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Assessing antibody function as part of an immunologic evaluation

Assessing antibody function as part of an immunologic evaluation
Author:
Kenneth Paris, MD, MPH
Section Editor:
Jordan S Orange, MD, PhD
Deputy Editor:
Anna M Feldweg, MD
Literature review current through: Nov 2022. | This topic last updated: May 20, 2020.

INTRODUCTION — Two critical functions of antibodies in the immune response to infection are the opsonization of bacteria and neutralization of viruses. However, an assay that fully assesses these functions is not available for routine clinical use. Instead, antibody function is estimated by measuring an individual's response to specific vaccinations. This topic will review normal immunologic responses to vaccinations, methods for assessing these responses, and patterns of abnormal responses. A more general evaluation of the immune system, including measurement of antibody levels and functional assessments of different immune cells, is presented elsewhere. (See "Laboratory evaluation of the immune system" and "Primary humoral immunodeficiencies: An overview".)

INDICATIONS FOR ASSESSING VACCINE RESPONSE — Vaccine response is part of the evaluation of possible immunodeficiency. The clinical indications for assessing vaccine responsiveness include frequent and recurrent sinopulmonary or ear infections, chronic gastrointestinal infections, any severe or unusual infections, and abnormal need for antibiotics (table 1). Most patients have already had serum levels of immunoglobulin (Ig)G, IgA, and IgM measured, but if not, these can be obtained at the same time that vaccine response is assessed. The different warning signs of immunodeficiency are reviewed in more detail elsewhere:

(See "Approach to the child with recurrent infections", section on 'Clinical features suggestive of a primary immunodeficiency'.)

(See "Approach to the adult with recurrent infections", section on 'What is an excessive number of infections?'.)

Evaluation of primary immunodeficiency — Vaccine responsiveness is central to the diagnosis of several primary immunodeficiencies, including (but not limited to):

Common variable immunodeficiency

Combined T cell and B cell immunodeficiencies

Hyperimmunoglobulin M syndromes

Transient hypogammaglobulinemia of infancy

Specific pneumococcal antibody deficiency (also known as, selective antibody deficiency or selective antibody deficiency with normal immunoglobulins)

IgG subclass deficiency

Selective IgM deficiency

Selective IgA deficiency

Hyperimmunoglobulin E syndrome with recurrent infections

Wiskott-Aldrich syndrome

Ataxia-telangiectasia

Hypogammaglobulinemia and agammaglobulinemia of unclear etiology (unless serum IgG is <200 mg/dL or undetectable, in which case specific antibodies can be assumed to be low)

Vaccine responsiveness is also utilized in the periodic evaluation of patients who were diagnosed with immune problems as children but may have outgrown their deficiencies and in patients previously treated with immune globulin in whom the original diagnosis is in question. In this situation, a waiting period of four to six months after that last immune globulin dose is recommended.

Evaluation of secondary immunodeficiency — Defective vaccine responses are also a feature of secondary immunodeficiency caused by various disease states including splenic deficiency, immunosuppression, chronic lung disease (eg, chronic obstructive pulmonary disease), HIV infection, and drug-induced hypogammaglobulinemia (eg, anticonvulsants, rituximab, chemotherapy). (See "Secondary immunodeficiency induced by biologic therapies" and "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Severe adverse reactions'.)

In some secondary immunodeficiency disorders, vaccine responsiveness is used to determine if a patient with infections would benefit from immune globulin replacement therapy.

GENERAL PRINCIPLES — Bacterial antigens are predominantly either proteins or complex polysaccharides, and the vaccines that are most informative in an immune evaluation contain predominantly either protein or polysaccharide antigens, whereas many other vaccines contain mixtures of both. When evaluating suspected immunodeficiency, responsiveness to vaccines containing each distinct type of antigen should be assessed separately [1]. Depending on the immunologic defect present, a patient may respond poorly to one or both types.

A working group of the American Academy of Allergy, Asthma, and Immunology published recommendations on the interpretation of vaccine responses in the evaluation of patients with possible immunodeficiency [1,2]. The material in this review is consistent with those recommendations.

IgG reflects long-term protection — Only IgG titers are used in the assessment of vaccine responses. Infections and immunizations elicit IgM, IgA, and IgG antibody responses, but only IgG antibodies confer long-term protection.

