immunization of the immunocompromised host- what to know...
TRANSCRIPT
Immunization of the immunocompromised host-what to know & what to do?
26.11.2016
Klara M. Posfay-BarbeHead of Pediatric Infectious Diseases UnitDepartment of Pediatrics
Faculty of Medicine, University of Geneva
The plan
What to know
� Burden of vaccine-preventable diseases in IC patients
� Barriers to vaccination� Barriers to vaccination
� Immunogenicity: No response
� Safety: Risks
What to do
Where are the answers…
BURDEN OF VACCINE-PREVENTABLE DISEASES IN IMMUNOCOMPROMISED HOSTS
Immunocompromised patients
� Congenital immunodeficiency� B/T cell, T cell, phagocytic cell, complement, …
� Acquired immunodeficiency� HIV, high-dose immunosuppression,
chemotherapy, HSCT, SOT, …chemotherapy, HSCT, SOT, …
� Other� Hypo/asplenia, nephrotic syndrome, renal
insufficiency, liver disease, cyanotic heart disease, CF and lung failure, prematurity, …
� Or high / middle/ low immunosuppression?
University of Minnesota Medical School Duluth
Focosi D et al . Clin Microbiol Infect 2011; 17: 1759
MHC TCR
CD28CD80/86
CD40L CD40
CD20
APCB cell
Plasma cell
Abatacept
Rituximab
IL-6R
rIL-1Ra
anakinra
anti-Il-1β
IL-1βIL-1α
Belimumab
BAFF-R
BLys
TNF-α
TNF-R
IL-1R
IL-1Ra
IL-6R
BAFF-RTACI
Atacicept
APRIL
Mϕ Complement
C5
C5a
C5b C5-9
MAK
Eculizumab
Biologics
CD20 Rituximab
Tocilizumab
anti-IL-12/23
ustekinumab
anti-IL17
Mastocyte / Basophil
anti-Il-1β
Canakinumab
Rilonacept Etanercept
TNF-α
infliximab, adalimumab, golimumab
certolizumab
pegol
Th1
lymphocyte
IL-23
IL-23-R
IL-12-RIL-12
IL-17
Th17
lymphocyte
Omalizumab
FcεRI
IgE
IgE
VLA-4
VCAM-1
Natalizumab
Endothelium
Delaloye Cohen. Infectious Diseases. 4th Edition
High dose
Valente Pinto M J Infect 2016
Infection risk increases with combination of immunosuppressive drugs
2
2.5
3
3.5
ratio
0
0.5
1
1.5
2
Anti-TNF + >10 mg PDN
Anti-TNF + 5-10 mg PDN
Anti-TNF + <5 mg PDN
Anti-TNF alone No biologics
Odds
ratio
Grijalva C JAMA 2011
Burden of disease: Influenza
� UK
� 2009/10: 64% children who died of influenza
had an underlying condition (none vaccinated)
� 2014/15: 22% confirmed hospitalization= � 2014/15: 22% confirmed hospitalization=
children, and 27% of these had underlying
condition
� CH
� 2009/10: 38.7% admitted had an underlying
condition
Valente Pinto M J Infect 2016
Hagerman A SMW 2015
Risk of influenza in patients with
rheumatic disorders
RR: 1.2 RR: 1.2 RR: 1.8 RR: 1.8 RR: 1.8 RR: 1.7
Blumentals W. BMC Musculoskelet Disord. 2012
Burden of disease:
Pneumococcus� Invasive pneumococcal disease (IPD)
� Untreated HIV: risk ↑ 156.7x
� HAART-treated HIV: risk ↑ 16.7x
� 29.3% children < 5 yo had comorbidities of
which 33.9% = immunodeficiency
Payne H PIDJ 2015
Ladhani SN Emerg Inf Dis 2013
Risk of invasive pneumococcal disease in autoimmune disorders
in England
4
5
6
ratio
0
1
2
3
Crohn disease
Psoriasis Rheumatoid arthiritis
SLE Polymyositis
Ris
kra
tio
Wotton C et al. JECH 2012
Burden of disease:
Meningococcus� Especially if deficits in the complement
cascade (C3 or terminal pathway (C5-9))
� In particular, patients lacking the ability to
activate C3 and therefore create the activate C3 and therefore create the
membrane attack complex
� Risk ↑ 5’000-10’000x
� 40-50% recurrent disease
Fijen CA Clin Exp Immunol 1998
Figueroa JE Clin Microbiol Rev 1991
Burden of disease: VZV, MMR, rotavirus
VZV
� HAART-treated HIV: hospitalization risk ↑ 16 x (untreated: 150x)
� Anti-TNF treated children: hospitalization risk ↑ >10x>10x
MMR
� Risk ↑ but numbers lacking
Rotavirus
