Principles of Vaccination in Patients With Primary Immunodeficiency

Prepared by Dr. Laura Tamašauskienė

 

About Primary Immunodeficiency

Primary immunodeficiency (PID) is a broad group of diseases characterized by a common feature—an innate defect in a specific component of the immune system. Today, this group includes more than 300 individual rare diseases. According to statistics, there are more than 6 million patients with PID worldwide (1).

Based on the affected component of the immune system, PID is classified into several groups (Table 1). PID is a genetic disease that can be passed on to children. Due to PID, the body is unable to adequately fight bacteria, viruses, fungi, or parasites. As a result, patients frequently suffer from various infectious diseases, which tend to be severe and may require prolonged courses of antibiotics, antiviral agents, or antifungal medications (1, 2).

Depending on the nature of the infections, the affected component of the immune system may be suspected. Bacterial infections are characteristic of complement component deficiencies, including deficiencies of C2, C3, Factor B, Factor H, Factor I, and properdin; meningococcal sepsis is characteristic of Factor D deficiency, while Neisseria infections are associated with deficiencies of C5–8 and properdin (1–5). Deficiencies of C1, C2, and C4 are associated with autoimmune diseases.

If a patient experiences recurrent bacterial infections, particularly those caused by gram-positive microorganisms, B lymphocyte and antibody deficiency may be suspected (1, 2). Viral, fungal, and opportunistic infections are characteristic of T lymphocyte deficiency. Infections caused by various microorganisms are typical of combined B and T lymphocyte deficiencies. If staphylococcal and gram-positive microorganism infections recur, phagocyte deficiency should be considered (1, 2).

Recurrent infectious diseases can lead to irreversible organ changes, life-threatening complications, and, in children, delayed development and impaired growth.

PID also includes congenital C1 esterase inhibitor deficiency, which manifests as angioedema affecting various parts of the body (1, 2). In addition, patients with PID are more prone to oncological and autoimmune diseases than other individuals.

Table 1. PID Classification (1, 2)

PID Grou	Most Common PID Types	Clinical Features
B Lymphocyte and Antibody Deficiency	Bruton's disease, selective IgA deficiency, common variable immunodeficiency, IgG subclass deficiency, hyper-IgM immunodeficiency	Bacterial infections
T Lymphocyte Count and/or Function Deficiency	Di George syndrome, chronic mucocutaneous candidiasis	Viral, fungal, opportunistic infections
Combined B and T Lymphocyte Deficiency	Severe combined immunodeficiency, Wiskott-Aldrich syndrome	Viral, fungal, opportunistic, bacterial infections
Complement Component Deficiency	C1 esterase inhibitor deficiency, C2, C3, C4, C5, C6, C7, C8, C9 deficiency, Factors H, I, D, B, properdin deficiency	Angioedema, autoimmune diseases, gram-negative microorganism infections (especially Neisseria)
Phagocytic Cell Deficiency	Hyper-IgE syndrome, leukocyte adhesion deficiency	Staphylococcal and gram-negative microorganism infections

When PID is suspected, laboratory tests are performed to identify the immune system defect. Treatment depends on the type of PID. In cases of B lymphocyte and antibody deficiency, effective immunoglobulin replacement therapy is used (1, 2, 6, 7). The aim of immunoglobulin therapy is to correct Ig levels and reduce susceptibility to infections.

Bone marrow transplantation is performed in cases of severe combined immunodeficiency and T-cell-related immunodeficiency (1, 2, 8). Fresh frozen plasma or specific complement components, such as C1 esterase inhibitor, are administered in cases of complement component deficiency (1, 2, 9, 10).

Patients with PID are closely monitored by physicians. Many questions arise regarding the appropriateness and safety of vaccination, and consequently these individuals often remain unvaccinated. This article discusses the principles of vaccination in patients with PID.

About Vaccines

Vaccination is one of the greatest achievements of modern medicine (11). Vaccines are biological preparations that enhance the immune response against specific diseases. Typically, vaccines contain a substance that mimics a disease-causing microorganism. They are usually made from weakened or killed microorganisms, their toxins, or surface proteins (12). After vaccination, the immune system recognizes the foreign material, destroys it, and remembers it so that it can rapidly recognize and destroy it during future encounters.

Vaccines are divided into two major groups. The first group includes live attenuated vaccines, which are composed of weakened pathogens. The second group includes subunit vaccines, toxoids composed of inactivated toxins, carbohydrate vaccines, and conjugate vaccines. The type of vaccine determines which part of the immune system will be activated—for example, whether antibody production will be initiated or a T lymphocyte-dependent immune response will occur.

Vaccination protects against morbidity, disability, and death caused by vaccine-preventable diseases. It is one of the most cost-effective preventive measures. In Lithuania, children are vaccinated with state funding against tuberculosis, diphtheria, tetanus, type B Haemophilus influenzae, pertussis, polio, measles, rubella, mumps, hepatitis B, and type B meningococcus (since 2018).

Another important group of individuals at high risk of infectious diseases is travelers. There is no single vaccination schedule applicable to all travelers. It is tailored individually, taking into account the risk of infectious diseases, age, health status, previous vaccinations, other risk factors, travel destination, and duration of travel.

Travel vaccines are divided into routine vaccines, such as hepatitis B and influenza vaccines; recommended vaccines, such as cholera and hepatitis A vaccines; and mandatory vaccines, such as the yellow fever vaccine. The most common vaccines are described in Table 2.

Table 2. Description of the Most Common Vaccines

Vaccine	Vaccine Type	Disease/Symptoms
BCG	Live	Tuberculosis
DTP	Combined, inactivated	Acute upper respiratory tract infection (diphtheria), acute disease characterized by generalized muscle spasms (tetanus), whooping cough (pertussis)
Hib	Polysaccharide, inactivated	Meningitis
HPV (Human Papillomavirus)	Inactivated	Genital warts, anogenital cancer
Influenza	Inactivated, live attenuated	Acute upper respiratory tract infection
IPV/OPV	IPV – inactivated; OPV – live	Poliomyelitis infection causing fever, meningitis, and paralysis
Meningococcal	Inactivated	Meningitis, meningococcemia
MMR	Combined, live attenuated	Measles, mumps, rubella infection
Pneumococcal	Inactivated	Sinusitis, otitis, pneumonia, systemic infection, meningitis
VZV	Live attenuated	Chickenpox, shingles
Cholera	Oral, inactivated	Acute diarrhea
Hepatitis A	Inactivated	Infectious liver disease, commonly accompanied by jaundice
Hepatitis B	Inactivated	Infectious liver disease that may present with flu-like symptoms
Japanese Encephalitis	Inactivated	May be asymptomatic or progress to severe encephalitis
Rabies	Inactivated	Affects the central nervous system, leading to respiratory failure and death
Tetanus	Inactivated	Muscle stiffness and spasms
Tick-borne Encephalitis	Inactivated	Flu-like symptoms; may involve CNS damage
Tick-borne Encephalitis	Oral, live; injectable, inactivated	Fever, muscle pain, diarrhea, headache, potential multi-organ damage
Yellow Fever	Live	Fever, photophobia, vomiting, progressing to jaundice and hemorrhage

Vaccination of a Patient With PID

Vaccines for individuals with primary immunodeficiency (PID) can reduce disease complications, the frequency of hospitalization, and mortality. However, the immune response to vaccines in these individuals may be weaker. The safety of vaccination depends on the type of PID diagnosed. In cases of antibody, complement, and phagocytosis deficiencies, almost all vaccines are safe. In cases of severe PID, particularly T-cell or combined immunodeficiency, live attenuated vaccines should not be administered because they can cause infection.

Many patients with PID and antibody deficiencies receive immunoglobulin replacement therapy to protect against infections by maintaining normal antibody levels. Patients receiving immunoglobulin therapy do not require vaccines, except for the influenza vaccine, because the influenza virus mutates annually, potentially rendering immunoglobulin therapy ineffective. There is increasing evidence that vaccines have a positive effect not only in preventing specific infectious diseases but also on overall immune system function. Vaccination can therefore be beneficial for patients with PID and should be performed.

Table 3. Vaccine Recommendations for Patients With Different Types of PID

PID Type	Not Recommended Vaccines	General Recommendations
T-cell deficiency and/or dysfunction (e.g., severe combined immunodeficiency)	• All live vaccines• Tuberculosis• Oral poliovirus• Rotavirus (in severe combined immunodeficiency and newborns with a family history of the disease)	Administer the inactivated poliovirus vaccine by injection rather than the oral poliovirus vaccine.
B-cell and antibody deficiency (e.g., common variable immunodeficiency)	• Yellow fever• Oral poliovirus	• All childhood vaccines can be administered according to standard recommendations (Hib, pertussis, tetanus, diphtheria, injectable inactivated poliovirus, meningococcal, measles, mumps, rubella)• Administer the inactivated poliovirus vaccine by injection rather than the oral poliovirus vaccine• Conjugate pneumococcal vaccine for children up to 2 years of age and polysaccharide vaccine from 2 years of age• Inactivated influenza vaccine annually from 6 months of age• Tuberculosis vaccine according to the vaccination schedule
Complement component deficiency	–	Most specialists recommend additional vaccination with Hib, pneumococcal, and meningococcal vaccines.
Phagocytosis disorder	• Tuberculosis• Live Salmonella typhi vaccine	All other vaccines, including live oral vaccines, can be administered.

