Active immunization in immunocompromised hosts Presented by Pannipa Kittipongpattana, MD. September27, 2019

1. Active Immunization in
Immunocompromised Host
Pannipa Kittipongpattana, MD
27 September 2019
Pediatric Allergy and Immunology Department
King Chulalongkorn Memorial Hospital

2. References
2013
2018
2014
J Allergy Clin Immunol 2015;136:1186-205, e1-78.

3. Outlines
- Introduction
- Diagnostic use of vaccine
- Tetanus and diphtheria toxoid
- Pneumococcal vaccine
- Other vaccines and natural exposure
- Therapeutic use of vaccine
- Harm of vaccine in immunocompromised host
- Level of immunosuppression
- Timing of vaccination for ‘planned’ immunosuppression
- Efficacy and recommendation from guidelines
- Summary

4. Introduction

5. Vaccination in Normal Host
Wild pathogen
Live attenuated
vaccine
Non-viable
vaccine

6. Live-attenuated vaccine
Wild-type
pathogens are
virulent to human
Scientists culture them in a new ‘home(s)’
(tissue, cell, animal). In time, the pathogens
‘drop’ (mutate) their virulence factors and
become less hostile.
Vaccine-type
pathogens are
less virulent and
can still stimulate
host immunity.
Example: MMR, VZV, Yellow fever, Rotavirus, OPV, BCG, Smallpox, influenza
(nasal)

7. Non-viable vaccine
Killed / Inactivated
vaccine
Toxoid / Inactivated
toxoid vaccine
Subunit / Conjugate
vaccine
IPV, Hepatitis A, Rabies,
Anthrax, Influenza, JE
Diphtheria, Tetanus
HBV, HPV, HiB, Pertussis,
Pneumococcal, Meningococcal,
Typhoid

8. Vaccination in Immunocompromised Host
Wild pathogen
Live attenuated
vaccine
Non-viable
vaccine
?
?
?
?

9. Active immunization in immunodeficiency
Diagnosis
- To assess type and degree of immune response
Therapeutic (Prophylaxis)
Consideration
- May be less effective in immunodeficient patient
- May be harmful in immunodeficient patient

10. Diagnostic use
of vaccines
for Primary Immunodeficiency

11. How vaccines train our immune system?
Abbas et al, Cellular and Molecular Immunology 9th edition
JACI 2012;130:S1-24.
Vaccine
T-cell
dependent
HIB conjugate ✓
Meningococcal conjugate ✓
Meningococcal polysaccharide ❌
Pneumococcal conjugate ✓
Pneumococcal polysaccharide ❌
Rabies ✓
Tetanus ✓

12. Middleton's Allergy: Principles and Practice, 8th Edition, 3, 30-44 Abbas et al, Cellular and Molecular Immunology 9th edition

13. Fold increase
Assessment of Humoral Immune Response
Reduce
incidence
of infection
Seroconversion %
Achieve
protective level
No cut-point for
immunocompromised
Data not available for
all vaccine even in
healthy population
Limitation
Irrelevant for non-B-cell defect immunodeficiency
(e.g. phagocyte, complement)

14. Bonilla FA. Update: Vaccines in primary immunodeficiency. J Allergy Clin Immunol 2018;141:474-81.

15. Seroconversion 100% 1-mo after 2nd/3rd dose
Seroconversion 98-100% after 3rd dose
Seroconversion 95-100% after 2nd dose
Seroconversion 95-99% at 15-mo
Seroconversion 83-97% after 3rd dose
Seroconversion 63--98% after 3rd dose
Seroconversion 99-100%
after 1-2 dose

16. Tetanus & Diphtheria toxoid vaccines
High seroconversion rate
100% at 1-mo after 2nd-3rd dose
Most normal host has
Ab > protective level
(> 0.1-0.2 IU/mL)
Ab level can increase
upto x 20-30 fold
after another booster
Initially low Ab level in fully
immunized subject should
predict immunodeficiency
Lower end of normal response
is not well defined
Usual assay does not read
beyond 7 IU/mL
Fold increase after booster
has limited role in diagnosis

