Three-Year Follow-Up of COVID-19 Immune Responses in Immunocompromised People: Contributions of Vaccination, Infection, and Passive Antibodies
Background: How did immunity change after vaccination?
In the COVAXID study, which followed immunocompromised participants and healthy controls, antibody levels and surrogate neutralization activity were maintained or increased between months 24 and 36 in most study groups and subgroups. These immunogenicity findings reflect the combined effects of booster doses, infection, and immunoglobulin replacement therapy (IGRT) received by some patients. They are difficult to interpret as showing that the effects of the initial vaccination alone persisted unchanged for three years.
Immunocompromised people face a higher risk of severe COVID-19, but most were excluded from the pivotal early messenger RNA (mRNA) vaccine trials. Vaccine responses also vary with the underlying condition and its treatment, making separate long-term follow-up necessary. COVAXID, launched at Karolinska University Hospital in Sweden, extended follow-up beyond the initial open-label clinical trial to examine these changes. The three-year analysis was published in EBioMedicine.
Key findings: Antibody increases amid vaccination, infection, and IGRT
The original cohort included 539 people, combining healthy controls and immunocompromised participants, across six major categories and 21 subgroups. At month 36, 218 participants remained. The researchers measured antibodies that bind to the virus and surrogate neutralization activity in blood. The surrogate neutralization assay measures how strongly binding between the viral spike protein and angiotensin-converting enzyme 2 (ACE2), a cellular receptor, is inhibited. These results must be distinguished from direct measurements of protection against infection or severe disease.
Antibody levels were maintained or increased between months 24 and 36 in most groups and subgroups. Surrogate neutralization activity against the Omicron lineages XBB.1.5 and BA.2.86, which were circulating at the time, also rose overall in the main study groups. However, subgroups with common variable immunodeficiency (CVID), X-linked agammaglobulinemia (XLA), and chronic lymphocytic leukemia in patients taking or having discontinued ibrutinib showed low responses, particularly to BA.2.86. Some subgroups remained weak responders despite the overall improvement.
By month 36, more than 80% of participants had experienced at least one infection. The researchers interpreted the later antibody increases as reflecting a substantial contribution from hybrid immunity, combining vaccination and infection, in addition to booster doses. In some patients who received IGRT, particularly those with CVID or XLA, SARS-CoV-2 antibodies in the administered products also contributed to the measured levels. High antibody levels are therefore difficult to explain solely by the patients’ own ability to produce antibodies.
T-cell responses were assessed in 130 participants at month 36. CD4 and CD8 T cells responding to the ancestral strain and BA.2.86 were detected in all major study groups, with no statistically significant differences observed between patient groups and healthy controls. These findings alone do not establish that every individual had the same response or that T-cell responses were maintained throughout all three years.
Meaning and outlook: Why immune history must be considered
The findings support considering the number and timing of vaccine doses, infection history, and IGRT exposure together when interpreting long-term antibody changes in immunocompromised people. The researchers proposed tailored booster strategies that account for these factors, but did not validate criteria for omitting vaccination based on antibody tests or a strategy for prescribing IGRT for prevention.
There are also limitations to the interpretation. This was a single-center study, and loss to follow-up as well as small, unevenly sized subgroups may have affected the results. Infection classification may also be inaccurate if antibodies are undetectable after infection or if IGRT-derived antibodies contribute to infection markers. Because vaccination, infection, and IGRT exposures overlapped, their independent contributions were difficult to separate, and no multivariable analysis was performed. Antibody decline after the last antigen exposure was not formally modeled, so there is insufficient evidence to conclude that waning immunity has been resolved.
The study design and results are available in the COVAXID three-year follow-up paper.
BACKGROUND: Immunocompromised individuals were identified early in the pandemic as being at increased risk of severe COVID-19 and have demonstrated variable immune responses to SARS-CoV-2 vaccination. Although coordinated vaccination programmes are now well established, their long-term effects on sustained immunity in the present patient populations remain insufficiently understood. METHODS: The prospective SARS-CoV-2 mRNA vaccine trial COVAXID was conducted in a well‑characterised, real‑world cohort of 539 immunocompromised and healthy individuals across 21 subgroups, organised into six main categories. At the 36-month time point, 218 participants remained. Participants provided blood samples for assessment of binding antibody titres and pseudo‑neutralisation activity against ancestral SARS‑CoV‑2 and 21 variants, including Omicron sub‑lineages. T cell responses were evaluated in a defined subset of participants. Immunogenicity outcomes were analysed over a three-year period in relation to SARS‑CoV‑2 vaccination, SARS‑CoV‑2 infection, and immunoglobulin replacement therapy (IGRT). FINDINGS: Between years two and three, antibody titres and neutralisation capacity showed a consistent pattern of maintenance or increase across most study groups and subgroups. These increases were driven by cumulative exposure to vaccine booster doses, SARS‑CoV‑2 infection, and, in some cases, passive immunisation through IGRT. CD4 INTERPRETATION: The findings support continued, tailored vaccination strategies for elderly and immunocompromised individuals. Integrating immune monitoring with infection history and adjunctive therapies may help refine booster policies, optimise protection, and strengthen future vaccination programmes for high‑risk populations. FUNDING: The present studies were supported by the European Research Council, Karolinska Institutet, Knut and Alice Wallenberg Foundation, Nordstjernan AB, Region Stockholm, and the Swedish Research Council.
Antibody test results in immunocompromised people can reflect infection and treatment history as well as vaccine response. For example, a high antibody level in a patient with antibody deficiency receiving IGRT is difficult to interpret solely as evidence that the patient mounted a sufficient vaccine response on their own. The contribution of antibodies transferred in the product must also be considered. Future vaccine studies could compare immune responses across patient groups more accurately by distinguishing underlying conditions and treatments, vaccination timing, infection history, and IGRT exposure in their analyses. This study supports that approach, but does not establish that a particular antibody level guarantees clinical protection or can serve as a basis for deciding whether a booster is needed.