Types of vaccines — Vaccines may be categorized as polysaccharide vaccines, protein vaccines, or conjugate vaccines.

Polysaccharide vaccines – The polysaccharide pneumococcal vaccines (ie, 23-valent pneumococcal polysaccharide vaccine [PPV-23], including Pneumovax 23, Pnu-imune 23, and others) are usually used to assess the response to polysaccharide antigens, which requires functional B cells only. Patients may be exposed to pneumococcal antigens either from vaccination or from natural infection. Of note, children are normally vaccinated with conjugate pneumococcal vaccines, which are not useful in assessing polysaccharide responsiveness. Uncommonly, other polysaccharide vaccines can be used to evaluate the polysaccharide response, although the "normal" response to these vaccines is not as well-characterized. (See 'Other polysaccharide vaccines' below.)

Protein vaccines – Tetanus and diphtheria vaccines are the two most common vaccines used to evaluate the antibody-mediated response to protein antigens because most patients have been exposed through primary and booster vaccination. Responses to protein antigens require intact B and T cell function. An impaired response indicates that both B and T cell function are abnormal, which is characteristic of more severe forms of immunodeficiency.

Response to the conjugate vaccine for Haemophilus influenzae type B (Hib) can also be used to assess responses to protein antigens. While the Hib vaccine includes H. influenzae surface polysaccharide, the vaccine induces antibodies to the protein component of the conjugate and thus represents a protein response. (See 'Interpretation of Hib titers' below.)

Conjugate vaccines – The other common type of vaccines are conjugate vaccines, which contain polysaccharide antigens complexed to immunogenic proteins. These have limited use in assessing either protein or polysaccharide responses, with the notable exception of the Hib vaccine discussed above. Conjugate vaccines were developed because many children under the age of two years generate weak responses to polysaccharide antigens alone but can respond to protein antigens. The antibody response to conjugate vaccines is predominately stimulated by the protein component and thus is not representative of either a pure polysaccharide response or a pure protein response. Therefore, in a patient who received a conjugate vaccine series, measurement of titers to the specific polysaccharides contained in the conjugate vaccine does not allow for an assessment of responsiveness to pure polysaccharide or protein antigens. Measurement of titers to the protein component of the conjugate vaccine, which is usually a diphtheria or tetanus toxoid, is similarly uninformative because these titers also reflect the patient's response to routine tetanus/diphtheria vaccinations. (See 'Nonresponse to conjugate polysaccharides' below.)

Mechanisms of the normal antibody responses to protein and polysaccharide antigens are reviewed elsewhere. (See "The adaptive humoral immune response", section on 'Types of antigens'.)

Patterns of nonresponse — Two patterns of nonresponse are well-described in immunodeficiency:

An inability to respond effectively to polysaccharide antigens only ("polysaccharide nonresponse")

An inability to respond effectively to both polysaccharide and protein antigens

It is highly unusual for a patient to have an impaired response to protein antigens with a normal response to polysaccharide antigens.

The disorders in which each type of nonresponse is seen are reviewed below. (See 'Disorders associated with abnormal vaccine responses' below.)

Timing of pre- and postvaccination measurements — When vaccines are administered for the purpose of assessing response, it is critical to wait at least four to eight weeks after administration before measuring postvaccination titers. Assessing responses earlier than this with any method may result in low titers. Longer periods (eg, 6 to 12 months) are also less informative because when antibody concentrations are low after longer periods, it is not possible to differentiate patients who did not respond at all from those who did but subsequently lost the antibodies over time (ie, patients with impaired immunologic memory). (See "Specific antibody deficiency", section on 'Degrees of nonresponse'.)

Variability among laboratories — It is important that any evaluations of pre- and postvaccination titers be performed by the same laboratory using the same assay method because there are many other variables in technique. This is particularly critical for pneumococcal serotype-specific titers. Methods for the measurement of antigen-specific antibodies against individual pneumococcal serotypes include enzyme-linked immunosorbent assay (ELISA), multiplex pneumococcal serology (eg, Luminex), nephelometry, turbidimetry, radial immunodiffusion, and radioimmunoassay. ELISA or a similar immunologic assay is the preferred method in most situations [1,2], although the method employed depends upon the laboratory and the antibody class or subclass being measured. The assay should be standardized to World Health Organization standards. Laboratories may determine their own reference ranges or use data provided by reagent manufacturers. Consistency among the results obtained by different methods and even with the same method performed in different laboratories is poor [3].