17. Pneumococcal conjugate and polysaccharide vaccines
Cell
membrane
Peptidoglycan
cell wall
Polysaccharide
capsule
Polysaccharide vaccine
Conjugated vaccine
CRM
197Diphtheria toxin
T-cell independent
= less immunogenicity
T-cell dependent
= more potent and
immune last longer
Use for assess humoral
immune response

18. Evaluation of humoral immune response with PPSV23
Result to evaluate
- Before and after antibody level of each serotype
- Number and % of serotypes that response
- Fold increase
- Protective level
Factor to consider
- Age
- Under 2-year: unpredictable response
- Over 6-year: consistently good response
- High baseline level → less fold-increase, usually < 4x
- History of prior PCV-13
≥ 1.30 μg/mL protects against mucosal infection
≥ 0.35 μg/mL protects against invasive infection

19. The current state of the use of pneumococcal vaccines in PID diagnosis
Sorensen et al. Specific Antibody Deficiencies in Clinical Practice. J Allergy Clin Immunol Pract 2019;7:801-8
Orange et al. Use and interpretation of diagnostic vaccination in PID. JACI 2012;130:S1-24.

20. X
X
X
X
X
X
X
X Sorensen et al. Specific Antibody Deficiencies in Clinical Practice. J Allergy Clin Immunol
Pract 2019;7:801-8
Lab Siriraj
Girl 3-year old

21. Girl 3-year old
Protective
titer
= 50%
X2 fold
increase
= 62%
1
2 3 4 5

22. Neoantigens
Assessment of humoral immune response in patient
receiving IVIg
- Passively acquired pathogen or vaccine-specific IgG confounds the
results of the most commonly used assays (tetanus and diphtheria
toxoid and pneumococcal polysaccharide)
- Require antigen not frequently found in normal population
“Neoantigens”
- non-EPI vaccine
- Non common pathogen
Bonilla FA. Update: Vaccines in primary immunodeficiency. J Allergy Clin Immunol 2018;141:474-81.

23. Neoantigens
Orange et al. Use and interpretation of diagnostic vaccination in PID. JACI 2012;130:S1-24.

24. Orange et al. Use and interpretation of diagnostic vaccination in PID. JACI 2012;130:S1-24.

25. Therapeutic use
of vaccines
for Immunocompromised host

26. Practice parameter for the diagnosis and management of PID
21
“ Live vaccines should not be administered
to patients with severely impaired specific immunity ”
● Attenuated vaccines + severely immunocompromised patients → disseminated disease
● Live rotavirus vaccine + SCID (before their diagnosis) → severe diarrhea
● Should also be withheld in milder PIDs because lack of vigorous study
● Risk is low in some situations (e.g. partial DGS)
● IVIg provides circulating antibodies against polio, MMR, and varicella
● MMR and varicella vaccines would be inactivated if given to patients receiving IVIg.
○ After IVIG dose (300-800 mg/kg), MMR or varicella immunization should be delayed by 8 months.
○ After high-dose (2 g/kg) infusion → delayed by 11 months
Bonilla et al. Practice parameter for the diagnosis and management of primary immunodeficiency.
J Allergy Clin Immunol 2015;136:1186-205, e1-78.

27. 22
“Non-viable vaccines can be administered
to immunocompromised patients”
● no risk of disease
● There might be some protective immunity even in immunocompromised hosts
● Especially for pathogen that IVIg may not cover, such as influenza
● Immunization beyond routine guidelines in some circumstances:
○ patients with phagocytic cell defects and complement deficiency
Practice parameter for the diagnosis and management of PID
Bonilla et al. Practice parameter for the diagnosis and management of primary immunodeficiency.
J Allergy Clin Immunol 2015;136:1186-205, e1-78.

