Page 173 - Haematologica May 2022

LETTERS TO THE EDITOR
BNT162b2 COVID-19 and ChAdOx1 nCoV-19 vacci- nation in patients with myelodysplastic syndromes
Many patients with hematological cancers are not com- pletely protected after the initial dose or after both pri- mary doses of the vaccines1,2 with most failing to serocon- vert on completion of the two-dose vaccine schedule.2 These reports only included three patients with myelodysplastic syndrome (MDS). MDS represents a spectrum of clonal bone marrow neoplasms from low- risk disease through to those transforming into acute myeloid leukemia. Patients with MDS, especially with lower-risk disease, many of whom are minimally treated and who might be expected to have a comparable immune response to healthy volunteers, and as such a better immune response to COVID-19 vaccines than other hematological cancers. Previous studies looking at the immune response to influenza vaccination in those with MDS had shown promising results with immune responses3 not differing from those of healthy family members. However, a recent study which included six MDS patients, reported poor seroconversion rates follow- ing a single dose of COVID-19 vaccine in a group of 60 myeloid cancer patients, including those who are not on cytoreductive treatments and those in complete hemato- logical remission, suggesting a clear need for more detailed interrogation of COVID-19 vaccination in this group of patients.4 Here, we report the humoral and T-cell responses of 38 patients with MDS 2 weeks following completion of the second dose vaccine schedules of ChAdOx1 or BNT162b2 nCoV-19 vaccines.
Following approval by the Institutional Review Boards, patients with MDS (n=38) vaccinated with either BNT162b2 mRNA or ChAdOx1 nCoV-19 COVID-19 vac- cine provided written informed consent. Eligibility criteria for the study included diagnosis of MDS as per the World Health Organization classification5 and age ≥18 years. The study also included healthy volunteers (HV) (mainly healthcare workers, n=30) serving as a reference group, included principally to provide an experimental control for study assays and facilitate their comparison with results of other studies of BNT162b2 in healthy popula- tions. Plasma samples were tested for immunoglobulin G (IgG) binding the SARS-CoV-2 spike (S) protein and nucleoprotein (N) and neutralization assays against HIV-1 based virus particles pseudotyped with SARS-CoV-2 Wuhan strain (WT), variant of concern (VOC)B.1.1.7 (a) or VOC.B.1.617.2 (δ) spike as previously described.1,2,6 Cellular responses were assessed using interferon g (IFNg) ELISPOT and flow cytometry (CD25 and CD69 expres- sion) after 24 hours of peptide stimulation. IFNg ELISpot analysis was performed ex vivo for assessment of T-cell response following stimulation with SARS-CoV-2 peptide pools, Cytomegalovirus (CMV), Epstein-Barr virus (EBV), and influenza virus positive control (CEF) peptides for 24 hours.
Thirty-eight MDS patients and 30 HV provided a blood sample 2 weeks following a second primary dose of their initial vaccine. Clinical characteristics along with median times to second dose are provided in Table 1. We observed significant differences between the ages of the HV and MDS cohorts (Student’s t-test, equal variance, P<0.001). 42% (n=16) of the MDS patients received BNT162b2 and 58% (n=22) received ChAdOx1 nCoV-19 vaccines. All HV received a delayed BNT162b2 second dose. As per UK government guidelines at the time of vac- cination, individuals receiving BNT162b2 second doses received these between 8-12 weeks following the first
dose, representing a delay compared to the licensed administration. Prior SARS-CoV-2 infection can influence the magnitude of the vaccine response,7 and as such we excluded two MDS and four HV based on being positive for nucleoprotein-specific IgG (IgG(N)) (representing response to prior infection) (Online Supplementary Figure S1A). We observed that the anti-S IgG titres at approxi- mately 2 weeks following the second dose were within the upper quantile in these previously virus-exposed indi- viduals (Online Supplementary Figure S1B, red dots). These were excluded from the overall immune efficacy analysis.
In the remaining (HV BNT162b2, n=26; MDS BNT162b2, n=15 and MDS ChAdOx1, n=21) cohort; we assessed the anti-S IgG titres following their second pri- mary dose. Overall serological responses were: HV BNT162b2 100% (26/26); MDS BNT162b2 100% (15/15) and MDS ChAdOx1 76.2% (16/21) (Figure 1A); notably, the MDS ChAdOx1 cohort demonstrated significantly decreased serological titres to the MDS BNT162b2 cohort (Figure 1A). It is noteworthy that the median titre for the MDS BNT162b2-vaccinated patients is higher (>103) compared to the median reported in a heterogenous BNT162b2-vaccinated hematological cancer population (<103) observed in McKenzie et al.2 Of the five non- responders within the MDS ChAdOx1, three patients were on disease-modifying treatments (5-azacytidine, venetoclax and danazol), with the patient on venetoclax/rituximab having a concurrent diagnosis of chronic lymphocytic leukemia (CLL). None of these patients were noted to be on steroid therapy around the time of vaccination; and no differences in the clinical white blood cells were observed between serological responders or non-responders (Online Supplementary Figure 1C). Similar to our previous reports1,2 there was no significant correlation between spike IgG titres and age or the time between the first and second doses of the vac- cine in the two MDS cohorts (Online Supplementary Figure S1D).
Next, we assessed the functional implications of sero- conversion by neutralization assays for SARS-CoV-2 WT and VOC a and δ (Figure 1B). All but four MDS patients (Figure 1B; colored dots) could neutralize all variant strains, but MDS cohorts showed significantly reduced median neutralizations for all three variant strains com- pared to HV (Figure 1B); importantly this was the case for both the MDS ChAdOx1 and MDS BNT162b2 cohorts. We acknowledge the younger age of the HV cohort may contribute to this reduction, although age was not a deter- minant of neutralization response in cancer patients in our previous reports.1,2 Review of the four MDS (2 BNT162b2 mRNA and two ChAdOx1 nCoV-19 COVID- 19-vaccinated) patients classified as non-responders by neutralization assay demonstrated that these patients were predominantly low risk MDS on no treatment, except one patient with excess of blasts on 5-azacytidine. These data clearly support the need for a third primary dose for this clinically vulnerable patient group irrespec- tive of the seroconversion rates across cohorts. This is especially the case in those who have seroconverted but have a low anti-S IgG titre after the second dose. Third doses have demonstrated higher anti-S IgG titres in other hematological cohorts,8 and in keeping with our previous reports,1,2 anti-S IgG titres were highly correlated with neutralization among all cohorts (Figure 1C).
In order to measure functional SARS-CoV-2 T-cell responses to vaccination, peripheral blood mononuclear cells (PBMC) from our study participants were assessed by ELISpot assays as described. It is noteworthy that no differences in the percentages of T cells amongst the
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