Immunodeficiencies Evaluated with Diagnostic Vaccination

  • CVID
  • Specific antibody deficiency (SAD) aka selective IgG deficiency
    • Normal total Ig levels, normal tetanus/diphtheria (protein) and conjugate vaccine (Hib, PCV13) response, deficient PPSV23 response; sometimes transient in early childhood
    • SAD may be isolated or a component of:
      • Transient hypogammaglobulinemia of infancy
      • IgG1,2, or 3 subclass deficiency
      • Selective IgA deficiency
      • Wiskott Aldrich syndrome
      • Partial DiGeorge syndrome
      • HIV
      • Splenic deficiencies
  • XLA and other immunodeficiencies with absence of B-cell development
  • T-cell immunodeficiency




Pneumococcal Diagnostic Vaccination

Vaccines and Serotypes

pneumococcal vaccine serotypes.png

  • Converting serotypes from American to Danish nomenclature:
American
Danish
1
1
3
3
4
4
8
8
9
9N
12
12F
14
14
19
19F
23
23F
26
6B
51
7F
56
18C
57
19A
68
9V

  • Acronyms (trade names)
    • PPSV23 or PPV23 – pneumococcal polysaccharide vaccine 23-valent (Pneumovax)
    • PCV7 – pneumococcal conjugate vaccine 7-valent (Prevnar) - replaced by PCV13 in 2010
    • PCV13 – pneumococcal conjugate vaccine 13-valent (Prevnar13)

  • To strictly assess novel polysaccharide response in patients that have been given PCV but have never had PPSV23:
    • in PCV7-immunized patients: serotypes 1, 3, 5, 7F, 8, 9N, 12F
    • in PCV13-immunized patients: serotypes 8, 9N, 12F

  • Immediate repeat booster doses of PPSV23 are ineffective and might promote hyporesponsiveness
    • Initial vaccination with PPSV23 may hinder response to subsequent vaccination with PCV13, therefore if PCV13 needs to be given after PPSV23 it should be deferred for at least 1 year
    • Initial vaccination with PCV13 does not hinder response to subsequent vaccination with PPSV23 and may in fact cause a priming effect that bolsters vaccination, but a deferring PPSV23 for at least 8 weeks after PCV13 is still recommeded


Antibody Response in Children <2 Years Old

1_year_old_PPSV23.png

  • No consensus for definition of an adequate response to PPSV23 under 2 years old, but many toddlers will have good responses to at least several types
    • From the above data, 1 year old infants (2 weeks post vaccination with PPSV23) have best response to serotypes 2, 3, 8 and least response to serotypes 6B, 14, 23F
    • Conversely, older adults >58 years old have best response to serotype 14 and worst response to serotype 3
  • Ballow: nonconjugate polysaccharide vaccines should not be a component for the routine investigation of antibody deficiency in children <18 months while they are receiving their primary immunization series


Meningococcal Diagnostic Vaccination


Vaccines and Serotypes

  • Menomune (MPSV4), Menactra (MCV4), and Menveo (MCV4) are quadrivalent and all contain Neisseria meningitides serogroups A, C, Y, and W-135
    • Studies have demonstrated a reduced response to a second dose of MPSV4 vaccine compared with a previously unimmunized group
    • Children <2 may not be able to respond well to MPSV4, and an immune response similar to what has been found in adults is not achieved until 4-5 yo



Neoantigen Diagnostic Vaccination

Neoantigens.png



Protein Antigen Diagnostic Vaccination

  • Tetanus and diptheria toxoid vaccines
  • Current tetanus toxoid vaccines are immunogenic in all immunocompetent subjects, irrespective of age (from birth), with a protective 5-year time span in 95% of the population
  • Immunocompromised subjects (e.g. transplantation (solid organ or bone marrow), receive chemotherapy, or HIV) will demonstrate variable response to tetanus toxoid antigen, depending on the degree of immunosuppression


Protein-conjugated Diagnostic Vaccination

  • Includes PCV13, MCV4, HIB
  • Bonilla:
    • PCV13 protective level is 0.35 µg/mL (vs. 1.3 µg/mL for PPSV23) likely due to higher avidity antibodies produced by the T-dependent (vs. T-indpendent) mechanism
    • HIB response (PRP antibody titer) checked <2 years old because it is clinically important to have adequate immunity and I boost if it is low. I don’t look in older people because I’m not convinced it has any additional impact on the evaluation of immunocompetence.



Interpretation



Overview

Characteristics diagnostic vaccines.png

PPSV23 Vaccination

Protective level
1.3 µg/mL
  • Controversial; 1.3 is a consensus value that has been used in several studies, but 1.6 µg/mL has been used in other studies, and some commercial laboratories use 1-2 µg/mL
  • In healthy subjects <65 yo given PPSV23, levels decline to prevaccination levels in 5 years (>65 yo, in 2 years)
  • Note:
    • After vaccination with a pneumococcal conjugate vaccine (Prevnar), the protective level is 0.35 µg/mL likely due to higher avidity antibodies produced by the T-dependent mechanism
    • Ballow: If a patient has a baseline 70% of pneumo serotypes tested at levels 1.3 µg/mL or greater, I do not give a Pneumovax, and consider the patient immune competent at least for this vaccine
Adequate response to PPSV23 vaccination
  • 24 mo - 5 years: at least 2-fold increase to >1.3 µg/mL in 50% of serotypes

  • 6 - 65 years: at least 2-fold increase to >1.3 µg/mL in 70% of serotypes
  • Antibody titers to a minimum of 12-14 serotypes including serotypes present in PCV7, PCV13, and/or PPV23, should be performed 4-8 weeks after pneumococcal vaccination
  • Interpretation of the response to vaccination when the preimmunization titer is greater than 1.3 µg/mL is not entirely clear
    • In children and adults with a protective pre-vaccine antibody titer (>1.3 µg/mL) a 2-fold response may be considered a normal response
    • Only 10-40% of patients attained a 4-fold response when the initial titer was >1.3 µg/mL
    • The probability of a 4-fold response approaches zero if the initial titer is between 4.4-10.3 µg/mL, depending on the serotype
  • If someone has a very low pre-immunization level and has a 2-4 fold rise in titer, but the final level is still <1, then that would still be scored as a “non-response”


MPSV4 Vaccination

Protective level
2 µg/mL

Adequate response to MPSV4 vaccination
  • 2-4 fold or greater of at least 2 serotypes
  • This has not been rigorously studied in relation to the workup of the immune system and in the diagnosis of immunodeficiency
  • Levels are expected to peak around 4 weeks after vaccination


PPSV23 Response Phenotypes

PPSV23 response deficiency phenotypes.png

Normal Seroconversion Rates (Bonilla)

Vaccine
Normal seroconversion rate
Tetanus
100% 1 mo after 3rd dose, all ages
Diphtheria
99% 1 mo after 3rd dose, all ages
Hep B (HBSAg)
98-99% after 3 doses
Polio (IPV)
95-100% after 2 doses (varies by type)
Measles
95-99% after single dose at 15 mo, 100% after 2 doses
Mumps
95-99% after single dose at 15 mo, 100% after 2 doses
Rubella
95-99% after single dose at 15 mo, 100% after 2 doses
Varicella
95 after single dose, 100% after 2 doses
HIB conjugate
80-100%
Prevnar (PCV13)
64-98%, varies with serotype
Pneumovax (PPSV23)
  • 25-100% have 2-fold rise in titer
  • 0-100% have 4-fold rise in titer
  • Varies widely with serotype
Menactra (MCV4)
50-100%, varies with serotype
Menomune (MPSV4)
30-100%, varies with serotype




Reference