Interfering factors — The immunologic response to vaccination cannot be reliably evaluated in patients who have received immune globulin replacement within the past four to six months or in those who have received single doses of immunoglobulins for prevention of specific infections (eg, hepatitis A or measles) within the past three to five months because the results obtained could reflect antibodies from either donor or patient origin. Most immunologists wait at least four months after discontinuing immune globulin therapy to revaccinate patients for evaluation.

Other conditions and treatments that potentially interfere with immunoglobulin production and vaccine response include cancer, chemotherapy, and some immunosuppressive therapies (eg, long-term glucocorticoids, rituximab, etc). These are discussed separately. (See "Glucocorticoid effects on the immune system" and "Secondary immunodeficiency induced by biologic therapies", section on 'Impact on vaccination'.)

ASSESSING PNEUMOCOCCAL POLYSACCHARIDE RESPONSES

Children under two years of age — The response to polysaccharide vaccines cannot be reliably assessed in children under two years of age, because response to polysaccharide antigens is normally variable in young children, even in the absence of an immune disorder [1,4-7]. The ability to respond to polysaccharide vaccines normally increases with age. In addition, there is some evidence that use of polysaccharide vaccines in young children can interfere with the efficacy of conjugate vaccines given subsequently, so the polysaccharide vaccine is not used in young children for this reason also [8].

Isohemagglutinin testing — Because young children do not respond vigorously to polysaccharide vaccines, isohemagglutinins may be measured instead as a means of assessing polysaccharide response, although there are significant limitations to their usefulness. The authors do not use isohemagglutinins in this manner, but they may be used in resource-limited settings. Testing is usually performed by blood banks.

Isohemagglutinins are antibodies that are normally generated in response to polysaccharides antigens from common gut bacteria. These antibodies are cross-reactive with A and B blood group antigens on the surface of erythrocytes [9]. They generally appear in the blood by six months of age and can be measured in young children who have not completed a primary vaccination series. Patients with type A blood should have anti-B isohemagglutinins, and patients with blood type O should have both anti-A and anti-B. Patients with type AB blood do not have isohemagglutinins under normal circumstances. Since isohemagglutinins are both IgM and IgG antibodies that are measured together, they do not allow the assessment of IgG-mediated immunity.

Adults and children over two years

Which vaccines are used? — The polysaccharide pneumococcal vaccine (eg, Pneumovax 23; Pnu-imune 23) is the primary means of assessing responsiveness to polysaccharide antigens in adults and in children older than two years. Rarely, other polysaccharide vaccines may be used. (See 'Other polysaccharide vaccines' below.)

IgG responses to pneumococcal serotypes in normal individuals of different ages across populations with and without infections have not been studied extensively, so a solid definition of normal and abnormal antibody responses to immunization in different age groups and different areas of the world is lacking. However, the approach to interpreting vaccine responses described in this section is consistent with the recommendations of an expert working group [1,2].

Vaccination and infection history — Evaluation of pneumococcal vaccine response begins with a detailed history of past infectious illnesses and of vaccinations to pneumococcus. The following information is helpful in interpreting results:

Has the patient received a pneumococcal conjugate vaccine (PCV-13, -10, or -7) or pneumococcal polysaccharide vaccine (PPV-23)? If yes, how long ago?

Has the patient had sinusitis, otitis media, or pneumonia? How many episodes of each type of infection? Is culture data available?

Patients who have either had an identified infection or recently received a vaccine for the infection-causing agent would be expected to have protective titers against it. If a patient was vaccinated more than a decade earlier, low titers may reflect normally waning immunity, rather than an immune disorder.

Childhood vaccination schedules for the United States are available on the Centers for Disease Control and Prevention (CDC) website. Recommendations for vaccination of adults in the United States are summarized in the figure (figure 1). Detailed discussions of the routine vaccination of children and adults are found separately. (See "Standard immunizations for children and adolescents: Overview" and "Standard immunizations for nonpregnant adults" and "Pneumococcal vaccination in adults".)

