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 New vaccines
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 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 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.

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 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. 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.

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
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

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 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

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. 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 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.

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 (2002-2005)
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 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.

21. CLINICAL EFFICACY of influenza vaccination
177 transplant recipients (118 allo, 71%) followed for 1 year
134 were < 6 months post-transplant (unvaccinated)  (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 2nd 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 1/5th 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

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 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-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.

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-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”

28. 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

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. 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.

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 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 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+
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)
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. 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

34. 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

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 = 0.145
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
Trials with clinical endpoints

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: