Immunizations in patients with inborn errors of immunity

INTRODUCTION — Infections in patients with inborn errors of immunity (IEI; formerly "primary immunodeficiency disorders"), often result in excessive morbidity and mortality, and antimicrobial therapy may be less effective than in the unimpaired host. Therefore, prevention through vaccination is an important component of care for patients with these diseases [1].

This topic review will discuss immunizations in patients with IEI. Other measures to prevent infection in this patient population include immune globulin therapy, prophylactic antimicrobials, and lifestyle modifications, which are reviewed separately. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management".)

Topics on vaccination of patients with various forms of secondary immunodeficiency are found separately:

●(See "Immunizations in adults with cancer".)

●(See "Immunizations in persons with HIV".)

●(See "Immunizations in patients with end-stage kidney disease".)

●(See "Immunizations for adults with chronic liver disease".)

●(See "Prevention of infection in patients with impaired splenic function", section on 'Vaccinations'.)

●(See "Immunizations in hematopoietic cell transplant candidates and recipients".)

●(See "Immunizations in solid organ transplant candidates and recipients".)

APPROACH TO THE PATIENT — Two questions should always be considered before vaccinating a patient with an IEI:

●Could the patient be harmed by administration of a live viral or bacterial vaccine? In some IEI, infectious agents in live vaccines can proliferate and cause disseminated infection and vaccine-induced disease.

●Will the patient make a sufficient response to the vaccine to justify its use?

The approach presented in this topic review is consistent with recommendations from the United States Centers for Disease Control and Prevention (CDC) [2].

Safety — During vaccine development, tests of safety and efficacy are performed on immunologically normal individuals, so safety in immunodeficient patients must be estimated based on the immune defect present.

Adverse events associated with vaccines should be reported to the United States Department of Health and Human Services using the Vaccine Adverse Events Reporting System (VAERS; telephone number 1-800-822-7967). Reportable events are reviewed separately. (See "Standard immunizations for nonpregnant adults", section on 'Adverse event reporting' and "Standard immunizations for children and adolescents: Overview", section on 'Reporting adverse events'.)

The United States government Vaccine Injury Compensation Program (VICP), established in 1988, compensates patients, including immunodeficient infants, children, and adults, who are thought to have suffered death or other injury as a result of administration of a childhood vaccine. Full details are available elsewhere on the Health Resources and Services Administration website [3].

Killed, inactivated, mRNA, or subcomponent vaccines — Killed or subcomponent vaccines may contain inactivated whole, fragmented, or modified bacteria and viruses, as well as toxoids, purified polysaccharides, and protein-polysaccharide conjugate vaccines. The messenger ribonucleic acid (mRNA) vaccines in use against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be considered to be subcomponent vaccines as well. These types of vaccines have no risk beyond what is encountered in immunocompetent individuals and may be given to immunodeficient patients when they offer possible benefit [4-6]. Among those vaccines that are unlikely to be harmful, some are of particular importance to patients with certain IEI because they are at increased risk for these infections, such as pneumococcal and meningococcal vaccines in patients with complement deficiencies (table 1) [1].

Live vaccines — The safety of live (also called live-attenuated) vaccines varies with the degree of immunodeficiency. Particularly in patients with combined immunodeficiencies (but also in other rare instances discussed below), vaccination with live vaccines can cause disseminated infection. Vaccine-induced infection in patients with unrecognized immunodeficiency has been reported with oral polio vaccine [7-10], rotavirus [11-13], Bacille Calmette-Guérin (BCG) [14], varicella vaccines [15,16], and with measles from the measles-mumps-rubella (MMR) vaccine [17-19]. Beginning in 2000, oral polio vaccines were no longer licensed in the United States and Canada, although they are still used in other parts of the world.

In countries that are implementing newborn screening for severe combined immunodeficiency (SCID) disorders, the vast majority of affected infants will be detected before any live vaccines are given. Infants with a positive screening test should not be given any live vaccines until SCID and other conditions involving T cell lymphopenia have been excluded. The principal exception to this generalization occurs in countries where BCG vaccine is routinely administered before discharge from the hospital, which may occur before the results of newborn screening are available in some cases. In contrast, in countries without newborn screening programs, inadvertent administration to a newborn with an IEI remains a risk. Rotavirus vaccines should not be given to infants in the hospital or the nursery, because of possible spread to severely immunocompromised patients. (See "Newborn screening for inborn errors of immunity".)

Viral — Live viral vaccines include:

●MMR (see "Measles, mumps, and rubella immunization in infants, children, and adolescents")

●Measles-mumps-rubella-varicella

●Oral poliovirus (not available in the United States) (see "Poliovirus vaccination", section on 'Live attenuated oral poliovirus vaccine')

●Live-attenuated influenza vaccine (see "Seasonal influenza in children: Prevention with vaccines")

●Yellow fever (see "Immunizations for travel", section on 'Yellow fever vaccine')

●Varicella (see "Vaccination for the prevention of chickenpox (primary varicella infection)")

●Herpes zoster (no longer available in the United States) (see "Vaccination for the prevention of shingles (herpes zoster)")

●Rotavirus (see "Rotavirus vaccines for infants")

●Smallpox (vaccinia)

●Adenovirus (used predominantly in military personnel)

Bacterial — Live bacterial vaccines include:

●BCG (see "Prevention of tuberculosis: BCG immunization and nutritional supplementation")

●Oral Ty21a Salmonella typhimurium (see "Immunizations for travel", section on 'Typhoid vaccine')

Efficacy of vaccination — Patients with specific disorders may not respond fully to vaccines, although the general advice is to vaccinate if there is possible benefit to the patient. The greater the degree of immunosuppression, the less likely the patient is to generate protective immunity.

RISK ACCORDING TO TYPE OF IEI — All patients with IEI can receive inactivated vaccines according to the routine schedule (provided the patient has the theoretical ability to respond to vaccines). The use of live attenuated vaccines is discussed in this section.

Combined immunodeficiencies — Patients with combined immunodeficiencies have impaired cellular (T cell) and humoral (B cell) immunity. All live vaccines (viral and bacterial) are contraindicated in severe and partial combined immunodeficiencies (table 1) [1].

●Severe IEI include severe combined immunodeficiency (SCID) and complete DiGeorge syndrome (DGS). All live vaccines of any type are contraindicated in these disorders. Inactivated vaccines are unlikely to be effective and are not typically administered.

●Partial combined immunodeficiencies include Wiskott-Aldrich syndrome (WAS), ataxia-telangiectasia, and many others. All live vaccines are generally contraindicated in these disorders. Inactivated vaccines may be at least partially effective in some cases and can be administered.

●Vaccination in less severe DGS (most patients) is considered on a case-by-case basis. Those patients with >500 CD3+ T lymphocytes/mm³, >200 CD8+ T lymphocytes, and normal proliferative response to mitogens can be considered for measles-mumps-rubella (MMR) and varicella vaccination. Measles-mumps-rubella-varicella is contraindicated [20].

Antibody deficiencies — Some live viral and bacterial vaccines are contraindicated in antibody deficiencies, depending upon the severity of antibody dysfunction (table 1) [1].

Severe — Severe IEI affecting B cell function (ie, humoral immunity) include X-linked (or autosomal recessive) agammaglobulinemia and common variable immunodeficiency. These patients should not receive certain live vaccines, such as oral poliovirus, smallpox, live-attenuated influenza vaccine, yellow fever, or live oral typhoid vaccines. Other live vaccines, such as MMR or varicella, are not given, because patients on immune globulin therapy should have passive immunization.

Mild — Patients with milder antibody deficiencies, such as symptomatic immunoglobulin A (IgA) or immunoglobulin G (IgG) subclass deficiencies or specific antibody deficiency, should not receive the oral poliovirus, Bacille Calmette-Guérin (BCG), or yellow fever vaccines but can receive other live vaccines if they are not receiving IgG replacement [20].

