Factors that lead to variations in vaccine responses
Immunomodulatory therapy is used to treat a range of diseases and conditions, such as organ transplantation, multiple sclerosis, inflammatory bowel disease, malignant diseases, dermatological conditions and rheumatic disorders. These medications affect the immune system in different ways and can impair both the humoral (B-cell–mediated) and cellular (T-cell–mediated) immune responses. In the article, we discuss a selection of medications that are particularly relevant in clinical practice in Norway (Table 1) (5–26), but there are numerous other immunosuppressive medications that are not covered here.
Table 1
Immunomodulatory medications and vaccine response (5–26)
| Class of medication | Examples | Effect on vaccine response | Typical increased infection risk |
|---|
| Corticosteroids (5, 6) | Prednisolone ≥ 20 mg/day for > 2 weeks | Reduced antibody and T-cell responses, depending on dose and duration | Opportunistic infections (Pneumocystis jirovecii, herpes viruses) |
| Anti-CD20 antibodies (7–10) | Rituximab, ocrelizumab, ofatumumab | Markedly reduced antibody response; with preserved T-cell function | Bacterial infections (pneumococci, meningococci), influenza, COVID-19 |
| Plasma cell-targeted antibodies (11–13) | Daratumumab, isatuximab | Markedly reduced antibody production | Viral and bacterial infections, particularly respiratory infections |
| Bispecific antibodies (12, 14) | Epcoritamab, Glofitamab, Mosunetuzumab | Impaired T- and B-cell responses | Severe COVID-19, bacterial and viral infections |
| TNF inhibitors (15–18) | Infliximab, adalimumab | Often with preserved vaccine response | Tuberculosis, moderate bacterial infections |
| Calcineurin inhibitors (19, 20) | Tacrolimus, ciclosporin | Impaired T- and B-cell responses | Viral infections (cytomegalovirus, Epstein-Barr virus), opportunistic infections |
| JAK inhibitors (21) | Baricitinib, tofacitinib | Impaired T- and B-cell responses | Herpes zoster, severe viral infections |
| Complement inhibitors (22) | Eculizumab, ravulizumab | With preserved antibody response, but lost complement-mediated protection | Meningococcal infections |
| CAR-T therapy (23, 24) | Anti-CD19, anti-BCMA | Prolonged absence of antibody and T-cell responses | Severe COVID-19, bacterial and viral infections |
| Stem cell transplantation (25, 26) | Autologous/allogeneic | Profound and prolonged immunodeficiency | Broad risk of bacterial, viral and fungal infections |
Prolonged treatment with systemic corticosteroids (≥ 20 mg prednisolone daily for > 2 weeks) leads to broad immunosuppression with reduced T-cell function, antibody production and inflammatory responses. This increases the risk of opportunistic infections and impairs vaccine responses, particularly during ongoing treatment. The effect is dependent on dose and duration and is gradually reduced after discontinuation (5, 6).
Antibodies against B cells and plasma cells cause profound and prolonged immunosuppression. CD20 antibodies (rituximab, ocrelizumab, ofatumumab, etc.) are used in, for example, multiple sclerosis, lymphoma, transplantation and rheumatoid arthritis, and result in effective B-cell depletion with reduced or absent vaccine responses, particularly to novel antigens, although T-cell function is largely preserved (7–10). The risk of severe bacterial (pneumococci, meningococci) and viral infections is significantly increased. Toxin-conjugated antibodies targeting B-cell markers (CD79b, CD22) also reduce antibody production. Plasma cell-targeted agents (CD38 antibodies) cause similar immunodeficiency in multiple myeloma, while CD52 antibodies (alemtuzumab) affect both T and B cells (11, 12). New bispecific antibodies and T-cell-engaging antibodies against B-cell maturation antigens (BCMA), GPRC5D, CD19 and CD20 are expected to become increasingly important and may cause combined B- and T-cell failure (13, 14).
TNF inhibitors (e.g. infliximab and adalimumab) are used for chronic inflammatory conditions such as arthritis, spondyloarthritis, inflammatory bowel disease and psoriasis. TNF blockade suppresses T-cell and macrophage activation, granuloma formation and control of intracellular pathogens, particularly Mycobacterium tuberculosis. Vaccine responses are generally preserved but can be reduced when combined with other immunosuppressive agents. The risk of infection is moderately increased, particularly for severe bacterial infections and reactivation of latent tuberculosis, while the risk of severe viral infection is lower than with B-cell-targeted therapies (15–18).
Calcineurin inhibitors (tacrolimus and ciclosporin) are primarily used to prevent transplant rejection and in certain autoimmune diseases. They inhibit calcium- and calcineurin-dependent T-cell activation and reduce the cellular immune response. This impairs vaccine responses and increases the risk of viral and opportunistic infections (19, 20).
JAK inhibitors (e.g. baricitinib and tofacitinib) are used for autoimmune diseases, myeloproliferative disorders and graft-versus-host disease following allogeneic stem cell transplantation. By blocking Janus kinase signalling pathways, they suppress cytokine-driven T- and B-cell activity, reducing vaccine responses and increasing the risk of infection, particularly herpes zoster and other severe viral infections (21).
Complement inhibitors that target complement protein C5 (e.g. eculizumab and ravulizumab) are used for complement-mediated diseases such as atypical haemolytic uraemic syndrome, paroxysmal nocturnal haemoglobinuria and certain autoimmune neuromuscular disorders. Treatment causes pronounced and persistent functional hyposplenism with markedly reduced bacterial clearance and is associated with a 1000–2000-fold increased risk of invasive meningococcal disease (22). Vaccination against meningococcal disease (ACWY and B vaccines) is therefore required prior to treatment, despite the significant reduction in vaccine efficacy and the risk remaining high. Patients should also be vaccinated against Haemophilus influenzae type b and pneumococci. Clinical vigilance for severe infection is essential during ongoing therapy.
CAR-T cell therapy (chimeric antigen receptor T-cell therapy) involves the genetic modification of the patient's T cells to recognise tumour antigens, typically CD19 in B-cell malignancies and BCMA protein (B-cell maturation antigen) in multiple myeloma, but it is also used in certain autoimmune diseases. The treatment can lead to long-term remission but often results in persistent B-cell aplasia, reduced antibody responses and an increased risk of severe infection, including COVID-19 (23, 24).
Haematopoietic stem cell transplantation, either autologous or allogeneic, is used for haematological malignancies, bone marrow failure, immunodeficiency, metabolic disorders and certain autoimmune diseases such as multiple sclerosis, systemic sclerosis and lupus. The procedure causes profound, transient immunosuppression with markedly reduced vaccine responses and high infection risk, particularly following allogeneic transplantation (25, 26).