Use and interpretation of diagnostic vaccination in primary immunodeficiency: A working group report of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma & Immunology

Abstract

A major diagnostic intervention in the consideration of many patients suspected to have primary immunodeficiency diseases (PIDDs) is the application and interpretation of vaccination. Specifically, the antibody response to antigenic challenge with vaccines can provide substantive insight into the status of human immune function. There are numerous vaccines that are commonly used in healthy individuals, as well as others that are available for specialized applications. Both can potentially be used to facilitate consideration of PIDD. However, the application of vaccines and interpretation of antibody responses in this context are complex. These rely on consideration of numerous existing specific studies, interpolation of data from healthy populations, current diagnostic guidelines, and expert subspecialist practice. This document represents an attempt of a working group of the American Academy of Allergy, Asthma & Immunology to provide further guidance and synthesis in this use of vaccination for diagnostic purposes in consideration of PIDD, as well as to identify key areas for further research. A major diagnostic intervention in the consideration of many patients suspected to have primary immunodeficiency diseases (PIDDs) is the application and interpretation of vaccination. Specifically, the antibody response to antigenic challenge with vaccines can provide substantive insight into the status of human immune function. There are numerous vaccines that are commonly used in healthy individuals, as well as others that are available for specialized applications. Both can potentially be used to facilitate consideration of PIDD. However, the application of vaccines and interpretation of antibody responses in this context are complex. These rely on consideration of numerous existing specific studies, interpolation of data from healthy populations, current diagnostic guidelines, and expert subspecialist practice. This document represents an attempt of a working group of the American Academy of Allergy, Asthma & Immunology to provide further guidance and synthesis in this use of vaccination for diagnostic purposes in consideration of PIDD, as well as to identify key areas for further research. The majority of patients given a diagnosis of primary immunodeficiency disease (PIDD) have some impairment of humoral immunity. These most typically include quantitative deficiencies of antibodies, qualitative deficiencies of antibodies, or both. Patients with antibody deficiencies often present with recurrent respiratory tract infections, but there can be a wide array of infectious susceptibilities, as well as other presenting or subsequent comorbidities. Therefore the assessment of humoral immunity is a critical component in the evaluation of patients suspected of having a PIDD. Importantly, indications for and interpretation of humoral immune testing must rely on clinical correlation because an overriding theme of PIDDs is the susceptibility to infectious disease, the atypical manifestations of infectious disease, or both.Presently, there are a variety of laboratory-based tools available for the evaluation of suspected PIDDs with deficits in humoral immunity. These include direct genetic diagnosis of single-gene disorders,1Morra M. Geigenmuller U. Curran J. Rainville I.R. Brennan T. Curtis J. et al.Genetic diagnosis of primary immune deficiencies.Immunol Allergy Clin North Am. 2008; 28: 387-412Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar, 2Notarangelo L.D. Fischer A. Geha R.S. Casanova J.L. Chapel H. Conley M.E. et al.Primary immunodeficiencies: 2009 update.J Allergy Clin Immunol. 2009; 124: 1161-1178Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar flow cytometric analysis of lymphocyte subpopulations,3Wehr C. Kivioja T. Schmitt C. Ferry B. Witte T. Eren E. et al.The EUROclass trial: defining subgroups in common variable immunodeficiency.Blood. 2008; 111: 77-85Crossref PubMed Scopus (200) Google Scholar and quantitative and qualitative evaluation of serum immunoglobulins.4Bonilla F. Bernstein I. Khan D. Chinen J. Frank M. Kobrynski L. et al.Practice parameter for the diagnosis and management of primary immunodeficiency.Ann Allergy Asthma Immunol. 