Interpretation of pneumococcal titers — The evaluation begins with a vaccination and infection history, followed by measurement of serum titers to the capsular polysaccharides in the polysaccharide pneumococcal vaccine before and after immunization. An algorithm of the steps in the evaluation is provided (algorithm 1).

Pneumococcal titers are available commercially as panels of IgG antibodies to specific serotypes. For the purposes of assessing vaccine response, the clinician should request a panel of at least 14 serotypes and preferably up to 23 serotypes, if available. The relevant serotypes are those included in the 23-valent vaccine but not in the conjugate vaccines. Pneumococcal titers are generally reported in micrograms/mL using a standard provided by the US Food and Drug Administration (FDA).

Normal responses are age-dependent — A serotype-specific IgG concentration ≥1.3 mcg/mL is indicative of a normal ability to respond to polysaccharide antigens in all age groups [1,10,11]. Note that lower levels (ie, ≥0.35 mcg/mL) are considered adequate for protection against invasive pneumococcal disease [10,12]. However, higher titers may be necessary to protect against mucosal sinus disease, otitis media, and nasopharyngeal carriage [13]. Defining a more precise protective concentration for specific serotypes is difficult due to variations in antibody avidity and opsonizing properties that may differ with both age and serotype. In addition, the concentration of ≥1.3 mcg/mL may not apply if different methods and standards are used, especially in countries outside of the United States. Very specific laboratory standardization rules have been developed for the measurement of antipneumococcal polysaccharide in different countries [14].

The number of antipneumococcal serotypes to which an immunologically normal person is expected to respond is dependent upon age (table 2) [1]:

Normally vaccinated children between two and five years of age are expected to have an adequate response to at least 50 percent of nonconjugate vaccine serotypes tested. If a child does not have adequate levels to at least 50 percent of serotypes when initially evaluated, the PPV-23 should be given and titers reassessed in four to eight weeks. Postvaccination, >50 percent of serotypes should be protective.

Older children (ages 6 to 18) and adults who have never been vaccinated frequently have adequate titers to at least 70 percent or to all serotypes tested due to clinical or subclinical infection in the past, although the presence of adequate titers to fewer serotypes does not necessarily indicate an immune disorder. If an adult does not have adequate titers to at least 70 percent of serotypes when initially evaluated, PPV-23 should be given and titers reassessed. Older children and adults with normal immune responsiveness should achieve adequate titers to at least 70 percent of serotypes four to eight weeks after vaccination.

Note that if an adult is presenting for evaluation of recurrent sinopulmonary infections, the evaluation can be consolidated by obtaining preimmunization titers and giving the PPV-23 at the initial visit and then measuring postvaccination titers four to eight weeks later. Even if retrospectively it is found that antibody concentrations were normal, vaccination with the polysaccharide vaccine has been observed to decrease infection in some patients.

Some experts believe that the normal response in adults to the pneumococcal polysaccharide vaccine should be reduced to greater than 50 percent of the serotypes rather than 70 percent of the serotypes [15,16]. The percentage of patients deemed to have a normal response can vary significantly depending upon which cutoff is used [17]. However, practice parameters have defined a normal response as at least 70 percent [1,18]. We use this criterion but also carefully consider the patient's history of infectious complications.

There are few studies addressing the normal immune response of older adults (>65 years of age) to PPV-23. One study suggested that older adults make specific antibodies in similar concentrations as younger adults, but the effectiveness of these antibodies is reduced [19]. Another study found that in healthy adults older than 65, titers can drop to prevaccination levels within two years of receiving the vaccine [1]. However, other data indicate that most titers persisted for at least five years [20]. Further information about this age group is needed.

Patients who received pneumococcal conjugate vaccines in the past — If a patient received a conjugate vaccine in the recent past, then only those serotypes unique to the unconjugated (native) polysaccharide vaccine should be considered for assessing polysaccharide response. Children in the United States have been receiving conjugated pneumococcal vaccines routinely since 2001. In 2010, the 7-valent conjugate vaccine (containing serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) was replaced in the United States by a 13-valent vaccine. This vaccine additionally includes serotypes 1, 3, 5, 6A, 7F, and 19A. Outside of the United States, 10-valent conjugate vaccines are also in use, and these vaccines include serotypes that are present in the 13-valent vaccine. The table shows serotypes in the commonly used vaccines (table 3). When exclusion of serotypes in the conjugate vaccine results in a small number of serotypes remaining to analyze, the >50 or >70 percent criteria may not apply, and the patient's clinical history must guide interpretation.