It is important to protect not only the patient but also their family members from infections; therefore, family members of a patient with PID should also be vaccinated. Close relatives of patients with severe immunodeficiency, such as severe combined immunodeficiency, are advised not to receive live attenuated vaccines, except for measles, mumps, rubella, and tuberculosis vaccines.

Patients with PID and their close relatives should receive the inactivated poliovirus vaccine by injection rather than the oral poliovirus vaccine. Patients with PID should avoid contact with individuals who have received the oral poliovirus vaccine during the first 24 hours after vaccination and should avoid close physical contact for 4–6 weeks. These measures are unnecessary if patients receive immunoglobulin replacement therapy and have sufficient IgG levels in their blood. Vaccine recommendations for patients with different types of PID are summarized in Table 3.

Summary

PID is a broad group of diseases characterized by an innate defect in a specific component of the immune system. These diseases are classified as rare diseases. Depending on which component of the immune system is affected, PID is associated with various frequent, severe, and often complicated infections.

Vaccination of these individuals is one of the most common issues faced by healthcare professionals. To select a safe vaccine, it is important to know which type of PID the individual has and how the vaccine is manufactured, for example, whether it is a live or subunit vaccine. In cases of antibody, complement, and phagocytosis deficiencies, many vaccines can be administered. In cases of severe PID, particularly T-cell or combined immunodeficiency, live attenuated vaccines should not be administered because they can cause infection.

There are data showing that vaccines not only protect against specific diseases but also have a positive effect on overall immune system function. It is important to note that the response to vaccines in patients with PID may be weaker; nevertheless, vaccination can reduce disease complications, the frequency of hospitalization, and mortality.

Publication "Internist," No. 6, 2018.

REFERENCES 1.    Šitkauskienė B, Blažienė A. Recommendations for the diagnosis and treatment of primary immunodeficiency. Kaunas, 2016. 2.    Šitkauskienė B. Immunodeficiencies. Kaunas: KMU, 2006. 3.    Pettigrew HD, et al. Clinical significance of complement deficiencies. Ann N Y Acad Sci. 2009;1173:108-23. 4.    Brodszki N Immune responses following meningococcal serogroups A, C, Y and W polysaccharide vaccination in C2-deficient persons: evidence for increased levels of serum bactericidal antibodies. Vaccine. 2015;33(15):1839-45. 5.    Spickett G. Oxford handbook of clinical immunology and allergology. Oxford university press 2013. 6.    Lingman-Framme J, Fasth A. Subcutaneous immunoglobulin for primary and secondary immunodeficiencies: an evidence-based review. Drugs. 2013;73(12):1307–19. 7.    Torgerson TR. Overview of routes of IgG administration. J Clin Immunol. 2013;33 Suppl 2:S87–9. 8.    Slatter MA, Cant AJ. Hematopoietic stem cell transplantation for primary immunodeficiency diseases. Ann N Y Acad Sci. 2011;1238:122-31. 9.    Craig T, et al. WAO Guideline for the Management of Hereditary Angioedema. World Allergy Organ J. 2012;5(12):182-99. 10.    Cicardi M, et al. Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group. Allergy. 2014;69(5):602-16. 11.    Pulendran B, Ahmed F. Immunological mechanisms of vaccination. Nat Immunol. 2011 Jun; 12(6): 509–517. 12.    World Health Organisation. Vaccines. http://www.who.int/topics/vaccines/en/, accessed 2018-05-26. 13.    Užkrečiamųjų ligų ir AID centras. Vaccines. http://www.ulac.lt/lt, accessed 2018-05-26. 14.    International Patient Organisation for Primary Immunodeficiencies (IPOPI). Vaccines and primary immunodeficiencies (1st edition), 2013. 15.    Sobh A, Bonilla FA. Vaccination in Primary Immunodeficiency Disorders. J Allergy Clin Immunol Pract. 2016;4(6):1066-1075. 16.    Chapel H, Prevot J, Gaspar HB, Español T, Bonilla FA, Solis L, Drabwell J; Editorial Board for Working Party on Principles of Care at IPOPI. Primary immune deficiencies - principles of care. Front Immunol. 2014;5:627. 17.    Shearer WT, Fleischer TA, For the Medical Advisory Committee of the Immune Deficiency Foundation. Recommendations for live viral and bacterial vaccines in immunodeficient patients and their close contacts. J Allergy Clin Immunol. 2014,133:961–6.