Phagocyte defects — Phagocyte defects include congenital neutropenias, chronic granulomatous disease (CGD), leukocyte-adhesion deficiency, and myeloperoxidase deficiency. Patients with these disorders should not be given live bacterial vaccines (table 1) [1]. However, all can safely receive live viral vaccines with the exception of those with leukocyte-adhesion defects and cytotoxic granule defects, who may have some deficiency in viral responses as well [5,21-23].

Influenza vaccine is strongly recommended for CGD as influenza infection has an important association with severe secondary bacterial infections in these patients [24].

Complement deficiencies and congenital asplenia — Patients with complement deficiencies have intact cellular and humoral immunity and can receive all live and inactivated vaccines. It is especially important to vaccinate these patients against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae. Similarly, patients with congenital asplenia should be immunized against these encapsulated bacteria using protein-conjugated vaccines. (See 'Vaccines recommended for specific IEI' below.)

Innate immune defects — In patients with defects in innate immunity, the specific susceptibilities seen with each disorder should guide vaccine use. Examples are given below:

●Patients with innate immune defects that are associated with invasive bacterial infections should not be given live bacterial vaccines, such as the Salmonella vaccine. Examples of these disorders include defects in the interleukin (IL) 12-interferon (IFN) gamma axis, nuclear factor-kappa-B essential modulator (NEMO) deficiency, and GATA-binding protein 2 (GATA2) deficiency. (See "Mendelian susceptibility to mycobacterial diseases: Specific defects".)

●Patients with innate immune defects associated with severe viral infections (eg, defects in type 1 interferon signaling, such as signal transducer and activator of transcription 1 deficiency and signal transducer and activator of transcription 2 deficiency) should not receive live viral vaccines [25,26]. (See "Mendelian susceptibility to mycobacterial diseases: Specific defects", section on 'STAT1 defects'.)

●Patients who have increased susceptibility to mycobacterial infections (all the disorders mentioned above) should not be given the BCG vaccine. (See "Mendelian susceptibility to mycobacterial diseases: Specific defects", section on 'STAT1 defects'.)

●All live viral and bacterial vaccines are contraindicated in disorders of the nuclear factor-kappa-B pathway that present as a combined immunodeficiency. (See "Syndromic immunodeficiencies".)

Phenocopies of IEI — The term "phenocopy" refers to an acquired somatic mutation or autoimmune process resulting in a phenotype that mimics an inherited germline mutation. A category called "phenocopies of inborn errors of immunity" includes disorders caused by somatic mutations in genes, as well as disorders caused by autoantibodies to various cytokines, cell surface glycoproteins, or complement factors. The presence of autoantibodies to cytokines can result in immunodeficiency states similar to those caused by inherited defects in the affected pathways. Infections associated with these disorders are variable, as with defects of innate immunity, and similar considerations apply. For example, patients with autoantibodies to IFN-gamma are similar to those with Mendelian susceptibility to mycobacterial disease and should not receive live bacterial vaccines (BCG or Salmonella vaccine). Those with autoantibodies to type 1 interferons should not receive live viral vaccines [27-29]. (See "Mendelian susceptibility to mycobacterial diseases: An overview", section on 'Differential diagnosis'.)

VACCINES RECOMMENDED FOR SPECIFIC IEI — The vaccines that are particularly important for patients with different types of IEI and secondary immunodeficiency states because of underlying susceptibilities are reviewed in the table (table 1) [1,6].

Inactivated influenza — A yearly inactivated influenza vaccine is recommended for all patients with IEI who are capable of responding to vaccination in any capacity. This is especially important for some IEI, such as chronic granulomatous disease (CGD).

Some patients may respond better to repeated doses or higher doses (ie, two standard doses at least one month apart or high-dose vaccine).