28. V
S

29. Redbook 2018-2021 (31st Edition). Immunization in special clinical circumstances. P.72-90
SOBH AND BONILLA.Vaccination in Primary Immunodeficiency Disorders. J Allergy Clin Immunol Pract 2016;4:1066-75
Degree of susceptibility to infection
High Modest
Severe CID or SCID
Severe antibody deficiency
e.g. agammaglobulinemia, CVID
Mild antibody deficiency
e.g. specific antibody deficiency
Primary innate immunity defect e.g. phagocyte defect Primary complement deficiency
HIV with
- CD4+ < 200/mm3 for adult
- CD4+ < 15% for children
Asymptomatic HIV with
- CD4+ ≥ 200/mm3 for adult
- CD4+ ≥ 15% for children
Prednisolone ≥ 20 mg/d (or > 2mkd in BW <10 kg)
for ≥ 14 d
Lower dose of prednisolone
Methotrexate > 0.4 mg/kg/week Methotrexate ≤ 0.4 mg/kg/week
Azathioprine > 3 mkd Azathioprine ≤3 mkd
6-mercaptopurine > 1.5 mkd 6-mercaptopurine ≤ 1.5 mkd
Immune modulator agents e.g. TNF antagonists, Autoinflammatory / Immune dysregulation
Anti lymphocyte monoclonal antibodies
Cancer chemotherapy
2-month after solid organ transplant

30. BCG Bacille bilié de Calmette-Guérin
Contraindication
- Combined immunodeficiency
- Phagocytic cell defects
- Patients receiving immunosuppressive therapy
- Mendelian susceptibility to mycobacterial
disease (defects of the IFN-gamma/IL-12 axis)
** Humoral deficiency is also contraindication
in Redbook & Middleton 8th edition,
but not mentioned in practice parameter PID 2015 **
SOBH AND BONILLA.Vaccination in Primary Immunodeficiency Disorders. J Allergy Clin Immunol Pract 2016;4:1066-75
Bonilla FA. Update: Vaccines in primary immunodeficiency. J Allergy Clin Immunol 2018;141:474-81.
- Live attenuated Mycobacterium bovis
- Many reports of disseminated disease
after BCG in severely
immunocompromised.
- Significant localized disease (eg, axillary
lymphadenopathy) or a family history of
serious complications of BCG
immunization is a potential warning sign
of an underlying PID.

31. MMR and VZV vaccines
- Serious infections from these vaccines have been recognized in severe CMI defects.
- Contraindication
- SCID
- Complete DiGeorge syndrome
- Patients with severe immunosuppression should not receive the vaccine.
- May be safe in B cell immunodeficiency
- May be safe and effective in children with milder forms of T-cell defects, such as partial
DiGeorge syndrome
- But unlikely benefit in patients receiving IVIG replacement
SOBH AND BONILLA.Vaccination in Primary Immunodeficiency Disorders. J Allergy Clin Immunol Pract 2016;4:1066-75
Bonilla FA. Update: Vaccines in primary immunodeficiency. J Allergy Clin Immunol 2018;141:474-81.

32. J Allergy Clin Immunol. 2010 Oct;126(4):868-9.

33. Bonilla et al. Practice parameter for the diagnosis and management of primary immunodeficiency.
J Allergy Clin Immunol 2015;136:1186-205, e1-78.
Complete DGS: naive T cells < 50 cells/μL
Partial DGS: naive T cells > 50 cells/μL
Practice parameter for the diagnosis and management of PID
Patients with DGS or CHARGE syndrome should be evaluated
to define the degree of immunodeficiency. Live vaccines do
not pose a risk to most patients with DGS, but they should not be
administered without evidence of normal T-cell responses to
mitogens and antigens and normal responses to nonviable vaccines.