2005; 94 (S1-63)PubMed Google Scholar Although age, sex, environmental exposures, medications, and geography can influence some of these measures, these tests are, in the vast majority of cases, objective and useful for providing definitive diagnoses. However, the evaluation of immunoglobulin quality is complex and can be difficult to assess. Considerations involve antibody repertoire, antigen-specific immune responses, development of immunologic memory, and specific avidities for antigens. This is of critical relevance because subjects incapable of generating protective antibody responses are more susceptible to infection and, under many circumstances, can benefit from immunoglobulin replacement therapy.Therapeutic immunoglobulin preparations are expensive and of limited supply, thus further necessitating careful evaluation of patients for antibody deficiency states that might require immunoglobulin replacement therapy. Qualitative assessment of antibody function is an evolving topic. The procedure presently involves the use of in vitro assays with the objective of determining whether the specificity of the in vivo antibody response is appropriate. Additionally, results can provide a reasonable correlate for protection against infection. Because a variety of tests and measures are available, the thoughtful selection of an approach is important.Qualitative antibody responses are routinely assessed by measurement of antibody specificity for fairly standardized antigens to which a significant proportion of subjects are exposed. Prophylactic vaccines provide a relatively ubiquitous source of standardized antigenic exposure. Vaccines licensed for prophylactic use in the United States at the time of the writing of this document are listed in Table I. In most subjects vaccines are administered with stringent regulation of dosage, adjuvant content, route, and schedule. Thus evaluation of the vaccine response through measurement of antibody titers provides some measure of antigen standardization between patient populations. However, there are variations in the approach to and interpretation of these measurements that present complexities through which the clinician must navigate. These include the age of the patient, which can influence both the response to vaccine challenges and the manifestation of the PIDD. Some PIDDs and diagnostic approaches are specific to children, whereas others are more common in adult patients. Throughout this document, concerns relevant to pediatric and adult patients are specifically noted as they relate to the individual vaccines used to elicit humoral immunity.Table IVaccines currently licensed for use in the United StatesVaccineTrade nameLive vaccineManufacturerNotesAdenovirus type 4 and type 7 vaccine, liveNo trade nameYesBarr LabsOralAnthrax vaccine adsorbedBiothraxNoEmergent BioDefense Operations LansingAdsorbedBCG liveTICE BCGYesOrganon Teknika CorpDiphtheria and tetanus toxoidsNoneNoSanofi PasteurAdsorbedDiphtheria and tetanus toxoids adsorbedNo trade nameNoSanofi PasteurAdsorbedDiphtheria and tetanus toxoids and acellular pertussisTripediaNoSanofi PasteurAdsorbedDiphtheria and tetanus toxoids and acellular pertussis vaccine adsorbedInfanrixNoGlaxoSmithKline BiologicalsRecombinantDiphtheria and tetanus toxoids and acellular pertussis vaccine adsorbedDAPTACELNoSanofi PasteurRecombinantDiphtheria and tetanus toxoids and acellular pertussis + hepatitis B + poliovirusPediarixNoGlaxoSmithKline BiologicalsAdsorbed recombinant (hepatitis B) Inactivated (poliovirus)Diphtheria and tetanus toxoids and acellular pertussis poliovirus vaccineKINRIXNoGlaxoSmithKline BiologicalsAdsorbed and inactivatedDiphtheria and tetanus toxoids and acellular pertussis + poliovirus and Haemophilus b conjugatePentacelNoSanofi PasteurAdsorbed, inactivated, Haemophilus–tetanus toxoid conjugateHaemophilus b conjugate vaccinePedvaxHIBNoMerck & CoMeningococcal protein conjugateHaemophilus b conjugate vaccineActHIBNoSanofi Pasteur, SATetanus toxoid conjugateHaemophilus b conjugate vaccineHiberixNoGlaxoSmithKline Biologicals, SATetanus toxoid conjugateHaemophilus b conjugate and hepatitis BComvaxNoMerck & CoMeningococcal protein conjugate, hepatitis B (recombinant)Hepatitis AHavrixNoGlaxoSmithKline BiologicalsInactivatedHepatitis AVAQTANoMerck & CoInactivatedHepatitis A and hepatitis BTwinrixNoGlaxoSmithKline BiologicalsInactivated (hepatitis A), recombinant (hepatitis B)Hepatitis BRecombivax HBNoMerck & CoRecombinantHepatitis BEngerix-BNoGlaxoSmithKline BiologicalsRecombinantHuman papillomavirus (types 6, 11, 16, 18)GardasilNoMerck and CoRecombinant quadravalentHuman papillomavirus (types 16, 18)CervarixNoGlaxoSmithKline BiologicalsRecombinant bivalentInfluenza A (H1N1) 2009NoneNoCSL LimitedMonovalentNoneNoMedImmuneMonovalentNoneNoID Biomedical Corporation of QuebecMonovalentNoneNoNovartis Vaccines and Diagnostics LimitedMonovalentNoneNoSanofi PasteurMonovalentInfluenza virus H5N1No trade nameNoSanofi PasteurInfluenza virus, types A and BAfluriaNoCSL LimitedTrivalentFluLavalNoID Biomedical Corp of QuebecTrivalentFluarixNoGlaxoSmithKline BiologicalsTrivalentFluvirinNoNovartis Vaccines and Diagnostics LtdTrivalentAgrifluNoNovartis Vaccines and Diagnostics S.r.l.TrivalentAgrifluNoNovartis Vaccines and Diagnostics S.r.l.TrivalentFluzone and Fluzone High-DoseNoSanofi PasteurTrivalentInfluenza vaccine, types A and BFluMistYes∗Boldfaced vaccines represent those that are live. Specific guidance in the use of live vaccines in immunocompromised patients is recommended as directed in the licensing information for the individual vaccines and as per this document’s Summary Statement 8.MedImmuneIntranasal trivalentJapanese encephalitis virusIxiaroNoIntercell BiomedicalInactivated, adsorbedJE-VaxNoResearch Foundation for Microbial Diseases of Osaka UniversityInactivatedMeasles virusAttenuvaxYesMerck & CoMeasles, mumps, and rubella virusM-M-R IIYesMerck & CoMeasles, mumps, rubella, and varicella virusProQuadYesMerck & CoMeningococcal (groups A, C, Y, and W-135) oligosaccharideMenveoNoNovartis Vaccines and DiagnosticsDiphtheria CRM197 conjugate vaccineMeningococcal polysaccharide (serogroups A, C, Y and W-135)MenactraNoSanofi PasteurDiphtheria toxoid conjugate vaccineMeningococcal polysaccharide vaccine, groups A, C, Y and W-135 combinedMenomune-A/C/Y/W-135NoSanofi PasteurMumps virus vaccine, liveMumpsvaxYesMerck & CoPneumococcal vaccine, polyvalentPneumovax 23NoMerck & CoPneumococcal 7-valent conjugatePrevnarNoWyeth PharmaceuticalsDiphtheria CRM197 protein conjugatePneumococcal 13-valent conjugatePrevnar 13NoWyeth PharmaceuticalsDiphtheria CRM197 protein conjugatePoliovirusIPOLNoSanofi Pasteur, SAInactivated (monkey kidney cell)RabiesImovaxNoSanofi Pasteur, SARabAvertNoNovartis Vaccines and DiagnosticsRotavirusROTARIXYesGlaxoSmithKline BiologicalsOralRotaTeqYesMerck & CoOral, pentavalentRubella virusMeruvax IIYesMerck & CoSmallpox (vaccinia)ACAM2000YesSanofi Pasteur BiologicsTetanus and diphtheria toxoidsNo trade nameNoMassBiologicsAdsorbed for adult useDECAVACNoSanofi PasteurAdsorbed for adult useTENIVACNoSanofi Pasteur (not available)Adsorbed for adult useTetanus toxoidNo trade nameNoSanofi PasteurAdsorbedTetanus toxoid, reduced diphtheria toxoid and acellular pertussisAdacelNoSanofi PasteurAdsorbedBoostrixNoGlaxoSmithKline BiologicalsAdsorbedTyphoid Ty21aVivotifYesBerna BiotechOralTyphoid Vi polysaccharideTyphim ViNoSanofi Pasteur, SAVaricella virusVarivaxYesMerck & CoOka strainYellow feverYF-VaxYesSanofi PasteurZosterZostavaxYesMerck & CoOka strain∗ Boldfaced vaccines represent those that are live. Specific guidance in the use of live vaccines in immunocompromised patients is recommended as directed in the licensing information for the individual vaccines and as per this document’s Summary Statement 8. Open table in a new tab When poor antibody response is perceived, it is standard practice to provide an antigenic challenge (through “booster” immunization) to determine whether a subject retains the ability to generate a qualitative antibody response. Although the process of diagnostic vaccination is routine, there are many variables for clinical consideration. These include which vaccines or antigens to use, how to administer and use them, which tests to use to measure responses, and how to interpret the data in the context of complex clinical scenarios. As a result, the interpretation of diagnostic vaccination can result in more