Pneumococcal vaccine — Pneumococcal vaccination with the conjugate vaccine is recommended for patients with combined immunodeficiencies, antibody deficiency, complement deficiencies, congenital asplenia, and phagocyte disorders who are not receiving immune globulin (table 1) [1]. In addition, patients with interleukin (IL) 1-receptor-associated kinase 4 (IRAK4) deficiency or myeloid differentiation primary response gene 88 (MyD88) deficiency are particularly susceptible to invasive pneumococcal disease and should be vaccinated.

During the course of evaluation for humoral immunodeficiency, patients with milder antibody deficiencies, such as symptomatic IgA or IgG subclass deficiencies or specific antibody deficiency, are frequently vaccinated with the pneumococcal polysaccharide vaccine (PPV23) after two years of age for purpose of assessing responsiveness to polysaccharide antigens (ie, as part of the diagnosis). Patients who are complete nonresponders are often treated with immune globulin. However, partial responders may derive some protection as a result of vaccination.

Meningococcal vaccine — Meningococcal vaccine should be administered to patients with complement defects, congenital asplenia, and those with combined immunodeficiencies. For patients with asplenia, conjugated meningococcal vaccines are recommended as patients may not respond to the pure polysaccharide vaccine. The different conjugated vaccines for prevention of meningococcal infection are reviewed separately. (See "Meningococcal vaccination in children and adults", section on 'MenACWY'.)

Haemophilus influenzae b vaccine — One dose of H. influenzae type b (Hib) conjugate vaccine should be given after five years of age to unimmunized patients at increased risk for infections with encapsulated bacteria [4].

Human papilloma virus vaccine — The human papilloma virus vaccine should be considered for all patients but especially for those with increased susceptibility to papilloma virus infection, including ataxia-telangiectasia, CD40/CD40 ligand deficiency, common variable immunodeficiency, dedicator of cytokinesis 8 (DOCK8) deficiency, epidermodysplasia verruciformis, GATA-binding protein 2 (GATA2) deficiency, idiopathic CD4 lymphopenia, leukocyte-adhesion deficiency type 1, nuclear factor-kappa-B essential modulator (NEMO) deficiency, Netherton syndrome, serine threonine kinase 4 (STK4) deficiency, WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome, WILD (warts, immunodeficiency, lymphedema, and anogenital dysplasia) syndrome, or Wiskott-Aldrich syndrome (WAS) [1].

Zoster vaccine — The recombinant zoster (shingles) vaccine (Shingrix [brand name]) is a non-live subunit vaccine for use in adults over the age of 50 years and for patients 18 years or older with immunodeficiency conditions that increase the risk of varicella-zoster virus (VZV) infection. This includes patients with combined immunodeficiencies and natural killer (NK) deficiency but also a growing number of disparate IEI that share susceptibility to VZV and other herpes viruses [30]. The vaccine is normally given as two doses separated by two to six months, but, in immunodeficient patients, the second dose can be given one to two months after the first. (See "Vaccination for the prevention of shingles (herpes zoster)".)

Note that vaccination against VZV is not needed in patients receiving regular infusions of immune globulin. (See 'Passive protection' below.)

SPECIAL POPULATIONS

Patients receiving immune globulin — There are several issues to consider in patients with IEI who are receiving immune globulin.

Passive protection — Patients receiving regular infusions of immune globulin should have protective titers to most common vaccine agents (eg, measles-mumps-rubella-varicella) given to the general population and are at least partly protected from these diseases. Immune globulin contains protective titers of antibodies to pneumococcus and H. influenza type B (Hib) and variable (but usually protective) titers to meningococcus [31-33]. In contrast, immune globulin contains low levels of antibodies to circulating pathogenic strains of influenza because antigenic drift and shift with influenza are sufficient to prevent the formation of herd immunity, necessitating yearly immunization [4].

Immunodeficient patients on maintenance immune globulin who are exposed to an illness for which a "hyperimmune" immune globulin is recommended (eg, rabies, hepatitis B, tetanus) should receive the pathogen-specific immune globulin in the recommended dose since standard immune globulin preparations have no or variable levels of antibodies to these pathogens.

