INTRODUCTION — Infections in patients with primary immunodeficiency disorders (PID), which are now referred to as inborn errors of immunity (IEI), 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 .
This topic review will discuss immunizations in patients with IEIs. Other measures to prevent infection in this patient population include immune globulin therapy, prophylactic antimicrobials, and lifestyle modifications, which are reviewed separately. (See "Primary immunodeficiency: Overview of management".)
Topics on vaccination of patients with various forms of secondary immunodeficiency are found separately:
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 IEIs, 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) .
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 .
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 mRNA vaccines in use against 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 IEIs because they are at increased risk for these infections, such as pneumococcal and meningococcal vaccines in patients with complement deficiencies (table 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) , varicella vaccines [15,16], and with measles from the measles-mumps-rubella (MMR) vaccine . 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 primary immunodeficiencies".)
Viral — Live viral vaccines include:
●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')
●Herpes zoster (no longer available in the United States) (see "Vaccination for the prevention of shingles (herpes zoster)")
●Rotavirus (see "Rotavirus vaccines for infants")
●Adenovirus (used predominantly in military personnel)
Bacterial — Live bacterial vaccines include:
●BCG (see "Vaccines for prevention of tuberculosis")
●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. As an example, one study of 26 patients with humoral IEIs given the trivalent influenza vaccine found that only 29 percent had a significant increase in titer and 83 percent attained protective levels, compared with 77 and 100 percent, respectively, of healthy controls .
RISK ACCORDING TO TYPE OF IEI — All patients with IEIs 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) .
●Severe IEIs include severe combined immunodeficiency 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 largely irrelevant.
●Partial combined immunodeficiencies include Wiskott-Aldrich syndrome, 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 .
Severe — Severe IEIs 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 (OPV), 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 (Ig)A or IgG subclass deficiencies or specific antibody deficiency, should not receive the OPV, Bacille Calmette-Guérin (BCG), or yellow fever vaccines but can receive other live vaccines if they are not receiving IgG replacement .
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) . 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.
Influenza vaccine is strongly recommended for CGD, as influenza infection has an important association with severe secondary bacterial infections in these patients .
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 IEIs' 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 (NF)-kappa-B essential modulator (NEMO) deficiency, and 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) should not receive live viral vaccines . (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 NF-kappa-B pathway that present as a combined immunodeficiency. (See "Combined immunodeficiencies".)
Phenocopies of IEIs — 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 [22,23]. (See "Mendelian susceptibility to mycobacterial diseases: An overview", section on 'Differential diagnosis'.)
VACCINES RECOMMENDED FOR SPECIFIC IEIs — The vaccines that are particularly important for patients with different types of primary 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 IEIs who are capable of responding to vaccination in any capacity. This is especially important for some IEIs, such as chronic granulomatous disease.
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) . In addition, patients with 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 .
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, GATA2 deficiency, idiopathic CD4 lymphopenia, leukocyte-adhesion deficiency type 1, nuclear factor (NF)-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) .
Zoster vaccine — The recombinant zoster (shingles) vaccine (Shingrix [brand name]) is a non-live subunit vaccine that was approved in the United States in 2017 for use in adults over the age of 50. In 2021, it was approved 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 NK deficiency, but also a growing number of disparate primary immunodeficiencies that share susceptibility to VZV and other herpes viruses . 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. Note that vaccination against VZV is not needed in patients receiving regular infusions of immune globulin. (See 'Passive protection' below.)
Patients receiving immune globulin — There are several issues to consider in patients with IEIs 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 [26-28]. 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 .
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) .
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 [19,29,30]. 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 :
●HHCs should be given the vaccines for varicella, measles-mumps-rubella (MMR), and rotavirus [19,32]. 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. Diligent handwashing after changing the diaper of an immunized infant minimizes rotavirus transmission .
●Inactivated influenza vaccine is recommended for HHCs (in preference to live influenza vaccine).
●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 IEIs undergoing hematopoietic cell transplantation — Recommendations for vaccination of patients with IEIs 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 women at risk for having an immunodeficient child — Pregnant women are routinely vaccinated with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) and inactivated influenza vaccine. However, if a woman is at risk for having a child with immunodeficiency, she 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 .