questions than answers.In an effort to provide guidance for practicing allergists/immunologists (and others clinically evaluating patients with potential PIDDs) in assessing antibody quality with regard to vaccination in potentially immunodeficient patients, a working group of the Basic and Clinical Immunology Interest Section of the American Academy of Allergy, Asthma & Immunology (AAAAI) was formed and charged in December 2007. It included members of the Primary Immunodeficiency Committee, as well as members of the Vaccines and Biological Threats Committee. The group was assembled with the task of developing individual summary statements relating to topics pertinent to diagnostic vaccination. The work in generating the statements was assigned to specific subcommittees and occurred between October 2008 and April 2009. These were then subjected to at least 2 rounds of blind review, after which they were revised and edited. Each statement was categorized according to the quality of the supporting evidence and assigned a strength of recommendation (Table II). This process was completed in August 2010, and then the document was submitted for independent peer review through the Practice and Policy Division of the AAAAI in March 2011, revised, and then completed in December 2011.Table IICategorization of evidence and basis of recommendation and strength of recommendationIaFrom meta-analysis of randomized controlled studiesIbFrom at least 1 randomized controlled studyIIaFrom at least 1 controlled trial without randomizationIIbFrom at least 1 other type of quasiexperimental studyIIIFrom nonexperimental descriptive studies, such as comparative, correlation, or case-control studiesIVFrom expert committee reports or opinions or clinical experience of respected authorities or bothABased on category I evidenceBBased on category II evidence or extrapolated from category I evidenceCBased on category III evidence or extrapolated from category I or II evidenceDBased on category IV evidence or extrapolated from category I, II, or III evidenceNRNot rated Open table in a new tab Although it is clear that many questions remain, the intent of this effort is to promote clarity and facilitate evidenced-based practice in this diverse clinical arena. The dynamic market landscape of vaccines, which include changes in licensure, availability of new vaccines, and innovations in diagnostic testing, will necessitate ongoing changes to this document and its recommendations.The summary statements are presented in the following text divided according to 4 broad topic areas. The first section (I) is the use of common vaccines to measure humoral immune function. The second section (II) relates specifically to the use of pneumococcal polysaccharide vaccine for measurement of humoral immunity. The working group determined that the pneumococcal polysaccharide vaccine warranted a full section because of the historical emphasis placed on its use, as well as its application in certain health care coverage guidelines. This section on Pneumococcal vaccination includes the topics of preexisting antipneumococcal titers, as well as titers used to measure resistance to infection. The third section (III) addresses the use and interpretation of responses to meningococcal vaccination. The fourth section (IV) is focused on the use of neoantigens and alternative vaccines in measuring humoral immune function. The fifth and final section (V) covers measurement and variability in the response to currently available vaccines, including the variability defined in the limited studies of immunodeficient populations.With these specific areas of focus, the document consists of a series of 70 summary statements that are first listed and then reiterated along with a more detailed explanation, including key supporting references. This format is similar to that used in other key documents in the field of primary immunodeficiences4Bonilla F. Bernstein I. Khan D. Chinen J. Frank M. Kobrynski L. et al.Practice parameter for the diagnosis and management of primary immunodeficiency.Ann Allergy Asthma Immunol. 