34. Criteria for MMR and varicella vaccine (not MMRV) in DiGeorge syndrome (DGS)
Complete DGS: → Avoid all live vaccines
Reference Criteria for live viral vaccines for partial DGS
Middleton 8th edition Avoid all live vaccines
Practice parameter
PID 2015
1.normal of T-cell responses to mitogens and antigens AND
2.normal responses to nonviable vaccines
JACI 2018 1.good response to nonviable vaccines AND
2.normal/near-normal in vitro T-cell response to mitogens and recall antigens AND
3.CD4 cell counts > 500 cells/mm3 AND
4.CD8 T-cell counts > 300 cells/mm3
Redbook 2018 1.Normal mitogen response AND
2.CD3 T-cell counts ≥ 500 cells/mm3 AND
3.CD8 T-cell counts ≥ 200 cells/mm3IDSA 2013

35. Rotavirus vaccine
- Contraindicated in SCID
- No reports of disease caused by this vaccine in other populations, but it is also
generally considered to be contraindicated in other severe immune defects such as
- Severe antibody deficiency (Agammaglobulinemia, CVID)
- HIV infection
- Severe immunosuppression due to medication
* Redbook 2018: Precaution in children with altered immunocompetent (Other
than SCID), no data for Severe antibody deficiency
** Middleton 8th Ed: no contraindication in antibody deficiency
SOBH AND BONILLA.Vaccination in Primary Immunodeficiency Disorders. J Allergy Clin Immunol Pract 2016;4:1066-75

36. OPV: Oral Polio Vaccine
- Causing severe diarrhea and paralytic disease in severe immunocompromised
- Contraindication
- Combined immunodeficiency
- Severe antibody deficiency
- Phagocytic cell dysfunction
- Innate immune defects: STAT1 deficiency and patients receiving immunosuppressive
therapy should not receive oral polio vaccine.
- Contraindication also extends to household contacts of these patients.***
SOBH AND BONILLA.Vaccination in Primary Immunodeficiency Disorders. J Allergy Clin Immunol Pract 2016;4:1066-75
Bonilla FA. Update: Vaccines in primary immunodeficiency. J Allergy Clin Immunol 2018;141:474-81.

37. Household members
of immunocompromised patients
JACI 2016/2018 Redbook 2018 IDSA 2013
Inactivated vaccines Recommended as usual schedule Recommended as usual schedule or for travel
Live vaccine Recommended as usual schedule
Immunocompromised patients should
avoid contact with people who develop
skin lesions after Varicella/Zoster vaccine
***and receive zoster immunoglobulin***
Recommended as usual schedule
Immunocompromised patients should avoid contact
with people who develop skin lesions after
Varicella/Zoster vaccine
LAIV contraindicated if the patient has SCID or within
2-month of HSCT or has GVHD
OPV CONTRAINDICATION CONTRAINDICATION

38. V
S

39. Influenza virus vaccine
- Annual influenza vaccine is recommended unless considered
incapable of any response (e.g. severe CID, SCID,
agammaglobulinemia)
- Most patients will not exhibit normal antibody production
- Patients with CVID also showed decreased cellular immune
responses
- Additional measures (eg,medication prophylaxis during outbreaks)
might be necessary to prevent influenza morbidity
Bonilla FA. Update: Vaccines in primary immunodeficiency. J Allergy Clin Immunol 2018;141:474-81.

40. Human papillomavirus vaccine (HPV)
- In one study, the HPV vaccine achieve 89% - 100% type-specific
seroconversion rates in immunosuppressed children:
- Solid-organ or stem cell transplantation
- Immunomodulators for autoimmune conditions
- WHIM syndrome
- HIV infection
- Patients might exhibit improvement in cutaneous warts after vaccination
- Should be used routinely except when there is no capacity for response
Bonilla FA. Update: Vaccines in primary immunodeficiency. J Allergy Clin Immunol 2018;141:474-81.

