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

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

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

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 2008. Lessons from 2009 H1N1

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 1990. 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.

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 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. 2012 Apr;61:253-7.

Seroepidemiologic survey in 156 BMT recipients 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 were immune, vs. 37/75 (51%) > 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 were immune, vs. 3/10 (30%) > 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.

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

Reported Pertussis Cases In The US: Then 300 Routine pertussis immunization begins 250 200 Cases (Thousands) 150 100 50 1922 1930 1940 1950 1960 1970 1980 1990 2000 Year MMWR 2002;51:73-76

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

???? Vaccine CIBMTR (2009) Tdap, then Td x 2 doses Three doses, 6-12 months IPV Hib (conjugate) Pneumococcal Conjugated PCV*, three monthly doses, 3-6 months Then, PPV23 after 3 doses of PCV HepB Three doses, 6-12 months (for those with risk factors) MMR 24 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

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)

Lang PO, et al. J of Aging Research 2012

Delayed recovery of adaptive immunity Bosch M, Khan FM, S J. Curr Opin Hematol 2012.

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

Preexisting immunity (donor* & recipient) Graft type Vaccine variables Host (donor/recipient) variables Age Preexisting immunity (donor* & recipient) Graft type Time post-transplant Immune suppressive regimen (conditioning & immune suppression) Monoclonal antibodies GvHD Timing Dosage Doses Route (IM, subcutaneous, intradermal) Conjugate Pathogen 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.

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 0.2-69.0) 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.

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.

127 HSCT recipients, adults & children (2002-2005) median age 23, range 0.1-64 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.

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 recipients Pauksen 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.

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.

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 2nd dose at 6 months post-transplant Ensure vaccination of family members/close contacts of transplant recipients & healthcare workers (cocooning)

Influenza vaccine formulations Trivalent vaccines Inactivated vaccines IM, all age >6 months intradermal (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 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

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 2007. 0% vs 38.6% 55.6% vs 90.9%, P=.02

Pneumococcal vaccination….is earlier better? 158 patients, 13 EBMT centers  PCV7 x 3 @ 3 months or 9 months post-transplant Primary endpoint: antibody level > 0.15µg/mL for each serotype at 1 month after 3rd 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 WHO threshold for response: >0.35 µg/mL 2011 update: PCV13 as replacement for PCV7 Ljungman P, et al. Bone Marrow Transplant 2011. Prospective open-label study underway Cordonnier C, et al. Clin Infect Dis 2009.

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.

Varicella zoster virus Studies of live attenuated varicella vaccine (LAVV) in children post-HSCT Chou 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”

Herpes zoster 20-59% of allogeneic recipients develop shingles within 5 years post-transplant Patient population Zoster incidence (per 1000 person-years) Older adults (>60) 7-11 HSCT recipient 200 (typically within 24 months) Hodgkin’s disease 50-70 NHL 25-50 Leukemia 55-50 Multiple myeloma 40-60 HIV/AIDS Solid tumor on chemotherapy 19 RA 10-15 In 2006, Zostavax® was licensed for prevention of herpes zoster in healthy, immunocompetent adults > 60 51.3% fewer episodes of HZ 66.5% less PHN

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.

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 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/mm3) 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.

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 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 V212-001 Vaccination 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

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

DRAFT: OHSU post-transplant vaccination schedule Time Post-Transplant Vaccine Comments 3 months PCV13 6 months 12 months HPV Females and males age ≤ 26 years Hep A** IPV HBV Tdap HiB Meningococcal conjugate 14 months Hep A Omit this dose for patients who did not receive initial dose at 12 months Td 18 months PPSV23 If cGvHD or ineligible by criteria£, substitute PCV13 Check HBsAb 1-2 months after last HBV injection. If negative, repeat series with doses at 1, 2 and 6 months; consider double dose formulation 24 months MMR Patient must meet dosing criteria to receive this immunization§ Annually Inactivated influenza vaccine Vaccines to Avoid Zostavax® Live vaccine with high viral load Varivax® Safety data not established DRAFT: OHSU post-transplant vaccination schedule 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

What to do with the family? Vaccines to AVOID Vaccines that are okay, but…. Intranasal influenza vaccine Oral poliovirus vaccine 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

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

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+ adults @ 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 = 0.145 Kharfan-Dabaja MA, et al. Lancet Infect Dis 2012.

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 Trials with clinical endpoints

Recent reviews of note Thom KA, et al. Infection prevention in the cancer center. Clin Infect Dis 2013;57:579-585. Baden LR, et al. Prevention and treatment of cancer-related infections. J Natl Compr Canc Netw 2012;10:1412-1445.