2005; 94 (S1-63)PubMed Google Scholar and is intended to serve as a lexicon for practitioners seeking further guidance on the topic of diagnostic vaccination as it applies to PIDDs. The present effort is not intended as a guideline for establishing individual PIDD diagnoses; for that, the reader is referred to the Joint Council on Allergy, Asthma & Immunology Practice Parameter on PIDD.4Bonilla F. Bernstein I. Khan D. Chinen J. Frank M. Kobrynski L. et al.Practice parameter for the diagnosis and management of primary immunodeficiency.Ann Allergy Asthma Immunol. 2005; 94 (S1-63)PubMed Google Scholar In this light the present document should be viewed as additional guidance on the specific topic of use and interpretation of vaccination responses in consideration of PIDD and not taken to replace anything stated in the present or future PIDD practice parameters. Because certain topics are relevant to more than 1 summary statement, the reader is encouraged to review the listing of summary statements before deciding which of the detailed statements are relevant to a specific diagnostic consideration.Listing of summary statementsI Use of common vaccines for measurement of humoral immune functionSummary Statement 1: The most commonly used vaccines for B-cell functional analysis are US Food and Drug Administration (FDA) approved and used worldwide in children to prevent communicable diseases. (Ia A)Summary Statement 2: The diagnosis and treatment of common variable immunodeficiency (CVID) has traditionally included assessment of vaccine responses. (IIa B)Summary Statement 3: There are 4 primary immunodeficiencies that largely depend on qualitative analysis of vaccination responses. (IV D)Summary Statement 4: Several genetically definable primary immunodeficiencies have been associated with poor polysaccharide antibody responses, and vaccination with pneumococcal polysaccharide vaccine (PPV) can be of diagnostic utility. (IIa B)Summary Statement 5: Antibody responses to T cell–independent (polysaccharide) antigens should not be a component of routine investigation for antibody deficiency in children less than 18 months of age still in the midst of receiving their primary vaccination series. (IIa A)Summary Statement 6: Certain immunodeficiencies are drastic, and pursuing evaluation of humoral immune function through vaccine antigen challenge would delay necessary therapy. (IV D)Summary Statement 7: The use of polysaccharide vaccines as a diagnostic tool must integrate numerous criteria. (IIa B)Summary Statement 8: The use of live viral vaccines should be avoided in patients with certain immunodeficiencies. (IIa B)II Use of the pneumococcal polysaccharide vaccine in evaluation of humoral immune function and in diagnosis of functional antibody deficiencySummary Statement 9: Pneumococcal vaccines are recommended for all children, adults older than 65 years, and certain high-risk groups. (Ib A)Summary Statement 10: Pneumococcal vaccines are usually well tolerated. (Ib B)Summary Statement 11: Different titers of pneumococcal antibodies might serve different anti-infective purposes. (IIb B)Summary Statement 12: Pneumococcal antibody titers vary over time in healthy subjects. (IIb B)Summary Statement 13: Pneumococcal antibody titers might be of value to determine the response to documented past pneumococcal infection if the infecting serotype is known. (IV D)Summary Statement 14: Pneumococcal IgG antibody responses are generally assessed by means of ELISA or related immunologic assay. (NR)Summary Statement 15: Functional assays for detecting specific anti-pneumococcal antibodies also exist and might provide a better measure of anti-pneumococcal antibody quality. (IV D)Summary Statement 16: PPV is widely used diagnostically in both adults and children having completed their primary pneumococcal conjugate vaccine (PCV) series who are suspected of immunodeficiency to ascertain response to polysaccharide antigens. (Ib A)Summary Statement 17: PCV7 and PCV13 are used occasionally in the diagnosis of immunodeficiency. (IIb C)Summary Statement 18: Measurement of individual pneumococcal serotype titers before and after immunization and enumeration of the number of serotypes responding is an accepted technique to evaluate humoral immune function. (IIb B)Summary Statement 19: Measurement of pneumococcal antibody titers to either vaccine should be done 4 to 8 weeks after vaccination. (Ib A)Summary Statement 20: A