41. Immunization in distinct categories
- IVIg therapy
- Planned immunosuppression
- Specific diseases
- Combined immunodeficiency
- Antibody deficiency
- Immune dysregulation, rheumatic or autoinflammatory diseases
- Phagocytic cell defects
- Innate immunity
- Complement deficiency

42. Patients receiving immunoglobulin therapy
- IVIg provides protective levels of antibody included in routine vaccination
- tetanus and diphtheria toxoids, measles, varicella, pertussis, pneumococci, and 3
of the common meningococcal serotypes (not type C)
- One study (N=23) in CVID patients receiving IgG
- Response to peptide/conjugate vaccine was 23%
- Response to pneumococcal polysaccharide vaccine was 18%
- Another study (N=23) in CVID patients, 65% achieved protective responses to
meningococcal polysaccharide (which had been replaced by conjugate vaccine)
Patient may has response to vaccine, but clinical benefit is doubtful
Bonilla FA. Update: Vaccines in primary immunodeficiency. J Allergy Clin Immunol 2018;141:474-81.

43. Adverse Reactions to Vaccines for Infectious Diseases. Middleton 8th edition

44. Patients receiving systemic steroid
- Steroid < 20 mg or < 2 mg/kg → vaccination as usual
- Steroid > 20 mg or > 2 mg/kg
- For < 14 days: defer until termination of steroid or 2 weeks later
- For > 14 days: preferably 2 weeks before, and 4 weeks after termination
SOBH AND BONILLA.Vaccination in Primary Immunodeficiency Disorders. J Allergy Clin Immunol Pract 2016;4:1066-75
Non-viable vaccine could be given through out treatment duration
Live vaccine should not be given
High dose steroid > 14 days
weeks

45. Other immunosuppressive therapy including biologic agents
- Low-level immune suppression: vaccines may be given safely
- methotrexate ≤ 0.4 mg/kg/wk
- azathioprine ≤ 3 mg/kg/d
- 6-mercaptopurine ≤ of 1.5 mg/kg/d
- In patients receiving higher doses of the drugs listed above or TNF-a antagonists, anti-B-
lymphocyte mAbs, or cancer chemotherapy
SOBH AND BONILLA.Vaccination in Primary Immunodeficiency Disorders. J Allergy Clin Immunol Pract 2016;4:1066-75
Redbook 2018-2021 (31st Edition). Immunization in special clinical circumstances. P.72-90
?????
?????
Non-viable vaccine could be given
through out treatment duration
Live vaccine should not be given
Immunosuppressive
- Rituximab, at least 6 months and often much longer after the last dose.
weeks

46. Combined immunodeficiency
● Inactivated vaccines
○ no benefit in children with SCID because
■ no adequate response
■ usually on IVIg
○ In mild CID (residual Ab response and not on IVIg) may benefit from
inactivated vaccines → so they are recommended as routine schedule
● Live vaccines
○ Contraindicated in SCID
○ May be well tolerated in milder syndromes, e.g. MMR and Varicella
vaccine in DiGeorge syndrome with CD4 > 500 cells/mm3
○ Insufficient data for other specific mild combined disorders or vaccines.
SOBH AND BONILLA.Vaccination in Primary Immunodeficiency Disorders. J Allergy Clin Immunol Pract 2016;4:1066-75

47. Antibody deficiency
Minor antibody deficiency
- selective IgA deficiency
- specific antibody deficiency with normal immunoglobulins
- IgG subclass deficiency
Antibody response may be decreased, but still achieve
protective level and safe
EXCEPT: Oral polio vaccine → always contraindicated
SOBH AND BONILLA.Vaccination in Primary Immunodeficiency Disorders. J Allergy Clin Immunol Pract 2016;4:1066-75

48. Antibody deficiency
Major antibody deficiency:
- CVID
- Agammaglobulinemia
- Almost always receiving immunoglobulin therapy. So, most routine inactivated
vaccines are not effective or unnecessary
- Exception
- (1) IVIg may not contains antibodies to the circulating strains (influenza)
- (2) Vaccine may induce some beneficial cellular immunity
- Live vaccines are contraindicated
SOBH AND BONILLA.Vaccination in Primary Immunodeficiency Disorders. J Allergy Clin Immunol Pract 2016;4:1066-75

