Update: Vaccines in primary immunodeficiency

doi:10.1016/j.jaci.2017.12.980

Journal of Allergy and Clinical Immunology

Volume 141, Issue 2, February 2018, Pages 474-481

https://doi.org/10.1016/j.jaci.2017.12.980 Get rights and content

Vaccines were originally developed to prevent or ameliorate infectious disease. As knowledge of immune function and appreciation of immunodeficiency has developed, researchers have used vaccine responses as a tool to characterize the phenotypes of patients exhibiting various syndromes. Thus it has become possible for a clinician to evaluate individual responses to vaccines to interrogate the immunocompetence of their patients. Although there have been many advances in these areas, we still have much to learn about the quantity and quality of humoral and cellular vaccine responses in healthy and immunodeficient subjects and how that knowledge can then be extrapolated to diagnostic purposes. Adverse effects of vaccines have been recognized for many years, especially the occurrence of infections caused by viable vaccine organisms in immunodeficient hosts. Nevertheless, vaccines are essential for disease prevention in immunodeficient patients, just as they are for healthy subjects. Clinicians must understand the appropriate and safe use of vaccines in patients with immunodeficiency. This review highlights some recent advances and ongoing challenges in application of vaccines for the diagnosis and treatment of immunodeficiencies.

Section snippets

Diagnostic use of vaccines for PIDs

Vaccine efficacy is established through reduction of the incidence of infection in vaccine recipients. The predominant surrogate marker for vaccine efficacy is production of specific IgG. This is appropriate in most cases because neutralizing or opsonizing antibody represents a principal protective mechanism induced by natural infection. This is also convenient because measurement of blood antibody levels is technically (relatively) simple and inexpensive.

The predictive value of diminished

Human papillomavirus vaccine

A variety of innate and adaptive cellular immunodeficiencies are associated with increased susceptibility to human papillomavirus (HPV) infection.³⁹ These include severe combined immunodeficiency (SCID); Wiskott-Aldrich syndrome; ataxia-telangiectasia; nuclear factor κB essential modulator deficiency; leukocyte adhesion deficiency (CD18 mutation); X-linked hyper-IgM syndrome; disseminated warts, immunodeficiency, lymphedema, anogenital dysplasia (WILD) syndrome; epidermodysplasia verruciformis

BCG

In patients with PIDs, most attention related to adverse events related to immunization involve administration of viable vaccines (Table I). This is borne out in one retrospective study of all vaccine-related adverse events in a fairly large cohort of 379 patients at a single center.⁵⁴ In this report 15 definite or probable vaccine adverse events were recorded. Nine (60%) of these involved live agent vaccines. Among these, 7 involved BCG.

The attenuated tuberculosis vaccine BCG (Mycobacterium

Conclusion

Educated and judicious vaccine use for immunoprophylaxis and in some cases for disease treatment are as critical for health maintenance in patients with PIDs as for all persons. Systematic study of normal vaccine responses will help refine their diagnostic use for PIDs. This is especially so for polysaccharide antigen responses, which remain challenging to characterize clinically, even in healthy subjects. It might be necessary to modify existing assays or develop new ones to realize this goal.