Interference with vaccine response — Although the presence of neutralizing antibodies against the organisms in common vaccines in immune globulin provides protection against infection, these same antibodies may render live-attenuated vaccines inactive. Thus, most experts do not administer routine vaccines to patients receiving immune globulin, except against those pathogens to which there is little antibody in the plasma donor pool (eg, influenza) [4].

Interference by immune globulin on vaccine response has been documented for measles, rubella, and varicella live vaccines, while the effect on mumps vaccine is not known [20,34,35]. If desired and appropriate based on the underlying diagnosis, these vaccines could be given once the patient has stopped immune globulin for a period of 3 to 11 months, depending upon the immune globulin dose. Other live vaccines that are not given routinely to the general population may be given to patients receiving immune globulin, provided they are considered safe for that patient.

Healthy household contacts of immunodeficient patients — All inactivated vaccines should be offered to healthy household contacts (HHCs) of immunocompromised patients, according to the usual schedule.

Recommendations about live viral vaccines are as follows and apply to HHCs of immunocompromised individuals who cannot receive live viral vaccines themselves [36]:

●HHCs should be given the vaccines for varicella, measles-mumps-rubella (MMR), and rotavirus [5,20,37]. MMR and varicella viruses are not significantly shed from the immunized individual after these vaccines. However, if the HHC develops a rash after varicella vaccine, the immunocompromised patient should be isolated from that contact, and zoster immune globulin should be administered to the immunocompromised individual. Immunocompromised patients should not handle diapers of infants who have been vaccinated with rotavirus vaccine for four weeks after vaccination [5,37].

●Inactivated influenza vaccine is recommended for HHCs (in preference to live influenza vaccine).

●HHCs should not be given oral polio vaccine, because of the possibility of fecal-oral transmission. Smallpox vaccine is also contraindicated [37].

●Other live viral and bacterial vaccines, aside from those discussed above (ie, oral polio, live influenza, and smallpox), can be safely given to HHCs because there is no evidence of increased risk of transmission of infection to immunocompromised contacts.

Patients with IEI undergoing hematopoietic cell transplantation — Recommendations for vaccination of patients with IEI following hematopoietic cell transplantation are reviewed separately. (See "Immunizations in hematopoietic cell transplant candidates and recipients".)

Infants and children with hypogammaglobulinemia of infancy — If otherwise well, these infants should receive the recommended doses of killed vaccines at the appropriate ages. Premature infants in the nursery should not receive oral rotavirus vaccine until the date of discharge, because of possible spread through the nursery. Older infants with transient hypogammaglobulinemia can also receive routine killed vaccines. Hypogammaglobulinemic infants beyond one year of age should be studied for an IEI before live virus vaccines are given.

Pregnant people at risk for having an immunodeficient child — Pregnant people are routinely vaccinated with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) and inactivated influenza vaccine. However, if a pregnant person is at risk for having a child with immunodeficiency, they should also receive pneumococcal, Hib, and meningococcal vaccines. This is recommended to generate protective maternal IgG antibodies that will be transferred to the newborn and provide protection in the first few months after birth [36].

Vaccinations for travel — Issues related to vaccination and travel in immunocompromised individuals are discussed elsewhere. (See "Immunizations for travel", section on 'Immunocompromised patients' and "Travel advice for immunocompromised hosts".)

ISSUES RELATED TO SARS-COV-2 VACCINATION — Three vaccines have been authorized by the US Food and Drug Administration (FDA) for prevention of coronavirus disease 2019 (COVID-19) in the United States (see "COVID-19: Vaccines"). Two of these vaccines are composed of lipid nanoparticle-enclosed RNA that encodes the spike (S) protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus (Pfizer and Moderna). A third vaccine (Novavax) is a protein subunit vaccine. As of May 2023, the Janssen/Johnson & Johnson COVID-19 vaccine (Ad26.COV2.S) is no longer available in the United States. All three vaccines are considered inactivated or subcomponent vaccines. They have no risk beyond what is encountered in immunocompetent individuals and may be given to immunodeficient patients when they offer possible benefit.

