Introduction

Allogeneic hematopoietic stem cell transplant (HCT) recipients are at increased risk of severe COVID-19 and complications, including psychologic distress [1,2,3,4]. There is limited data on specific side effects. We examined the safety of the SARS-CoV-2 Spikevax vaccine and COVID-19 risk perception in recently transplanted HCT recipients.

Methods

This single-center, prospective and observational study (IIBSP-COV-2021–43) included adult allogeneic HCT recipients between 3 and 26 months after their stem cell infusion date (“recently transplanted”). All patients received the mRNA-1273 vaccine (Spikevax) and were fluent in Spanish. Those receiving chemotherapy were excluded.

Patients completed a standardized phone survey 72 h to 7 days after each vaccine dose. Vaccine adverse events (AEs) were classified according to Baden et al. (graded 0–4) [5]. Disease risk perception was examined with the Brief Illness Perception Questionnaire (BIP-Q5), which consists of five items with a maximum total score of 50. The BIP-Q5 was validated in Spaniards during the COVID-19 pandemic [6].

Statistical analysis was performed using SPSS v. 25. Alpha = 0.05 was set for all statistics. Wilcoxon’s test was used for time-paired comparisons. A one-half-standard deviation was used to indicate clinically significant differences [7]. Correlations were performed with Pearson and Spearman tests; significant variables (p < 0.05) were entered in the multivariable models. Multivariable stepwise logistic and linear regression were performed to examine variables associated with AE degree and COVID-19 risk perception.

Results

From March to August 2021, 54 patients were evaluated. The median age was 53.5 years (range 25–73) and 48.1% were women. The median time from HCT to the first vaccine dose was 13 months (range 3–26). Forty patients (74%) were on active immunosuppression and 19 (35.2%) and 10 (18.5%) had prior acute and chronic graft-versus-host disease (GVHD), respectively. Five patients (9.3%) had suffered COVID-19 and 15 (27.8%) had a first-degree relative with COVID-19.

Vaccine safety data

Figure 1 shows AE incidences. Nearly all patients developed at least one AE: 94.4% with the first and 85.2% with the second dose. Pain at the site of injection was the most common AE (92.6% and 85.2% of patients after first and second doses). Systemic AEs were more frequent and severe after the second dose (p = 0.007) (Fig. 1).

Fig. 1
figure 1

Adverse event (AE) incidence and severity for doses 1 (D1) and 2 (D2). *Non-significant. **Significant differences between the distribution of medians (p < 0.05 in Wilcoxon’s test)

Full size image

Only three (5.6%) patients had grade 3 fatigue and/or chills, which occurred after the second dose. No serious AEs requiring hospitalization (i.e., grade 4) occurred. No new-onset GVHD, GVHD flares, graft dysfunction, or immune-mediated cytopenias were documented.

Female sex was significantly associated with a higher rate of overall AEs after the first dose (OR 3.94, 95% CI 1.14–13.58, p = 0.03). Time from HCT was associated with a higher rate of systemic AEs after the second dose (OR 1.09, 95% CI 1.01–1.18, p = 0.04), especially due to higher rates of chills (OR 1.15, 95% CI 1.01–1.31, p = 0.04). Systemic AEs were more common as the time interval since HCT increased. Having had prior COVID-19 correlated with the development of fever after the second dose (OR 10.22, 95% CI 1.21–86.59, p = 0.03).

Age, graft source, donor type, donor age, number of CD34+ cells infused, conditioning type, GVHD prophylaxis, disease type and status, GVHD, immunosuppression, T-cell chimerism, and total lymphocyte, CD4+, CD8+, and CD19+ lymphocyte counts and level of IgG had no apparent impact on the occurrence or severity of any AE.

Risk perception

COVID-19 risk perception tended to decrease over time (first dose: mean = 29.43, SD = 9.35; second dose: mean = 28.05, SD = 10.07) (p = 0.077). A post hoc exploratory analysis of the BIP-Q5 items revealed that, at the time of the second dose, patients perceived that the end of the pandemic was closer (first dose: mean = 7.07, SD = 2.06; second dose: mean = 6.11, SD = 2.67) (p < 0.0001) and reported being less concerned about COVID-19 than before vaccination (first dose: mean = 7.91, SD = 2.16; second dose: mean = 7.11, SD = 2.69) (p = 0.012). Both differences were also clinically significant (p < 0.05). Females (r = 0.42, p < 0.001), patients receiving myeloablative conditioning (r =  − 0.300, p = 0.027), post-transplant cyclophosphamide-based GVHD prophylaxis (r =  − 0.371, p = 0.006), having lower absolute neutrophil counts (r =  − 0.288, p = 0.034), prior acute GVHD (r =  − 0.355, p = 0.008), and having a relative with COVID-19 (r = 0.285, p = 0.036) were significantly associated with greater COVID-19 risk perception. None of these variables retained their significance in multivariable analysis (data not shown).

Discussion

The observed side effects of the mRNA-1273 SARS-CoV-2 vaccine in recent HCT recipients appear similar to those in the general population. Prior studies in HCT recipients with somewhat different characteristics, such as age, time from HCT, immunosuppression, or vaccine type, have reported variable incidence and severity of AE following SARS-CoV-2 mRNA vaccination [8,9,10]. In our series, systemic AEs were more frequent and severe after the second dose, which was also in line with that observed in the general population [5]. We found no new-onset cytopenias nor GVHD flares after vaccination. Contrarily, other groups have reported these complications in around 10% of patients [9].

A recent publication examined another mRNA vaccine (BNT163b2) in “long-term” HCT recipients and showed lower-than-expected AE incidence and severity [11]. Thus, time since HCT may have a strong impact on the occurrence of AEs. Prior COVID-19 and female sex were two other variables that led to higher rates of AE in our study and which have also been reported in large studies in the general population [12].

Our study is the first to report COVID-19 risk perception in HCT recipients. Patients reported lower disease risk perception over time, which may be due to a myriad of factors, including SARS-CoV-2 vaccination and changes in COVID-19 incidence rates in our city. Appropriate reductions in disease risk perception have been associated with precautionary behaviors [13], all of which may have contributed to managing the COVID-19 hazard and related restrictions [14, 15]. Despite some patient characteristics being associated with increased COVID-19 risk perception, none predicted risk perception in multivariable analysis. Future studies should evaluate longer periods of follow-up with more determinations of risk perception, and include a control group as well as additional variables, such as patients’ psychological symptoms, to further comprehend the role of vaccines and to identify risk factors associated with increased disease risk perception in this population.

Conclusion

Our study suggests a similar incidence and severity of AE in recent HCT recipients compared to the general population with no vaccine-associated cytopenias or GVHD flares. In addition, certain COVID-19 risk perception items decreased over time. Since HCT recipients reported increased distress during the ongoing COVID-19 pandemic [15], further understanding of the factors that predict emotional distress is needed to provide timely manner interventions.