protective (normal or adequate) response to each pneumococcal serotype is defined as a titer equal to or greater than 1.3 μg/mL antibody. (IIb C)Summary Statement 21: A normal response for a single serotype present in a pneumococcal vaccine is defined as the conversion from a nonprotective to a protective titer. (III D)Summary Statement 22: The number of pneumococcal serotypes that are protective after a vaccine can be used to define a normal (adequate or epidemiologic) response. (IV D)Summary Statement 23: Certain pneumococcal serotypes are considered to be more reliably antigenic than others. (Ib A)Summary Statement 24: The higher the preimmunization titer for a specific pneumococcal serotype, the less likely that the titer will have a significant increase after vaccination. (III C)Summary Statement 25: Most patients with a prevaccine titer of greater than 1.3 μg/mL can mount a 2-fold increase in titer on immunization. A minority of patients with high initial titers will be capable of mounting a 4-fold increase in antibody titers after vaccination. (III C)Summary Statement 26: The probability of a 4-fold antibody response approaches zero if the preimmunization titer is between 4.4 and 10.3 μg/mL, depending on the pneumococcal serotype. (III C)Summary Statement 27: Secondary immunodeficiencies might affect antigen-specific responses and diminish the response to the pneumococcal vaccine. (NR)Summary Statement 28: Immediate repeat booster doses of PPV are ineffective (and not recommended and might promote hyporesponsiveness). (Ib B)Summary Statement 29: Patients who have previously received PCV7 or PCV13 can be given PPV23. (III C)Summary Statement 30: A diagnosis of specific antibody deficiency (SAD) can be made if the response to PPV23 is deficient but the responses to protein antigens (eg, tetanus toxoid or diphtheria toxoid), conjugate vaccines (Haemophilus influenzae type b, PCV7, or PCV13), or both are intact and total immunoglobulin levels are normal. (III C)Summary Statement 31: PCV7 or PCV13 protein conjugate vaccines can be administered to patients who have a poor response to PPV23. (III C)Summary Statement 32: The degree of polysaccharide nonresponsiveness in selective antibody deficiency can be classified into 4 phenotypes. (IV D)Summary Statement 33: Further clinical research is warranted to refine best practice applied to patients with specific phenotypes of selective antibody deficiency. (NR)III Use of meningococcal vaccine to measure humoral immune functionSummary Statement 34: In the United States there are currently 3 meningococcal vaccines licensed for use in children aged 2 years and older and adults. (Ia A)Summary Statement 35: The 3 meningococcal vaccines contain the same serogroups. (NR)Summary Statement 36: MCV4 is a protein conjugate vaccine, and MPSV4 is a polysaccharide vaccine. Therefore they differ in the mechanism of immune response. (Ib A)Summary Statement 37: There are different methodologies for assessing the immunogenicity of meningococcal vaccines. (Ib A)Summary Statement 38: All of the currently licensed meningococcal vaccines in the United States have been found to be immunogenic. (Ib A)Summary Statement 39: Meningococcal polysaccharide vaccine is less reliable in young children. (Ib A)Summary Statement 40: Meningococcal polysaccharide vaccination can result in hyporesponsiveness to subsequent meningococcal vaccination. (Ib A)Summary Statement 41: There are commercially available laboratory tests for meningococcal antibody titers. (III C)Summary Statement 42: An increase in titers of at least 2 meningococcal serogroups is expected after vaccination of an immunocompetent subject. (IV D)Summary Statement 43: Immunogenicity might depend on several factors (which could have relevance if additional manufacturers begin to produce these vaccines). (IIb C)Summary Statement 44: Given that there are commercial laboratories that measure meningococcal antibody titers and both vaccines have been proved to be immunogenic, responses could be used in the clinical evaluation for immunodeficiency. (IV D)Summary Statement 45: There are specific considerations regarding the immunogenicity of certain meningococcal serogroups should they be available in vaccines. (III C)IV Use of alternative vaccines