Relative increases in individual titers — The ratio of post- to prevaccination titer is also included in the definition of a normal vaccine response. A twofold increase in any individual titer that has a baseline of ≥1.3 mcg/mL is considered an adequate response (table 2) [1]. Each serotype must be considered individually, and the table outlines the number of serotypes that are expected to increase by this amount in different age groups. The higher the prevaccination titer for a specific serotype, the less likely that titer will increase significantly after vaccination, even in patients with normal immune function [21,22].

There is no response to a single serotype-specific polysaccharide that predicts the ability to or inability to respond to most or all of the other serotypes, and serotypes differ in immunogenicity. As an example, serotypes 6B and 23F are weak immunogens, whereas serotype 3 is highly immunogenic. Responses to all serotypes should be given equal weight (eg, an isolated but strong response to serotype 3 should not be interpreted as suggesting the patient's immune responsiveness is normal).

Some patients who initially develop an adequate antibody response demonstrate a rapid decline in antibody titers over the ensuing year. When this occurs, a patient who may have experienced clinical improvement may become susceptible to recurrent infections again. Retesting of antibody titers after 6 to 12 months is indicated in patients who responded appropriately to vaccination but then continue to get infections. (See "Specific antibody deficiency".)

Utility of additional doses — In the majority of adult patients who do not develop protective titers to an initial dose of PPV-23, repeat or "booster" doses of PPV-23 are not recommended for assessing vaccine responsiveness or for providing improved immunity to pneumococcus. The normal response to a "booster" dose has not been studied, and it is our experience that most patients who do not respond to the polysaccharide vaccine initially, do not respond significantly to repeat doses either [11]. In addition, readministration of PPV-23 may actually blunt the patient's response to subsequent natural exposure [23,24]. Finally, there are some data to suggest that large local cutaneous reactions are more common when multiple doses of PPV-23 are given within close proximity. The incidence of adverse reactions to PPV-23 is discussed elsewhere. (See "Pneumococcal vaccination in adults", section on 'Adverse effects'.)

There are two possible exceptions to the above generalization [25]:

Young patients (two to five years of age) who demonstrated a poor response to the polysaccharide vaccine sometimes have a more vigorous response to a repeat dose given one to two years later. This probably represents slightly delayed maturation of the immune system.

Older patients with postvaccination titers that are slightly below protective levels and who are otherwise immunologically normal sometimes develop protective titers after an additional dose of vaccine.

Timing of PPV-23 versus conjugate vaccines — For unimmunized adults, recommendations by the Advisory Committee on Immunization Practices (ACIP) of the CDC changed in 2012. Recommendations are mentioned briefly in the next section and reviewed in more detail elsewhere. (See "Pneumococcal vaccination in adults".)

The ACIP specifies that the conjugate vaccine (Prevnar-13 or PCV-13 in the United States) should be administered first when possible, followed by the polysaccharide vaccine (Pneumovax 23 or PPV-23; Pnu-imune 23). If the polysaccharide vaccine is also indicated, it should be given no sooner than eight weeks after the conjugate vaccine. This approach is recommended because giving the conjugate vaccine first may result in stronger responses to the 13 serotypes present in PCV-13 and better immunologic memory, compared with administering the PPV-23 first. (See "Pneumococcal vaccination in adults", section on 'Vaccine selection'.)

Other tests — Another test, which is commercially available in many countries (although not in the United States), is the overall antipneumococcal polysaccharide response assay (OVA). The OVA measures the antibody response to all 23 polysaccharide antigens in the PPV-23 vaccine and assigns a single value for overall response. When compared with serotype-specific enzyme-linked immunosorbent assay (ELISA) titers, a low (ie, <110 mg/L) OVA response frequently but not always identifies low-specific serotype antibodies assessed by ELISA. However, because the OVA can be low with normal ELISA results and ELISA results can be low with a normal OVA, the test in its form is of limited diagnostic value [26].