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Inborn errors of immunity (IEI) that present with recurrent infections are largely due to antibody (Ab) deficiencies. Therefore, assessment of the B-cell and Ab compartment is a major part of immunologic evaluation. Here we provide an overview about cellular assays used to study B-cell function and focus on lymphocyte proliferation assay (LPA), opsonophagocytic assay (OPA), and the Enzyme-linked Immunosorbent Spot Assay (ELISPOT) including clinical applications and limitations of these techniques. LPAs assess ex-vivo cell proliferation in response to various stimuli. Clinically available LPAs utilize peripheral blood mononuclear cells and mostly assess T-cell proliferation with pokeweed mitogen considered the most B-cell specific stimulus. In the research setting, isolating B cells or using more B-cell specific stimuli such as CD40L with IL-4/IL-21 or the TLR9 ligand CpG can more specifically capture the proliferative ability of B cells. OPAs are functional in-vitro killing assays used to evaluate the ability of IgG Ab to induce phagocytosis applied when assessing the potency of vaccine candidates or along with avidity assays to evaluate the quality of secreted IgG. The B-cell ELISPOT assesses Ab production at a cellular level and can characterize the Ab response of particular B-cell subtypes. It can be used in patients on IgG therapy by capturing specific Abs produced by individual B cells, which is not affected by exogenous IgG from plasma donors, and when assessing the vaccine response in patients on immunomodulatory drugs that can affect memory B-cell function. Emerging approaches that are only available in research settings are also briefly introduced.
Development and validation of a microfluidic multiplex immunoassay for the determination of levels and avidity of serum antibodies to tetanus, diphtheria and pertussis antigens
2022, Journal of Immunological Methods
Citation Excerpt :
One of the laboratory-based tools to evaluate suspected humoral immunodeficiencies is the assessment of antigen-specific immune responses towards both protein and polysaccharide vaccine antigens (Orange et al., 2012; Marsh and Orange, 2019). Antibody responses towards tetanus or diphtheria toxoids are often used to determine a patient's ability to mount an immune response towards protein antigens, because they are potent immunogens with high seroconversion rates (Chouksey and Berger, 2008; Bonilla, 2018). This evaluation can be supplemented with other vaccine antigens such as pertussis, since the conclusions about the patient's ability to respond will be more valid when more different antigens are evaluated (Chouksey and Berger, 2008).
A multiplex assay for the quantitation of immunoglobulin G (IgG) serum antibodies directed against Clostridium tetani toxin (TT), Corynebacterium diphtheriae toxoid (DTxd), and the Bordetella pertussis antigens pertussis toxin (PT), filamentous hemagglutinin (FHA) and pertactin (Prn) was developed on an Evalution® platform to enhance the evaluation of the specific antibody response towards protein antigens in suspected humoral immunodeficiencies. Evalution® is a microfluidic and microparticle-based platform with the possibility to analyse single samples and to perform real-time kinetic measurements of antibody binding. All individual antigens were covalently linked to the carboxylated microparticles after which samples and fluorescently labelled detection antibodies were flowed over the microparticles in the microfluidic channels of the assay cartridges of the system. The developed assay showed very good sensitivity, specificity, and intra- and inter-assay coefficients of variation (CVs for the different antigens between 1.72-3.53% and 3.54‐5.79%, respectively). Furthermore, the correlation of the Evalution pentaplex with a Luminex pentaplex using a panel of 48 human serum samples was excellent, with Spearman correlation coefficients between 0.936 for PT and 0.982 for DTxd (p < 0.0001 for all). Finally, we showed in a proof-of-concept experiment the potential of the Evalution® platform to simultaneously measure concentrations and binding kinetics (as a surrogate for avidity) of the IgG antibodies to the selected protein antigens. Overall, these findings show that this new Evalution pentaplex can accurately measure the antibody response to TT, DTxd, PT, FHA and Prn. It also has the potential to measure antibody binding and dissociation kinetics.
Pneumococcal serotype-specific cut-offs based on antibody responses to pneumococcal polysaccharide vaccination in healthy adults
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Citation Excerpt :
Data on pneumococcal antibody responses from different laboratories show considerable variability in interpretation of data [29,30]. A prospective study would be required to ascertain whether the proposed serotype threshold provides greater sensitivity in identifying patients with defects in antibody response to pneumococcal polysaccharides, either due to a global humoral defect, or specific antibody deficiency [2-4,6]. Most of the pneumococcal vaccines available and in development are conjugate vaccines, which instigate a T-dependent antibody response, as opposed to the polysaccharide vaccine (Pneumovax®), which promotes a T-independent type 2 antibody response.
Antibody responses to pneumococcal polysaccharide vaccination are frequently used as a diagnostic tool for humoral immunodeficiencies, part of the larger collection of inborn errors of immunity. Currently, arbitrary criteria, such as a serotype specific titer of >/= 1.3 µg/mL is most often used as a cut-off for interpretation of pneumococcal antibody responses. The magnitude of the antibody response to each of the 23 serotypes in Pneumovax®, and serotype-specific cut-offs in healthy pneumococcal vaccine-naïve adults has not been previously characterized. IgG antibody concentrations were measured prospectively for 23 pneumococcal serotypes pre and 4–6 weeks post-Pneumovax® vaccination in 100 healthy adults, using a multiplex bead-based assay. Antibodies to 19 of 23 serotypes were informative for distinguishing subjects who responded to vaccination, and the serotype threshold was determined to be 9 of 19 serotypes, which characterized an antibody response to pneumococcal vaccination. While this study may facilitate classification of IgG serotype-specific antibody responses post-pneumococcal vaccination in adult patients undergoing diagnostic immunological evaluation for antibody immunodeficiencies or other relevant contexts, additional studies in healthy children and S. pneumoniae protein-conjugate-vaccinated healthy adults will need to be undertaken in the future.
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TCRαβ/CD19-depleted HCT has been used with excellent outcomes in pediatric patients with hematologic malignancies, and several studies have demonstrated rapid immune reconstitution in the nonmalignant setting. However, immune recovery following TCRαβ/CD19-depleted hematopoietic cell transplantation (HCT) for malignancy remains incompletely elucidated. Furthermore, the majority of studies to date have used haploidentical and matched unrelated donors. Here we report results of immune reconstitution following TCRαβ/CD19-depleted HCT for hematologic malignancy in 51 pediatric patients with hematologic malignancies, the majority of whom received grafts from unrelated donors. Grafts were from matched unrelated (n = 20), mismatched unrelated (n = 20), and haploidentical (n = 11) donors. The median CD34⁺ cell dose was 10.2 × 10⁶/kg (range, 4.54 to 20 × 10⁶/kg), and the median TCRαβ⁺ cell dose was 2.53 × 10⁴/kg (range, 0 to 44.9 × 10⁴/kg). Conditioning was myeloablative with either busulfan or total body irradiation, cyclophosphamide, and thiotepa. Thirty-three patients also received rabbit antithymocyte globulin. No prophylactic post-transplantation immune suppression was routinely given. Forty-three patients received rituximab on day +1 for recipient positive Epstein-Barr virus serology.
Forty-nine patients (96%) engrafted with a median time to neutrophil recovery of 13 days (range, 8 to 30 days). Thirty-seven patients (73%) are alive at a median follow-up of 25 months (range, 6 to 50 months). Nine patients (18%) developed grade II-IV acute graft-versus-host disease (GVHD), and 5 patients (11%) developed extensive chronic GVHD. Twenty-six patients (51%) experienced viral reactivation. T cell reconstitution was rapid with significant numbers of CD3⁺, CD4⁺, and CD8⁺ T cells present on first assessment at 4 months post-HCT, and significant numbers of naïve CD4⁺ T cells were present by 8 months post-HCT. Chronic GVHD was associated with delayed T cell recovery; however, T cell reconstitution was not affected by underlying diagnosis, donor source, TCRαβ⁺ T cell dose, conditioning regimen, or use of antithymocyte globulin. B cell recovery mirrored T cell recovery, and i.v. Ig was discontinued at a median of 8 months (range, 4 to 22 months) post-HCT in patients alive and relapse-free at last follow-up. Immune reconstitution is rapid following TCRαβ/CD19-depleted HCT in pediatric patients with hematologic malignancies. Donor graft source, haploidentical or unrelated, did not affect immune reconstitution. Viral reactivation is common in the first 100 days post-HCT, indicating that improved T cell defense is needed in the early post-HCT period.