� Oncology patients: Increased hospital stay 12.6 days vs 5.0 days
� Transplant recipients: severe diseasePayne H PIDJ 2015Garcia-Doval I Ann Rheum Dis 2010Rayani A Scand J Gastroenterol 2007Cui H TID 2015
Burden of disease: SOT
recipientsVZVDisseminated infection is a rare, but can be life-
threatening:
� 2-34% severe disease
� Recurrent infection uncommon, < 5%
� 34% mortality in adult SOT in review (82% primaryinfection)
� Ped KTx (Boston): frequency = 10% (83 kids, 1979-1991) � 4 with visceral disease; 2 died
Kashtan CE J Pediatr 1997Rothwell WS Transplantation 1999Fehr T Transplantation 2002Strenfeld T JID 2010
Feldhoff CM J Pediatr 1981McGregor R Pediatrics 1989Lynfield R Pediatrics 1992Demir Z Pediatr Transplant 2016
Turner A Am J Transplant 2006Agamanolis DP Arch Neurol 1979Klapper PE Arch Dis Child 1991Kalman S Pediatr Transplant 2002Chitasombat MN J Med Ass Thai 2016
SOT recipientsMeasles (case reports)
� Transplanted organ rejection
� Seizures
� Measles-associated encephalopathy
� Subacute measles panencephalitis
Influenza (H1N1 pandemic)
� More severe disease: higher morbidity & mortality
� 70% hospital admission
� Pneumonia ~30%, admission to ICU 16–20%, mortality 5-10%� Children less likely to have pneumonia
Kashtan CE J Pediatr 1997Rothwell WS Transplantation 1999Fehr T Transplantation 2002Strenfeld T JID 2010
Feldhoff CM J Pediatr 1981McGregor R Pediatrics 1989Lynfield R Pediatrics 1992
Turner A Am J Transplant 2006Agamanolis DP Arch Neurol 1979Klapper PE Arch Dis Child 1991Kalman S Pediatr Transplant 2002
Watcharananan SP TID 2010Helanterä I AJT 2015Kumar D Lancet ID 2010
SOT recipients
Yellow fever
No cases reported in Tx recipients (to my knowledge)
TuberculosisTuberculosis
� The risk of TB in transplant recipients is estimated to be
20 to 50 x higher than in general population, even in
developed countries
� Mortality rates vary from 20 to 40%
� Higher in SOT than HSCT Aguado JM Transplantation 1997Munoz P CID 2005Singh N CID 1998
IMMUNOGENICITY OF VACCINES IN IMMUNOCOMPROMISED HOSTS
Serologic markers of vaccine protection
Vaccine Antibody titers
No protection
Partial protection
Lasting protection
Tetanus Anti-toxin
(IU/l)
< 100 ≥ 100 ≥ 1000
Hib IgG anti-PRP
(mg/l)
< 0.15 ≥ 0.15 ≥ 1
(mg/l)
HBV IgG anti-HBs
(IU/l)
<10 ≥ 10 ≥ 100
Measles EIA IgG anti-
measles (IU/l)
< 50 50-149 ≥ 150
Rubeola IgG anti-
rubeola (IU/l)
< 10 ≥10
VZV IgG VZV or gp
VZV (IU/l)
< 50 50-149 ≥ 150
OFSP-CFV 2012 Bulletin OFSP n°21
Immunogenicity
� Often reduced immunogenicity compared to healthy controls
� MenC & asplenia, BMTx, HIV
� PCV7: OK response usually, but dependent of Tx � PCV7: OK response usually, but dependent of Tx
organ
� PCV13: few studies, seems OK
� PPV23: less effective + hyporesponsiveness with
repeat doses
Baliner P Infect Immun 2004Mahler MB Biol Blood Marrow Transplant 2012Lujan Zilbermann J JPeds 2012
Fletcher MA, Expert Rev Vaccines 2015Steele AD PIDJ 2011
InfluenzaHigher memory responses in HIV-infected and kidney transplanted patients than in healthy subjects following
priming with the pandemic vaccine.Siegrist CA, van Delden C, Bel M, Combescure C, Delhumeau C, Cavassini M, Clerc O, Meier S, Hadaya K, Soccal PM, Yerly S, Kaiser L, Hirschel B, Calmy
A; H1N1 Study Group.; Swiss HIV Cohort Study (SHCS) PLoS One. 2012
Responses of solid organ transplant recipients to the AS03-adjuvanted pandemic influenza vaccine.Siegrist CA, Ambrosioni J, Bel M, Combescure C, Hadaya K, Martin PY, Soccal PM, Berney T, Noble S, Meier S, Posfay-Barbe K, Grillet S, Kaiser L, van
Delden C; H1N1 study group. Antivir Ther. 2012