Other polysaccharide vaccines — The injectable polysaccharide Salmonella enterica serotype Typhi (formerly S. typhi) vaccine (also called the Vi polysaccharide vaccine) has been studied as an alternative to the pneumococcal polysaccharide vaccine for assessing the polysaccharide response. Several studies indicate that it has the advantage that antibodies are usually absent in the population and are not present in immune globulin preparations [27-30]. Normal subjects develop protective titers to this vaccine, but patients with proven antibody deficiencies do not make antibodies to this vaccine. Further, it can be used in individuals who are on immune globulin therapy or have received recent immunoglobulin. Antibody titers to this vaccine are available in several reference laboratories. Experience with this vaccine has not been widely used in less severe antibody deficiencies and may not be useful in persons from developing countries in which Salmonella infections are common, so some individuals already have antibodies to this vaccine. The Vi polysaccharide vaccine is reviewed elsewhere. (See "Enteric (typhoid and paratyphoid) fever: Treatment and prevention", section on 'Licensed vaccines'.)

Severity of deficient responses — The patient is considered to have a deficient response to pneumococcal vaccination if the age-based expected percentages of postvaccination titers are not protective. Deficient responses can be further classified as severe or moderate, and this is discussed in detail elsewhere. (See "Specific antibody deficiency".)

ASSESSING RESPONSE TO PROTEIN ANTIGENS

Which vaccines are used? — Titers of IgG antibodies to tetanus and diphtheria in vaccinated children and adults are used to evaluate immune responsiveness to protein antigens. Results are reported as IgG in general, although the antibody responses generated by these vaccines are largely (but not exclusively) composed of IgG1 and IgG3 antibodies, which is sometimes important in evaluation of IgG subclass deficiency.

Children normally receive the diphtheria-tetanus-acellular pertussis (DTaP) vaccine series, which contains both diphtheria and tetanus toxoids, beginning at two months of age. Antidiphtheria and antitetanus toxoid antibodies should be measured only after a series of three immunizations has been completed, usually after six months of age. (See "Diphtheria, tetanus, and pertussis immunization in children 6 weeks through 6 years of age", section on 'Routine immunization'.)

In adults, a booster of tetanus and diphtheria is recommended every 10 years, although compliance is variable (figure 1). It is therefore common to find nonprotective levels, particularly to diphtheria, in healthy adults with normal immune function. In a cross-sectional survey of individuals in the United States, only 47 percent of adults over the age of 20 had protective antibody titers to both organisms [31].

Interpretation of tetanus and diphtheria titers — The protective level for diphtheria is 0.01 to 0.1 international units/mL, and the protective level for tetanus is >0.1 international units/mL [10]. If postvaccination titers are above these levels, the patient's response to protein antigens is normal.

Low or borderline-low titers need to be considered in the context of the immunization history:

Titers of 0.1 international units/mL in a patient immunized or reimmunized within a few months is probably not sufficient to document immunocompetence, as a higher titer would be expected shortly after vaccination. A booster dose can be given in this situation and titers reassessed.

Borderline-low or low titers do not necessarily indicate an immune problem if the patient was vaccinated several years before. The exact timing of the decrease of antibodies to the minimum protective levels after vaccination has not been established. Therefore, if either tetanus or diphtheria titers are at the lower limit of protection and the patient was not recently vaccinated, a booster dose should be given and titers reassessed.

If a patient has titers below protective levels to either tetanus or diphtheria, then a booster should be administered and titers reassessed.

Interpretation of Hib titers — The capsular polysaccharide polyribosylribitol phosphate (PRP) is an important antigen in immunity to Haemophilus influenzae type B (Hib). Anti-PRP IgG titers ≥1 mcg/mL are considered protective [32]. Although the polysaccharide PRP is the primary antigen, the conjugate vaccines employ either diphtheria toxoid or the outer membrane protein complex of meningococcus as the immunogenic protein. Therefore, antibodies to the Hib capsular polysaccharide in patients who received the conjugated Hib vaccine reflect a protein response, and protective antibodies against the PRP polysaccharide do not exclude unresponsiveness to the pure pneumococcal polysaccharides. Children in the United States have been receiving conjugated vaccines for prophylaxis against Hib since the early 1990s.