49. Immune Dysregulation & Autoinflammatory diseases
Concern regarding immunization
- triggering autoimmunity or a flare up in predisposed individuals
- many clinical trials in SLE or RA have concluded that influenza and
pneumococcal vaccines are safe, but may produce lower responses
- frequent use of immunosuppressive therapy
Live vaccines are generally contraindicated
in patients receiving high risk immunosuppressive therapy
SOBH AND BONILLA.Vaccination in Primary Immunodeficiency Disorders. J Allergy Clin Immunol Pract 2016;4:1066-75

50. Phagocytic cell defects
- Non-viable vaccines → routine schedule
- Inactivated influenza vaccine is especially important in CGD to prevent
staphylococcal co-infection
- Live bacterial vaccines (e.g. BCG, oral salmonella vaccine) → AVOID
- Live viral vaccines
- should be given to patients with CGD or neutropenia
- contraindicated in patients with LAD or cytotoxic granule defects
(e.g. Chediak-Higashi syndrome) because of associated lymphocyte
cytotoxic functions defect.
SOBH AND BONILLA.Vaccination in Primary Immunodeficiency Disorders. J Allergy Clin Immunol Pract 2016;4:1066-75

51. Complement deficiency
All vaccines are safe and effective in these patients
Additional immunization: encapsulated bacteria
- Streptococcus pneumoniae
- Haemophilus influenzae
- Neisseria meningitidis
SOBH AND BONILLA.Vaccination in Primary Immunodeficiency Disorders. J Allergy Clin Immunol Pract 2016;4:1066-75
http://microbe-canvas.com

52. Other innate immune defects
Non-viable vaccines are safe and effective → give according to routine schedule
IRAK4- and MyD88-deficient patients are → pneumococcal vaccine
Congenital asplenia → encapsulated bacteria
Defects in
- IL-12-INF-gamma axis → contraindicated to live bacterial vaccines
- type 1 INF-a/b pathways → contraindicated to live viral vaccines
- NFκ-B pathways → contraindicated to ALL live vaccines
SOBH AND BONILLA.Vaccination in Primary Immunodeficiency Disorders. J Allergy Clin Immunol Pract 2016;4:1066-75

53. SOBH AND BONILLA.Vaccination in Primary Immunodeficiency Disorders. J Allergy Clin Immunol Pract 2016;4:1066-75
A = no harm, benefit likely C = may harm, benefit unlikely
B = no harm, benefit unlikely D = may harm, benefit likely
E = therapeutic benefit

54. SOBH AND BONILLA.Vaccination in Primary Immunodeficiency Disorders. J Allergy Clin Immunol Pract 2016;4:1066-75
A = no harm, benefit likely C = may harm, benefit unlikely
B = no harm, benefit unlikely D = may harm, benefit likely
E = therapeutic benefit

55. SOBH AND BONILLA.Vaccination in Primary Immunodeficiency Disorders. J Allergy Clin Immunol Pract 2016;4:1066-75
A = no harm, benefit likely C = may harm, benefit unlikely
B = no harm, benefit unlikely D = may harm, benefit likely
E = therapeutic benefit

56. SOBH AND BONILLA.Vaccination in Primary Immunodeficiency Disorders. J Allergy Clin Immunol Pract 2016;4:1066-75
A = no harm, benefit likely C = may harm, benefit unlikely
B = no harm, benefit unlikely D = may harm, benefit likely
E = therapeutic benefit

57. SOBH AND BONILLA.Vaccination in Primary Immunodeficiency Disorders. J Allergy Clin Immunol Pract 2016;4:1066-75
A = no harm, benefit likely C = may harm, benefit unlikely
B = no harm, benefit unlikely D = may harm, benefit likely
E = therapeutic benefit

58. Adverse Reactions to Vaccines for Infectious Diseases. Middleton 8th edition

59. Adverse Reactions to Vaccines for Infectious Diseases. Middleton 8th edition