Protective antibody responses to influenza A/H1N1/09 vaccination in children with celiac disease.Schäppi MG, Meier S, Bel M, Siegrist CA, Posfay-Barbe KM; H1N1 Study Group.J Pediatr Gastroenterol Nutr. 2012Schäppi MG, Meier S, Bel M, Siegrist CA, Posfay-Barbe KM; H1N1 Study Group.J Pediatr Gastroenterol Nutr. 2012
All of the children with CD reached protective antibody titers (≥40) and showed a geometric mean titer comparable with the control group (530 vs 573).
Strong serological responses and HIV RNA increase following AS03-adjuvanted pandemic immunization in HIV-infected patients.
Calmy A, Bel M, Nguyen A, Combescure C, Delhumeau C, Meier S, Yerly S, Kaiser L, Hirschel B, Siegrist CA; H1N1 Study Group.HIV Med. 2012
Graft-versus-host disease is the major determinant of humoral responses to the AS03-adjuvanted influenza A/09/H1N1 vaccine in allogeneic hematopoietic stem cell transplant recipients.
Mohty B, Bel M, Vukicevic M, Nagy M, Levrat E, Meier S, Grillet S, Combescure C, Kaiser L, Chalandon Y, Passweg J, Siegrist CA, Roosnek E; Blood and
Marrow Transplant Program.; Geneva University Hospitals H1N1 study group Haematologica. 2011
Impact of synthetic and biologic disease-modifying antirheumatic drugs on antibody responses to the AS03-adjuvanted pandemic influenza vaccine: a prospective, open-label, parallel-cohort, single-center study.
Gabay C, Bel M, Combescure C, Ribi C, Meier S, Posfay-Barbe K, Grillet S, Seebach JD, Kaiser L, Wunderli W, Guerne PA, Siegrist CA; H1N1 Study
Group. Arthritis Rheum. 2011
Influenza vaccine & cancer
treatment100 children� seroprotection and seroconversion rates :
� 55% and 43% for H3N2, � 61% and 43% for H1N1, � 41% and 33% for B strain
� Overall, there was a significant geometric mean fold increase � Overall, there was a significant geometric mean fold increase to H3N2 (GMFI 4.56, 95% CI 3.19-6.52, P < 0.01) and H1N1(GMFI 4.44, 95% CI 3.19-6.19, P < 0.01) strains
� Seroconversion was significantly more likely:� with solid vs. hematological malignancies � <10 years of age who received a two-dose schedule compared
to one
� Influenza infection occurred in 2% of the vaccinated study population, compared with 6.8% in unvaccinated controls
� Adjusted estimated vaccine effectiveness of 72% (95%CI -26-94%).
Kotecha RS Cancer Med 2016
Metanalysis influenza & SOT
Karbasi-Afshar R Saudi J Kidney Dis Transpl 2015
MMF vs other
All
Tacrolimus vs other
All
Karbasi-Afshar R Saudi J Kidney Dis Transpl
Different immunosuppressivetreatments, different response
Timing of vaccination after rituximab
and influenza vaccine response
67 patients with lymphoma receiving
rituximab <6 months
Yri OE Blood 2011
Timing of vaccination after rituximab
and influenza vaccine response
300
350
400
tite
rof
173 adult patients receiving the influenza A
/H1N1 pdm adjuvanted vaccine
0
50
100
150
200
250
300
< 12 weeks 12-24 weeks > 24 weeks
pre vaccination
after 1st dose
after 2nd dose
Geom
etr
icm
ean
tite
r
HA
I
Gabay C Arthritis Rheum 2011
Seroresponse & medication
� Immune-modulators: more strongly associated with reduced antibody response =
� Rituximab
� Mycophenolate mofetil (MMF)
Smith KG Nephrol Dial Transplant 1998Salles MJ Clin Transplant 2010Puissant-Lubrano B Exp Clin Transplant 2010Kapetanovic MC Arthritis Res Ther 2014
Efficacy of influenza vaccine in “at
risk” patients
� Between ~15% - >50%
� « Risk » with inactivated vaccine: no seroresponse to vaccinationseroresponse to vaccination
� Until there is influenza in the community, you can/should vaccinate!
