Interpretation of vaccine responses and identification of immunodeficiencies
The measurement of antibody responses to vaccines is commonly used as a diagnostic laboratory test to identify immunodeficiency.
In a situation where the clinical picture raises a suspicion of immunodeficiency, the patient should be examined for antibody concentrations resulting from previous vaccinations or infections for
- tetanus (2738 S-ClteAb)
- diphtheria (1253 S-CodiAb)
- pneumococcus (6297 S-SpnAbVT or 6296 S-SpnAbNV)
- haemophilus (3585 S-HibAb) – if the patient is known to have received a Hib vaccine.
If the patient does not already have protective antibody levels, vaccine responses to these antigens should be examined.
Instructions for measuring vaccine responses
- Examine vaccine responses using serum samples extracted just before vaccination and no earlier than 4 weeks or no later than 2 months after vaccination.
- At least 4 months, preferably 6 months, must have passed since the previous IgG therapy before the vaccine response can be reliably assessed.
Restrictions to the assessment of vaccine responses
- If, during the previous 6–12 months, the patient has been administered significant doses of, for example, glucocorticoid treatments or IgG treatments administered at, the response may be secondarily low.
- If the patient has received high-dose immunoglobulin, the response may be secondarily low for up to 9 months from the end of treatment.
T cell dependent and T cell independent B cell response
B cells activate after encountering an antigen, such as a protein or polysaccharide structure, that fits a receptor on the surface of the cell. The activated B cell differentiates into a plasma cell, which starts to produce antibodies such as the antigen receptors on the surface of the cell. B cells can be activated either directly after identification of the antigen or with the assistance of T cells.
In T cell dependent response, T cells also identify the antigen on the surface of the cells that present this. The activated T cells enhance B cell antibody production. Proteins, such as tetanus and diphtheria antigens, stimulate B cells through T cells. Even in healthy people, tetanus is an antigen that evokes a response that is stronger than with diphtheria.
The pneumococcal polysaccharide vaccine antigen, pneumococcal capsule polysaccharide, produces an immune response by direct stimulation of B cells, without the assistance of T cells. The T cell independent antibody response is short-lived. Antibody concentrations for pneumococcal capsule polysaccharides decline to baseline in typically 3-8 years, depending on serotype [1]. Additional doses cannot be used to enhance the vaccine response, as the polysaccharide vaccine does not constitute immunological memory [2]. In children under two years of age, the polysaccharide vaccine is poorly immunogenic.
The Hib vaccine is a conjugate vaccine in which the polysaccharide of Haemophilus influenzae type b bacteria is connected to a carrier protein. With the help of the carrier protein, a T cell dependent B cell response is formed for polysaccharide antigen. However, the Hib vaccine response cannot be used to evaluate a specific T cell dependent vaccine response to protein antigen.
B cell responses in patients with immunodeficiency
The laboratory diagnostics for immunodeficiency are used to examine B cell responses to vaccines (Table 1). Tetanus and diphtheria antibodies are measured to determine T cell dependent B cell response. The response to the pneumococcal conjugate vaccine is measured to assess the T cell independent B cell response.
In combined immunodeficiencies, both T-dependent and T-independent B cell responses to vaccines have typically decreased.
In primary antibody deficiencies, the amount or function of antibodies in infection defence has decreased. The condition is caused by the congenital deficiency of B cells in the body to form antibodies. The T cell independent B cell responses to capsular polysaccharides are incomplete. In some patients, T-dependent B cell responses are also weak.
Table 1. Interpretation of vaccine responses in immunodeficiency diagnostics
| T-dependent B cell response | T-independent B cell response | Laboratory findings support the following alternative diagnoses | |
|---|---|---|---|
| Tetanus (Strong antigen) | Diphtheria (Weak antigen) |
Pneumococcal polysaccharides | |
| + | + | + | no immunodeficiency |
| + | + | - | primary antibody deficiency secondary immunodeficiency |
| + | - | - | primary antibody deficiency mild form of combined immunodeficiency secondary immunodeficiency |
| - | - | - | combined immunodeficiency secondary immunodeficiency |
Immunological findings in antibody deficiencies
- In common variable immunodeficiency (CVI), both IgG and IgA or IgM antibody concentrations have decreased in the patient. In approximately 90% of patients, IgE concentrations have also decreased. The age of onset of the disease varies from early childhood to old age.
- In agammaglobulinemia, the patient has hardly any detectable antibody levels. The patient’s blood has a (nearly) complete lack of circulating B cells. The patient usually already presents symptoms in early childhood as the infant loses the antibodies received from the mother through the placenta.
- In Hyper-IgM syndromes, IgM antibodies are normally present in the blood or are highlighted, while other antibody types are missing. The analysis of B cells reveals that patients lack either class-switched B memory cells (AICDA, Ung) or all CD27 + B cells (CD40, CD40L).
- If the patient's antibody levels have decreased but vaccine responses are normal, the antibody deficiency is not considered a serious immunodeficiency. In this type of non-specific hypogammaglobulinemia, serious infections are usually rare and there is no evidence of the effectiveness of replacement therapy, for example, in extending the patient’s life expectancy.
- In some rare cases, antibody levels are normal or vaccine responses are decreased even when deficiencies are only found in IgG subclasses, most commonly in IgG2. The condition is called a specific antibody deficiency. When a person has the condition, the severity of the clinical condition determines the need for treatment and monitoring.
An assessment by a physician is necessary when deciding on diagnosis and treatment
The description of the interpretation of vaccine responses in immunodeficiency diagnostics is based on the recommendation by Mikko Seppänen, Chief Physician at the Helsinki University Hospital.
Internationally, the guidelines used for interpreting the results of antibody responses are also recommendations for diagnosing immunodeficiency by top specialists. They do not override the physician's personal assessment of the best possible treatment for an individual patient.
References
1. Musher DM, Manoff SB, Liss C, et al. Safety and antibody response, including antibody persistence for 5 years after primary vaccination or revaccination with pneumococcal polysaccharide vaccine in middle-aged and older adults. J Infect Dis. 2010;201:516–24
2. Clutterbuck EA, Lazarus R, Yu LM, Bowman J, Bateman EA, Diggle L, Angus B, Peto TE, Beverley PC, Mant D, Pollard AJ. Pneumococcal conjugate and plain polysaccharide vaccines have divergent effects on antigen-specific B cells. J Infect Dis. 2012 May 1;205(9):1408–16