and true neoantigens in evaluating defective humoral immunitySummary Statement 46: Immunization with neoantigens can be used in the evaluation of specific antibody response in the setting of immunoglobulin replacement therapy. (III C)Summary Statement 47: Sufficient experience does not exist regarding the use of routine vaccines in the context of a patient with primary immunodeficiency receiving immunoglobulin replacement therapy to assess antibody response. (IV D)Use of bacteriophage φX174 to measure humoral immune functionSummary Statement 48: The only neoantigen that has been extensively studied to assess human antibody responses is the T cell–dependent antigen bacteriophage φX174. (III C)Summary Statement 49: Immunization with the neoantigen bacteriophage φX174 and subsequent evaluation of specific antibody responses might be included in the diagnosis of primary immunodeficiency to assess antigen-specific class-switching and the kinetics of the antibody response, including in the evaluation of patients who are already receiving immunoglobulin supplementation. (III C)Summary Statement 50: Immunization with the neoantigen bacteriophage φX174 is relatively labor intensive and is performed as research. (IV D)Summary Statement 51: Keyhole limpet hemocyanin (KLH) is a potential alternative to φX174 as a neoantigen. (IV D)Use of human rabies virus vaccine as an alternative neoantigen to evaluate humoral immune functionSummary Statement 52: Rabies virus vaccines are available and used in the United States as postexposure prophylaxis. (Ib A)Summary Statement 53: Rabies virus vaccination is generally well tolerated. (Ib A)Summary Statement 54: Cell culture–derived rabies virus vaccines as pre-exposure vaccines elicit adequate humoral immune responses. (Ib A)Summary Statement 55: Rabies virus vaccines can be used as a neoantigen to assess humoral immune responses in healthy subjects. (IIb B)Summary Statement 56: Although rabies virus vaccines can elicit lymphocyte proliferative responses after immunization, the rabies virus nucleocapsid can produce a superantigen response by human T cells that might compromise its utility to assess cell-mediated immune responses as a neoantigen. (IIb B)Summary Statement 57: Rabies virus vaccine can be used as a neoantigen to evaluate humoral immune responses in patients with secondary immune deficiency; however, the degree of the response might be linked to the dose (micrograms of protein) of the vaccine. (IIb C)Summary Statement 58: Rabies virus vaccine can be used as a neoantigen to evaluate humoral immune responses in patients with primary immune deficiencies. (IIb C)Summary Statement 59: A single injection of rabies virus vaccine might be useful in eliciting a measurable antibody response, but further study of this intervention in primary immunodeficiency diagnostic evaluation is needed. (IV D)Summary Statement 60: Rabies virus vaccination can potentially be used to assess humoral immune function in a patient receiving immunoglobulin replacement therapy. (III C)Summary Statement 61: Testing for rabies virus vaccine–specific antibodies is available, but the general application of specific methods in patients suspected of having primary immunodeficiency needs to be established. (IV D)Summary Statement 62: In contrast to rabies virus vaccine, it is unlikely that meningococcal vaccine will be a suitable neoantigen for patients receiving immunoglobulin replacement therapy. (IV D)Summary Statement 63: The use of Salmonella typhi Vi vaccine has future potential as a diagnostic and alternative polysaccharide antigen in patients with primary immunodeficiencies, but sufficient data are not presently available to support its use. (IV D)V Variability in immunogenicity among currently available vaccinesGeneral considerationsSummary Statement 64: The FDA requires that vaccine manufacturers must test each lot and demonstrate conformance to established standards for that vaccine. (NR)Summary Statement 65: When assessing vaccine lot consistency, it is important to understand the interrelationship between efficacy, immunogenicity, and potency. (IV D)Summary Statement 66: Vaccine lot consistency is generally based on measures of potency. (Ib B)Summary Statement 67: Vaccine potency is dependent on numerou