DISORDERS ASSOCIATED WITH ABNORMAL VACCINE RESPONSES — Various types of impaired vaccine responses are discussed briefly in this section with links to more detailed reviews of specific disorders. There are two commonly encountered patterns of vaccine nonresponse: combined nonresponse to protein and polysaccharide antigens and nonresponse to polysaccharide antigens only. Other patterns are unusual.

Protein and polysaccharide nonresponse — This combined type of nonresponse is indicative of profound immune defects and is seen in the following severe disorders:

Common variable immunodeficiency – Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and recurrent sinopulmonary infections, chronic diarrhea, and an enhanced risk of malignancy, granulomatous disease, and autoimmune manifestations including rheumatic, hematologic, and endocrine disorders. (See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults".)

Severe combined immunodeficiency – The severe combined immunodeficiency (SCID) syndromes are a heterogeneous group of disorders arising from a disturbance in the development and function of both T and B cells. As a result, both cellular and humoral immunity are severely impaired. However, in suspected cases of SCID, vaccine responses are not usually assessed, because it would delay necessary therapy. Instead, in vitro mitogen proliferation studies can be performed more quickly [1]. (See "Severe combined immunodeficiency (SCID): An overview".)

Hyperimmunoglobulin M syndromes – Hyperimmunoglobulin M syndromes are characterized by selective deficiency of IgG, very poor specific vaccine responses, and normal or elevated serum concentrations of IgM. Isohemagglutinins are sometimes present. (See "Hyperimmunoglobulin M syndromes".)

Polysaccharide nonresponse — Isolated polysaccharide nonresponse with intact protein response is seen in several primary immune disorders.

Specific pneumococcal antibody deficiency (sometimes called polysaccharide nonresponse or selective antibody deficiency with normal immunoglobulins) – This disorder is characterized by normal levels of serum IgG, IgA, and IgM and IgG subclasses. Patients present with recurrent sinopulmonary infections and demonstrate impaired response to polysaccharide antigens. (See "Specific antibody deficiency".)

IgG subclass deficiency – IgG subclass deficiencies are a group of disorders characterized by normal levels of IgG, IgA, and IgM but low levels of one or more IgG subclasses in patients with recurrent sinopulmonary infections and impaired response to vaccination. (See "IgG subclass deficiency".)

IgA deficiency – A minority of patients with selective IgA deficiency have concomitant IgG subclass deficiency, particularly IgG2, and thus may have impaired antibody responses to polysaccharide vaccines. The finding of polysaccharide nonresponsiveness in young patients with IgA deficiency may also represent a presentation of an evolving CVID phenotype, rather than isolated IgA deficiency. (See "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis".)

Agammaglobulinemia and hypogammaglobulinemia – This spectrum of disorders is discussed elsewhere. (See "Primary humoral immunodeficiencies: An overview".)

Nonresponse to conjugate polysaccharides — Failure to respond to the pneumococcal conjugate vaccine has been observed regularly by the authors and others. The etiology and clinical implications of this finding are under investigation. Some of these patients subsequently respond to immunization with the polysaccharide vaccine, while others do not. Some patients with specific antibody deficiency with normal immunoglobulins (polysaccharide nonresponse) have also been reported to be unresponsive to an initial dose of conjugate pneumococcal vaccine [33]. (See "Specific antibody deficiency".)

Antibody disorders with normal vaccine response — Specific antibody measurements and vaccine challenge are essential components of the diagnosis of transient hypogammaglobulinemia of infancy (THI). In THI, immunoglobulin levels are low, but vaccine responses are normal or nearly normal. This disorder has been classically defined as an accentuation and prolongation of the "physiologic" hypogammaglobulinemia of infancy, which is normally observed during the first three to six months of life. Patients present with recurrent sinopulmonary and sometimes more severe infections. (See "Transient hypogammaglobulinemia of infancy".)

INVESTIGATIONAL TOOLS — Investigational tools include novel antigens and improved testing of antibody function.

Novel antigens — Novel antigens are used in research settings when patients have received immune globulin or other plasma products, and it is not possible to assess vaccine response unless those therapies are stopped for several months. To circumvent this, novel antigens can sometimes be used.

A few specialized centers have access to the bacteriophage phiX174 [34]. This is a "neoantigen" to which normal individuals have not been previously exposed and to which antibodies are not present in commercially available immune globulin products. The use of this bacteriophage typically requires special authorization and interpretation at research institutions [35].