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: Disclosure of potential conflict of interest: F. A. Bonilla has a board membership with the Louis August Jonas Foundation; has consultant arrangements with Grand Rounds Health, the Immune Deficiency Foundation, Charles River Associates International, Green Cross, Parexel, Sarepta Inc, Cowen Group, Gerson-Lehrman Group, Grifols, and Huron Consulting Group; has received a grant from Shire, Inc; has received payment for lectures from Albany Medical College and Drexel University; and has received royalties from UpToDate.

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Reviews and feature articleUpdate: Vaccines in primary immunodeficiency

Section snippets

Diagnostic use of vaccines for PIDs

Human papillomavirus vaccine

BCG

Conclusion

J Infect

J Allergy Clin Immunology Pract

J Autoimmun

Ann Allergy Asthma Immunol

J Allergy Clin Immunol

Blood

Ann Allergy Asthma Immunol

Vaccine

Ann Allergy Asthma Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Clin Immunol

Vaccine

Vaccine

Vaccine

Vaccine

J Allergy Clin Immunol

J Allergy Clin Immunol Pract

Vaccine

Clin Immunol

Clin Immunol

Clin Immunol

Clin Immunol

Vaccine

J Allergy Clin Immunol

J Microbiol Immunol Infect

J Allergy Clin Immunol

Vaccine

Vaccine

Clin Microbiol Infect

Vaccine

Vaccine

Vaccine

Measles and measles vaccination: a review

JAMA Pediatr

Recommendations for live viral and bacterial vaccines in immunodeficient patients and their close contacts

J Allergy Clin Immunol

Practice parameter for the diagnosis and management of primary immunodeficiency

J Allergy Clin Immunol

Different immunological pathways underlie the immune response to pneumococcal polysaccharides

J Clin Immunol

Travel advice for the immunocompromised traveler: prophylaxis, vaccination, and other preventive measures

Ther Clin Risk Manag

Routine vaccination practice after adult and paediatric allogeneic haematopoietic stem cell transplant: a survey of UK NHS programmes

Bone Marrow Transplant

Measurement of pneumococcal polysaccharide antibodies

J Clin Immunol

Measurement of pneumococcal polysaccharide vaccine responses for immunodeficiency diagnostics: combined IgG responses compared to serotype specific IgG responses

J Clin Immunol

Reviews and feature article
Update: Vaccines in primary immunodeficiency