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. Two of these vaccines are composed of lipid nanoparticle-enclosed RNA that encodes the spike (S) protein of the SARS-CoV-2 virus (Pfizer and Moderna). A third vaccine (Johnson and Johnson) contains a replication-incompetent adenovirus that has been modified with DNA that encodes the spike protein of SARS-CoV-2. This adenovirus can enter cells but cannot replicate or cause illness . 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.
Data on immune responses to these vaccines in patients with primary immunodeficiency are limited but generally encouraging [34-37]. In addition, no significant adverse events have been reported in any study examining SARS-CoV-2 immunizations in patients with IEIs.
●One study examined antibody responses to Pfizer-BioNTech, Moderna, and Johnson & Johnson vaccines in 81 adult patients with IEIs. Patients included 13 with antibody deficiency, 14 with type I autoimmune polyendocrinopathy syndrome, 26 with autosomal dominant hyper-IgE syndrome, 10 with other immune regulatory disorders, and 20 with other IEIs, both pre and post-hematopoietic stem cell transplant . Anti-S antibodies were detected in 27 of 46 patients after one dose of mRNA vaccine and in 63 of 74 fully immunized patients. Patient groups with lower antibody responses included those with baseline CD3+T counts <1000 cells/mL, CD19+B cells < 100 cells/mL, or patients who had used rituximab prior to vaccination.
●In another study of 26 adults with different types of IEIs (four with X-linked agammaglobulinemia [XLA], 17 with predominantly antibody deficiency, and five with other defined defects), humoral and cellular immune responses were studied two weeks after the second dose of Pfizer-BioNTech and compared with healthy individuals (whose responses served as controls) . Overall, 19/26 mounted a cellular response. Antibody responses were absent in the four patients with XLA but intact in 18 of the remaining 22 patients. However, peripheral blood mononuclear cells from the patients with XLA showed robust interleukin-2 and interferon gamma production when stimulated with different peptide mixtures from SARS-CoV-2, which in some cases, was more vigorous than that of the healthy controls. Thus, vaccination was useful even in patients with no B cells.
In August 2021, the US Centers for Disease Control and Prevention (CDC) recommended and the US FDA approved an additional (third) dose of either the Pfizer (for ages 12 years and older) or Moderna (for ages 18 and older) COVID-19 mRNA vaccines for patients with "moderate to severe primary immunodeficiency (such as DiGeorge syndrome, Wiskott-Aldrich syndrome)" . Given this guidance, patients and physicians may question whether specific diagnoses are classified as "moderate to severe." It is important to note that primary immunodeficiencies 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 physicians 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 a primary immunodeficiency diagnosis should be considered for a third vaccine dose. Guidance from organizations focused on specific disorders may be available as an additional resource. The CDC has not yet offered guidance for immunocompromised people who received the Johnson & Johnson (Janssen) COVID-19 vaccine.
We do not obtain antibody levels following vaccination. Patients and physicians 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.
●There is presently no way to assess T cell responses.
●Vaccine efficacy studies were not based on antibody responses, but rather development of symptomatic infection and disease severity in vaccinated patients compared with controls.
Depending on the patient's diagnosis, we may advise patients to continue masking and taking other precautions that are commonly recommended for unvaccinated patients. Immune globulin may offer some protection when enough of the donor population has been immunized or exposed, but that remains to be established. Studies published in early 2021 found that commercial immune globulin products contained antibodies that were cross reactive to SARS-CoV-2 [39,40]. Vaccination remains necessary, particularly as antibodies from these IVIG preparations failed to confer in vitro viral neutralization .
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: Primary immunodeficiencies".)
SUMMARY AND RECOMMENDATIONS
●Two questions should be asked when considering immunization in a patient with primary immunodeficiency or an inborn error of immunity (IEI): Is the specific vaccine safe for this patient, and is it likely to be effective? (See 'Approach to the patient' above.)
●Vaccines containing killed micro-organisms, mRNA encoding proteins, or subcomponents of micro-organisms 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 and 'Efficacy of vaccination' above.)
●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. An important exception is influenza, which mutates frequently enough that titers in immune globulin are generally not sufficient to protect from the circulating strain. Immune globulin can also reduce the efficacy of some vaccines. (See 'Patients receiving immune globulin' above.)
●Certain vaccines are specifically recommended for patients with different types of primary and secondary immunodeficiency states because of underlying susceptibilities (table 1). (See 'Vaccines recommended for specific IEIs' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Francisco A Bonilla, MD, PhD, who contributed to an earlier version of this topic review.
The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to an earlier version of this topic review.