Rabies vaccines have also been used as neoantigens, although this practice cannot be recommended, because the normal response has not been sufficiently established [1]. Responses to either antigen represent protein responses.

A protein vaccine for tick-borne encephalitis virus (TBEV) is available in many European countries, although not in the United States. This can also be used to assess vaccine response in patients receiving immune globulin therapy [36,37].

Functional antibody testing — The only true functional antibody test is the measurement of opsonophagocytic activity against specific Streptococcus pneumoniae serotypes present in human serum. This in vitro method measures the extent to which a serum sample opsonizes pneumococci to promote ingestion and killing of bacteria by neutrophils [38]. Both IgM and IgG antibodies against protein and polysaccharide S. pneumoniae surface antigens are involved in opsonophagocytosis. Although routinely used to assess the effectiveness of new pneumococcal vaccines, the clinical use of this method to assess antibody function is labor intensive and costly and thus not feasible for use by commercial laboratories.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY AND RECOMMENDATIONS

Response to vaccination serves as a correlate of the patient's ability to fight natural infections and is a component of the diagnosis of several primary and secondary immunodeficiencies. The clinical indications for assessing vaccine response (and the humoral immune system) include frequent and recurrent sinopulmonary or otic infections, chronic gastrointestinal infections, any severe or unusual infections, and poor response to antibiotics (table 1). (See 'Indications for assessing vaccine response' above.)

Response to both protein (eg, tetanus and diphtheria) and polysaccharide (eg, pneumococcal) antigens should be assessed. Only immunoglobulin (Ig)G titers are used in the evaluation because IgG confers long-term immunity. When assessing vaccine response, it is essential that the same laboratory process both the pre- and postvaccination samples and that a minimum duration of one month be allowed to elapse between vaccination and measurement of response. (See 'General principles' above.)

There are two well-described patterns of nonresponse to vaccines: an inability to respond effectively to polysaccharide antigens only (polysaccharide nonresponse) and an inability to respond effectively to both polysaccharide and protein antigens. (See 'Patterns of nonresponse' above.)

The assessment of responsiveness to polysaccharide antigens is influenced by the patient's age:

In children under two years of age, the assessment of a pure response to polysaccharide antigens is difficult, and this is not recommended until the child has completed his/her primary vaccination series with the conjugate vaccine. (See 'Assessing pneumococcal polysaccharide responses' above.)

In adults and children older than two years, response to polysaccharide antigens can be evaluated by measuring at least 14 and preferably 23 serotypes to pneumococcal polysaccharides (table 3). In patients who received the conjugate vaccine, titers to serotypes in that vaccine are not relevant to polysaccharide responsiveness. Criteria for adequate responses have been proposed (table 2). (See 'Adults and children over two years' above.)

An algorithm of the evaluation is provided (algorithm 1). If an age-appropriate percentage of titers are protective (≥1.3 mcg/mL), then the patient can respond to polysaccharide antigens, and no further evaluation is needed. (See 'Interpretation of pneumococcal titers' above.)

If an age-appropriate percentage of titers are not protective (table 2), then the patient should be vaccinated with the polysaccharide vaccine and titers repeated four to six weeks later.

Antibodies to tetanus and diphtheria toxoids can be measured in vaccinated children and adults to evaluate responsiveness to protein antigens. (See 'Assessing response to protein antigens' above.)

There are two commonly encountered patterns of vaccine nonresponse: combined nonresponse to protein and polysaccharide antigens and nonresponse to polysaccharide antigens only. The former is characteristic of more global immunodeficiencies (eg, severe combined immunodeficiency, common variable immunodeficiency), and the latter is characteristic of less severe problems (eg, specific antibody deficiency, IgG subclass deficiencies). Normal vaccine responses are typical of transient hypogammaglobulinemia of infancy. (See 'Disorders associated with abnormal vaccine responses' above.)

ACKNOWLEDGMENTS — The editorial staff at UpToDate acknowledge E Richard Stiehm, MD, who contributed as a Section Editor to an earlier version of this topic review.

The editorial staff at UpToDate also acknowledge Ricardo U Sorensen, MD, who contributed as an author to an earlier version of this topic review.

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Topic 3929 Version 23.0

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