Dominguez A Expert Rev Vacc 2016
Immunogenicity of MenC vaccine in
SOT recipients10 pediatric kidney and/or liver transplant
recipients
Zlamy M Vaccine 2011
Immunogenicity of the meningococcal
B vaccine
Santolaya ME Lancet 2012
Intervention studies in SOT1st author Year Patient N Vaccine Best seroconversion
rate
Rand 1993 Ped OLT 18 Measles or MMR 41% measles
Zamora 1994 Ped KT 17 VZV 75% VZV
Kano 2002 Ped OLT 15 MMR/VZV
(re-immunization!)
85% measles
100% mumps & rubella
2008rubella
71% VZV
Chaves 2005 Ped KT 6 VZV 66.6% VZV
Weinberg 2006 Ped OLT
& IT
16 VZV 87% VZV
Khan 2006 Ped OLT 31 MMR
35 VZV
MMR/ VZV 73% measles
64.5% VZV
Shinjoh 2008 Ped OLT 18 M,M,R
VZV
100 % Measles, rubella43 or 86 % mumps
87 % VZV
Daners
eau
AM
W J
Pedia
tr2008
Intervention studies ≥ 20121st author Year Patient N Vaccine Best seroconversion
rate
Posfay-
Barbe
2012 Ped OLT 36 VZV 100 % VZV
Kulcsár 2013
(poster)
Ped OLT 36 VZV 100 % VZV
Shinjoh 2015 Ped OLT 48
(18 above)
M, M, R
VZV
100 % measles, rubella
75 % mumps(18 above) VZV 75 % mumps
81 % VZV
Kawano 2015 Ped OLT 19-28 MR, M, R, M,
VZV
44-100% M, M, R
32-50% VZV
NIAID Finished
2015
Adult
KTx
34 Zoster vaccine N/A … yet
Kumar ongoing Adult
KTx
~40 Zoster vaccine N/A
Posfay-
Barbe
ongoing Ped OLT ~40 MMR ~ 97.2 % measles
GSK Not recruiting
Adult
KTx
265
planned
Zoster vaccine N/A
Not published: Clinicaltrials.gov; ESPID book of abstract
VZV vaccine efficacy/ waning
Barb
e A
m J
Tra
nspla
nt 2012
pro
tectio
n
before afterfollow-upPed LTN= 36
After 1-3 vaccine dose(s), all patients had protective antibody titersMedian Ig titer 21 UI/L � 1135 UI/L (P<0.001)
97% were seroprotected at follow-up -median 1.7 years after immunization
Posfa
y-B
arb
e A
m J
Tra
nspla
nt 2012
pro
tectio
n50
VZV antibody UI/L
97.4%
MMR
Ped LT
Seroresponse to MMR primary vaccination
Posfay-Barbe, preliminary data
N= 40
Ped LT
N= 40
Mea
sles
-sp
ecif
ic I
gG t
iter
[IU
/L]
1000
10000P<0.001
P<0.001P=0.008
P=0.002
protection
Seroresponse MeaslesIg
G m
ea
sle
s-s
pecific
UI/L
Mea
sles
-sp
ecif
ic I
gG t
iter
[IU
/L]
Baseline after primary dose(s) 1-year follow-up after booster10
100
150
n
Inclusion After vaccination
150
1 year later
� After 1-3 dose(s), 97.4%97.4% of patients had protective antibody
responses
� 100% of patients responded to booster 1 year later
After booster
IgG
me
asle
s
Pittet LF, …,Posfay-Barbe, ms in writing
Other live vaccines in IC hosts
� Rotavirus:
� SCID patient: severe gastroenteritis & prolonged
shedding; HIV similar to controls
� VZV:
� breakthrough rash: HIV: 2/97; rheum 3/25 (MTX
+/- CS); leukemia 36%
� MMR:
� HIV:OK; 9-18 mo after BMTx: OK
Patel NC, NEJM 2010; Levin MJ JID 2006Pileggi GS Arthritis Care Res 2010Gershon AA JAMA 1984
Seth A PIDJ 2016Machado CM Bone Marrow Transplant 2005
SAFETY OF VACCINES IN IMMUNOCOMPROMISED HOSTS
Safety of immunizing IC patients