No significant adverse events have been reported in any study examining SARS-CoV-2 immunizations in patients with IEI.

Data on immune responses to COVID-19 vaccines in patients with IEI are generally encouraging [38,39]. With the exception of X-linked agammaglobulinemia and combined immunodeficiencies, most patients with IEI generate protective antibody responses. Notably, antigen-specific T cell responses have been detected in patients with X-linked agammaglobulinemia, suggesting a degree of T cell-mediated protection even in patients who are not able to make an antibody response [38].

The US Centers for Disease Control and Prevention (CDC) have been making recommendations regarding vaccination for patients with "moderate to severe primary immunodeficiency (such as DiGeorge syndrome, Wiskott-Aldrich syndrome)" [40]. Given this guidance, patients and clinicians may question whether specific diagnoses are classified as "moderate to severe." It is important to note that IEI are typically not classified by severity, and, for most disorders, little is known about the specific susceptibility to COVID-19 or the durability of the vaccine response. We therefore advise clinicians to consider their patients based on their diagnosis and an assessment of immune function, as well as their risk for acquiring COVID-19 infection in their community. We feel that any patient with an IEI diagnosis should be considered to have a moderate-to-severe immunodeficiency for the purpose of these guidelines. Guidance from organizations focused on specific disorders may be available as an additional resource. Recommendations for immunocompromised patients, including those with IEI, are described in detail separately. (See "COVID-19: Vaccines", section on 'Immunocompromised individuals'.)

We do not obtain antibody levels following vaccination. Patients and clinicians may wish to assess vaccine response after the vaccination series is complete by measuring levels of antibodies against the S protein. However, there are several issues that complicate interpretation of such testing:

●Protective antibody levels have not been identified for the general population.

●Antibody testing does not assess the efficacy of T cell responses, which are also relevant to a protective immune response.

There are data that suggest that immune globulin may offer some protection from COVID-19 as immune globulin preparations now contain neutralizing anti-SARS-CoV-2 antibodies [41-43]. Vaccination remains necessary as there are no data on clinical efficacy of immune globulin at reducing in SARS-CoV-2 infections or infection severity.

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

●Safety and efficacy – Two questions should be asked when considering immunization in a patient with an inborn error of immunity (IEI; formerly "primary immunodeficiency disorder"): Is the specific vaccine safe for this patient, and is it likely to be effective? (See 'Approach to the patient' above.)

•Vaccines containing killed microorganisms, messenger ribonucleic acid (mRNA) encoding proteins, or subcomponents of microorganisms are safe for all immunocompromised patients and should be given if the patient has sufficient ability to generate an immune response. In contrast, vaccines containing live-attenuated viruses or bacteria may result in unchecked proliferation and disseminated disease and are contraindicated in many forms of IEI (table 1). (See 'Safety' above.)

•Patients with specific disorders may not respond fully to vaccines, although the general advice is to vaccinate if there is possible benefit to the patient. (See 'Efficacy of vaccination' above.)

●Issues related to immune globulin – Immune globulin contains antibodies to common vaccine agents (eg, measles, varicella) and should provide at least partial protection from these diseases in patients who receive regular treatments. Important exceptions are influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) given that titers in immune globulin may not be specific for the circulating strains of these viruses. Immune globulin can also reduce the efficacy of some vaccines. (See 'Patients receiving immune globulin' above.)

●Some vaccines are important for specific IEI – Certain vaccines are specifically recommended for patients with different types of IEI and secondary immunodeficiency states because of underlying susceptibilities (table 1). (See 'Vaccines recommended for specific IEI' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Francisco A Bonilla, MD, PhD, and E Richard Stiehm, MD, who contributed to earlier versions of this topic review.