In February 2022, acknowledging the observed modest decrease in vaccine efficacy in preventing the need for hospital admission due to COVID-19 following the booster dose, some health authorities, including the Spanish Ministry of Health, recommended a booster campaign in the spring for people at a higher risk of severe COVID-19.1,2

The efficacy results of the vaccine booster dose suggest a potential benefit in the administration of a fourth dose, at least in patients at risk, where morbidity and mortality is higher.3,4 In addition, since a part of this population has an inadequate or even null vaccine response, other additional strategies need to be evaluated, such as preventive treatments with monoclonal antibodies, as for example the combination cilgavimab/tixagevimab.2

Both the vaccination programs and the adoption of new strategies imply an added and important human and economic strain for the healthcare system. Therefore, the objective of the present study was to identify, among patients at high risk of developing severe COVID-19, those individuals who have a greater chance of developing post-vaccination immunity.

A cross-sectional study was made of all patients included in vaccination group 7 (very high risk) by the Spanish Ministry of Health, or under immunosuppressive treatment (Table 1), scheduled to receive the third dose in September–October 2021. These patients received a booster dose between 21 February and 24 April 2022 in the healthcare area of Lugo (Spain). A fourth dose of mRNA vaccine (Comirnaty, BioNTech/Pfizer or Spikevax, Moderna) or one dose of Jcovden (Janssen) and two doses of mRNA were considered as booster doses.

All of them were proposed serological testing for SARS-CoV-2 with titer determinations 14 days after administration of the booster dose.

Vaccine response was classified as negative (IgG titers < 34 BAU/ml — the cut-off point established by the manufacturer), indeterminate (titers 34–259 BAU/ml, as indicated by the classification established by the Ministry of Health), or positive (≥260 BAU/ml). The LIAISON® SARS-CoV-2 TrimericS IgG assay (Diasorin, Saluggia, Italy), an indirect chemiluminescence immunoassay (CLIA), was used for the quantitative determination of specific IgG antibodies against the spicular trimeric protein of SARS-CoV-2 in human serum or plasma samples.

The data were entered in a database designed for this purpose. Quantitative variables included in the analysis were reported as the median and interquartile range (IQR), and qualitative variables as numbers and percentages.

Of the 3486 patients included in the list for administration of booster doses in our area, 2488 (71.4%) were vaccinated to date. A total of 765 patients gave consent for serological testing (31.25% of those vaccinated). Of these, 754 (98.6%) had received four doses of mRNA vaccine, and 11 (1.4%) had received one dose of Janssen completed with two doses of mRNA.

As regards the reason for inclusion in group 7, 54 patients (7.1%) were treated with biological drugs, 90 (11.8%) had hematological disease, 299 (39.1%) suffered oncological disease, 304 (39.7%) had undergone solid organ transplantation, and 18 (2.4%) presented immunosuppression due to other reasons.

The vaccine titer was determined a median of 20 (16–32) days after administration of the last dose; after that, 74 patients (9.7%) had negative serological results and 45 (5.9%) presented indeterminate titers.

The results of the vaccine response according to diagnostic group are shown in Table 2. The patients treated with biological drugs were the group with the highest percentage of negative or indeterminate serological findings (55.6%), followed by hematological patients (35.4%) and transplant patients (17.8%). The great majority of cancer patients showed a good vaccine response.

Among the patients receiving biological treatment, seronegativity was mainly associated to the use of anti-CD20 drugs. Within the group of transplant patients, a higher seronegativity rate was observed among the patients undergoing lung and, to a lesser extent, kidney transplantation.

Once the results corresponding to the IgG titers following the booster dose or fourth dose were available in the high risk patients, we identified three groups of individuals with a lower vaccine response: hematological patients, lung transplant patients and patients treated with anti-CD20 drugs. These data are consistent with those previously reported in a systematic literature review including 162 studies.5

Patients receiving anti-CD20 treatment were mainly patients with multiple sclerosis treated with ocrelizumab and/or with rheumatoid arthritis treated with rituximab. In fact, the relationship between the use of rituximab and a poorer humoral response as well as a more severe disease course in rheumatoid arthritis, has been previously reported.6

With regard to the hematological patients, several studies suggest that these diseases are particularly important non-response factors, even when compared to patients with solid organ tumors.7,8 Treatment with anti-CD20 drugs was associated to a lower response rate in both patients with hematological neoplasms,9 and in patients with autoimmune disorders10 or transplanted individuals.11 Although all solid organ transplant recipients are at greater risk of not responding to the vaccine,5 lower immunogenicity in lung transplant recipients was reported in another series,12 in agreement with our own results.

The main limitation of the present study is the sample size, and the fact that patient selection was not randomized. In any case, we believe it is a sufficiently representative sample to confirm clinical impressions — though larger studies will be needed to confirm our results.

Our results suggest that among these group 7 patients there are different subgroups with different humoral responses, resulting in different risks of suffering the infection. Their identification is essential for individualizing and improving management. Efforts should focus on prioritizing vaccination and identifying the subgroup of vaccine non-responders who could benefit from pre-exposure prophylaxis with tixagevimab/cilgavimab13 or the early use of antivirals or neutralizing antibodies.14 It also would be advisable to establish recommendations regarding strict personal protection measures (safety distance, use of masks) in this group of patients.

This research did not receive any specific aid from public or private agencies nor from not-for-profit entities.

The authors declare that they have no competing interests.