� Non-live vaccines: No specific safety issues� Live vaccines� Poor or no response
� Interaction with antibodies (maternal, IVIG, …)� Severe or fatal effect if uncontrolled replication of
vaccine virusvaccine virus� Mutation leading to reversion to original pathogenic form� Polio vaccine: 1/750’000 doses in healthy population� Yellow fever vaccine: vaccine-associated viscerotropic
disease & neurologic disease: 0.4 and 0.8 cases/100’000 doses, respectively
� Prolonged sheddingSiegrist CA J Comp Pathol 2007
� Vaccinate only beforeimmunosuppression
Rubin LG, CID 2014: 2013 IDSA Clinical Practice guideline for vaccination
of the immunocompromised host
VZV vaccine safety
� Frequency of local / systemic side effect
similar to healthy children (local: 54.8%; systemic: 64.5%)
� No change in liver function tests
� Only 1 rejection episode: >1 year after
immunizationimmunization (bad compliance with immunosuppressive therapy)
Before immunizationAfter immunization
Posfay-Barbe Am J Transplant 2012
0
5
10
15
20
25
30
35
40
45
ASAT ALAT Gamma-GT Bilirubine
Med
ian
AST ALT GGT
Bilirubin
Delay of administration of live vaccines in patient on immunosuppression
Drug Delay of administration
Steroids>2 weeks and > 20 mg/d
1 month
Azathioprine6-MPCyclosporin A
3 months
Cyclosporin AMMFCyclophosphamideTacrolimus
Sulfasalazine, Hydroxychloroquine No
Methotrexate 3 months
Leflunomide 2 years
Anti-TNF and other biologics 3 months
Etanercept 1-3 months
Rituximab 12 months
WHERE TO FIND THE ANSWERS
Fact sheet
At risk patients vaccination:
myvaccines.ch
1.
2.
3.
To see recommended vaccines, click on next vaccines Viavac
Viavac offers catch-up strategy
In blue, vaccines that can be given immediatelyClick and directly entered with today’s date
To print vaccine booklet and missing doses
IN SUMMARY
Primary immunodeficiencies
Combined B/T cell
Reduced T cell
Phagocytic cell
Complement deficiency
« Routine »
inactivated
Effectiveness?
IVIG?
MMR
Rotavirus
Avoid BCG
Rotavirus
BCG
VZV
Additional
inactivated
PCV13 Men ACWY
Men B
PCV13
Influenza Flu
Household VZV & Flu
Acquired immunodeficienciesHIV High-dose
immunosuppression
Chemotherapy
HSCT SOT
« Routine »
inactivated
VL<50
&CD4≥15%
for 6 mo
Before if
possible
Not during
induction or
consolidation
; 6 mo after
chemo
>1mo before
HSCT; 6-12
mo after (if
no IVIG)
>1 mo
before IS
MMR
Rotavirus
BCG
MMR : If
CD4≥15% ;
Rota=OK
Avoid BCG
Restart ≥ 6
mo after
treatment
Restart ≥ 6
mo after
treatment
Restart >18-
24 after
HSCT
VZV If CD4≥15%
Additional
inactivated
PCV13
Hep B
PCV
Men ACWY
+/-B
PCV
Influenza Flu
Household VZV & Flu
OtherHypo/asplenia
Nephrotic sy
Renalinsuff
Liver dis Cyanotic ♥
CF&lung failure
Premie
« Routine
»
inactivated
Chronolo
gical age
MMR
Rotavirus
During
remissionRotavirus
BCG
remission
VZVIf on
aspirin
Additional
inactivated
Men
ACWY
+ B
PCV13
PCV13 PCV13
HepB
PCV13
Hep A&B
PCV13
Influenza Flu
Household VZV/ Flu Flu
