates: “prime – boost” 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.MMWR October 12, 2012.
27 Varicella zoster virus Studies of live attenuated varicella vaccine (LAVV) in children post-HSCTChou JF, et al. Biol Blood Marrow Transplant 2011.Kussmaul SC, et al. Bone Marrow Transplant 2010.Sauerbrei A, et al. Bone Marrow Transplant 1997. CIBMTR: LAVV can be used in “select patient populations”
28 Herpes zoster20-59% of allogeneic recipients develop shingles within 5 years post-transplantPatient populationZoster incidence(per 1000 person-years)Older adults (>60)7-11HSCT recipient200 (typically within 24 months)Hodgkin’s disease50-70NHL25-50Leukemia55-50Multiple myeloma40-60HIV/AIDSSolid tumor on chemotherapy19RA10-15In 2006, Zostavax® was licensed for prevention of herpes zoster in healthy, immunocompetent adults > 6051.3% fewer episodes of HZ66.5% less PHN
29 Pilot study of Varilrix™ vaccination in 9 VZV-seropositive autologous HSCT recipients 3-4 months post-transplant2/9 with vesicle formation at injection siteno 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 VZV IgG+ pre-transplant 67 year old man with DLBCL, s/p BuMelT-conditioned autologous SCT 2006, relapse in 2009, on replacement hydrocortisone for adrenal insufficiencyVZV IgG+ pre-transplantVarivax in March 2010 (with MMR, HepB, and HepA vaccinations)June 2010 recurrent herpes zosterNovember 2010: cutaneous dissemination, pancytopenia with HPS, hepatitis (CD4 53 cells/mm3)BM & liver biopsy with granulomas, skin biopsy grew VZV (vOka strain) multiorgan system failure & deathBhalla P, et al. manuscript in preparationKraft 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 study111 autologous VZV-seropositive HSCT recipientsVaccinated within 30 days pre-transplant, then at 30, 60, and 90 days post-transplantZoster in 7/53 vaccinated (13%) vs 19/58 unvaccinated (33%), P=0.01In vitro CD4 T-cell proliferation response to VZV was greater in vaccine recipients & correlated with protection from zosterHata A, et al. N Engl J Med 2002.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 VVaccination prior to & at 1, 2, and 3 months post-transplant, 1:1 randomization, patients with history of primary varicella and/or VZV IgG+1259 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)CholeraTyphoid, 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 DRAFT: OHSU post-transplant vaccination schedule Time Post-TransplantVaccineComments3 monthsPCV136 months12 monthsHPVFemales and males age ≤ 26 yearsHep A**IPVHBVTdapHiBMeningococcal conjugate14 monthsHep AOmit this dose for patients who did not receive initial dose at 12 monthsTd18 monthsPPSV23If cGvHD or ineligible by criteria£, substitute PCV13Check HBsAb 1-2 months after last HBV injection. If negative, repeat series with doses at 1, 2 and 6 months; consider double dose formulation24 monthsMMRPatient must meet dosing criteria to receive this immunization§AnnuallyInactivated influenza vaccineVaccines to AvoidZostavax®Live vaccine with high viral loadVarivax®Safety data not establishedDRAFT: OHSU post-transplant vaccination scheduleRecommendations 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
34 What to do with the family? Vaccines to AVOIDVaccines that are okay, but….Intranasal influenza vaccineOral poliovirus vaccineRotavirus vaccine – transplant recipient should avoid changing diapers for 2-4 weeks after vaccinationVarivax™ – transplant recipients should avoid vaccinee if a rash develops within 3-6 weeks of vaccinationZostavax™ – transplant recipients should avoid vaccinee if a rash develops within 3-6 weeks of vaccinationMMRYellow fever vaccine
35 New vaccines on the horizon Heat-inactivated varicella-zoster virus vaccineCMV vaccine
36 CMV vaccine studyCMV DNA vaccine (TransVax; Vical) before conditioning and at 1, 3, & 6 months post-transplantPlasmids encoding glycoprotein B & pp65CMV R+ 16 US transplant centers, NOT T-cell depleted94 HSCT recipients & 14 paired donorsEfficacy evaluation in 74 unpaired recipients19/40 (48%) of vaccine recipients required CMV-specific antiviral therapy, vs. 21/34 (62%) controls, P = 0.145Kharfan-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 reconstitutionProspective study of immunization at fixed time points vs. as guided by immunologic milestonesMore, and more effective vaccinesTrials with clinical endpoints
38 Recent reviews of noteThom 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: