A third dose of COVID‐19 mRNA vaccine induces limited humoral response in stem cell transplant recipients who got two vaccine doses before transplant

To the Editor, Allogeneic hematopoietic stem cell transplantation (HSCT) recipients are at high risk of severe coronavirus disease 19 (COVID-19) [1, 2], and sufficient times of vaccinations are strongly recommended. In general, post-HSCT patients should be considered as “never vaccinated” regardless of the pre-HSCT vaccination history [3]. Limited immunogenicity can be obtained after one dose of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in HSCT recipients [4], and those patients should receive ≥2 vaccine doses several months after transplantation [5, 6]. However, in Japan, many HSCT recipients who had gotten two vaccine doses before transplantation are allowed to get only one mRNA vaccine dose as a “third” dose as of November 2022 due to social constraint, and those patients can be vaccinated “fourth” dose several months later, as “never transplanted”. In this single-centre study, we prospectively evaluated the humoral immunity before and after one vaccination dose in HSCT recipients who had gotten twovaccinationdosesbefore the transplant. This studywasperformed in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Tokyo Metropolitan Komagome Hospital. Written informed consent was obtained from each patient. The patients who met all the below criteria were included in this study. (1) adult patients who underwent allogeneic HSCT, (2) patients who received two doses of the COVID-19 mRNA vaccines before transplant, (3) patients who received one dose of the COVID-19 mRNA vaccine after HSCT, and (4) patients whose serum samples were collected before and approximately 2–5 weeks after post-HSCT vaccination. The anti–SARS-CoV-2 IgG titer was evaluated in serum samples using an iFlash 3000 chemiluminescence immunoassay analyzer (Shenzhen YHLO Biotech, Shenzhen, China) with an iFlash– SARS-CoV-2 IgG kit and iFlash–SARS-CoV-2 IgG-S1 kit, as previously described [7]. The iFlash-SARS-CoV-2 IgG kit primarily detects antinucleocapsid antibodies; thus, patients with positive SARS-CoV-2 IgG results were considered to have a previous history of COVID-19 and were not included in this study. The iFlash–SARS-CoV-2 IgG-S1 kit detects IgG specific to the S1 subunit of the spike (S) protein, which was used to estimate the humoral response of SARS-CoV-2 vaccines. According to the manufacturer’s instructions, ≥10 arbitrary units


A third dose of COVID-19 mRNA vaccine induces limited humoral response in stem cell transplant recipients who got two vaccine doses before transplant
To the Editor, Allogeneic hematopoietic stem cell transplantation (HSCT) recipients are at high risk of severe coronavirus disease 19 (COVID-19) [1,2], and sufficient times of vaccinations are strongly recommended. In general, post-HSCT patients should be considered as "never vaccinated" regardless of the pre-HSCT vaccination history [3]. Limited immunogenicity can be obtained after one dose of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in HSCT recipients [4], and those patients should receive ≥2 vaccine doses several months after transplantation [5,6]. However, in Japan, many HSCT recipients who had gotten two vaccine doses before transplantation are allowed to get only one mRNA vaccine dose as a "third" dose as of November 2022 due to social constraint, and those patients can be vaccinated "fourth" dose several months later, as "never transplanted". In this single-centre study, we prospectively evaluated the humoral immunity before and after one vaccination dose in HSCT recipients who had gotten two vaccination doses before the transplant. This study was performed in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Tokyo Metropolitan Komagome Hospital.
Written informed consent was obtained from each patient.
The patients who met all the below criteria were included in this study. (1) adult patients who underwent allogeneic HSCT, (2) patients who received two doses of the COVID-19 mRNA vaccines before transplant, (3) patients who received one dose of the COVID-19 mRNA vaccine after HSCT, and (4) patients whose serum samples were collected before and approximately 2-5 weeks after post-HSCT vaccination. The anti-SARS-CoV-2 IgG titer was evaluated in serum samples using an iFlash 3000 chemiluminescence immunoassay analyzer (Shenzhen YHLO Biotech, Shenzhen, China) with an iFlash-SARS-CoV-2 IgG kit and iFlash-SARS-CoV-2 IgG-S1 kit, as previously described [7]. The iFlash-SARS-CoV-2 IgG kit primarily detects antinucleocapsid antibodies; thus, patients with positive SARS-CoV-2 IgG results were considered to have a previous history of COVID-19 and were not included in this study. The iFlash-SARS-CoV-2 IgG-S1 kit detects IgG specific to the S1 subunit of the spike (S) protein, which was used to estimate the humoral response of SARS-CoV-2 vaccines.
Seven HSCT recipients, who got two vaccine doses median 5 months (range, 4-9) before HSCT, were included. Detailed patient characteristics and transplantation procedures are shown in Table S1. No patient has a history of COVID-19, which was confirmed by the absence of SARS-CoV-2 S1 IgG antibody (Ab) was positive in five of seven patients before post-HSCT vaccination, although the geometric mean titer (GMT) was as low as 33.41 AU/ml. SARS-CoV-2 S1 IgG Ab titer was reevaluated median of 25 days (range, 16-36) after post-HSCT vaccination, and GMT was 90.27 AU/ml ( Figure 1A). Importantly, a marked increase of SARS-CoV-2 S1 IgG titer was achieved in only one patient (Case 2), and the median fold change of SARS-CoV-2 S1 IgG titer (after/before revaccination) was 1.33 ( Figure 1B). We also evaluated the level of Nab against SARS-CoV-2 at the same time points.
GMT of Nab levels before and after post-HSCT vaccination was 19.2 and 42.1 AU/ml respectively ( Figure 1A). As with SARS-CoV-2 S1 IgG, a remarkable increase in Nab level was shown in only one patient (Case 2), and the median fold change of Nab level was 0.986 ( Figure 1B These results should be interpreted with caution because the number of cases in this study is highly limited and patient characteristics are not identical. In our cohort, all patients received a COVID-19 vaccine dose less than 1 year after HSCT, five out of seven patients suffered from hypogammaglobulinemia, and five patients were administered immunosuppressive therapy, which is common in this population.
These characteristics were associated with poor humoral response to the COVID-19 vaccines among vaccine-naïve HSCT recipients [6,10] and may also affect the vaccine response in this study.
In conclusion, our preliminary data first suggested that a third dose can induce a limited humoral response in allogeneic HSCT recipients who had gotten two vaccine doses before transplantation. Such individuals should be probably re-vaccinated as primary vaccine series, that is, ≥2 shots, to enhance the immunogenicity in this highly immunocompromised population.