Abstract
Background
Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination reduces the risk and severity of coronavirus disease 2019 (COVID-19), several variables may impact the humoral response among patients undergoing hematopoietic stem cell transplantation (HSCT).
Methods
A retrospective chart review was conducted among SARS-CoV-2-vaccinated HSCT recipients between 2020 and 2022 at a single center in Boston, Massachusetts. Patients age ≥18 years who received doses of Pfizer, Moderna, or J&J vaccines were included. Anti-spike (S) immunoglobulin G (IgG) titer levels were measured using the Roche assay. Responders (≥0.8 U/mL) and nonresponders (<0.8 U/mL) were categorized and analyzed. Multivariable linear and logistic regression were used to estimate the correlation coefficient and odds ratio of response magnitude and status.
Results
Of 152 HSCT recipients, 141 (92.8%) were responders, with a median (interquartile range [IQR]) anti-S IgG titer of 2500 (107.9–2500) U/mL at a median (IQR) of 80.5 (36–153.5) days from last dose, regardless of the number of doses received. Higher quantitative titers were associated with receipt of more vaccine doses (coeff, 205.79; 95% CI, 30.10 to 381.47; P = .022), being female (coeff, 343.5; 95% CI, −682.6 to −4.4; P = .047), being younger (<65 years; coeff, 365.2; 95% CI, −711.3 to 19.1; P = .039), and not being on anti-CD20 therapy (coeff, −1163.7; 95% CI, −1717.7 to −609.7; P = .001). Being male (odds ratio [OR], 0.11; 95% CI, 0.01 to 0.93; P = .04) and being on anti-CD20 therapy (OR, 0.16; 95% CI, 0.03 to 0.70; P = .016) were associated with nonresponse.
Conclusions
Overall, most HSCT recipients had high SARS-CoV-2 antibody responses. More vaccine doses improved the magnitude of immune responses. Anti-S IgG monitoring may be useful for identifying attenuated vaccine-induced responses.
Keywords: COVID-19 vaccine, allogeneic HSCT, antispike protein, autologous HSCT transplant
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination reduces the risk and severity of coronavirus disease 2019 (COVID-19) [1–3], but immunogenicity has been found to be reduced in patients with hematologic malignancies [4] and those undergoing hematopoietic stem cell transplantation (HSCT) [5]. HSCT recipients undergo various degrees of disease-related and therapeutic immunosuppression that may compromise their ability to produce an effective immune response and therefore increase their vulnerability to infections. The variables that may impact the humoral response, such as age, gender, pretransplant diagnosis, transplant type, prior treatments, and vaccine type and number, have not been comprehensively described.
Before the Food and Drug Administration (FDA)–authorized use of SARS-CoV-2 vaccines, transplant patients had a significantly higher mortality rate compared with healthy adults after infection with SARS-CoV-2 [6]. The pivotal clinical trials that led to the accelerated authorization of the SARS-CoV-2 vaccines were conducted among healthy participants [1, 2]. Immunocompromised patients, including HSCT recipients, were excluded from the phase 3 COVID-19 vaccine trials despite their uniquely higher risks of severe infection and death [7–10].
Several studies have demonstrated relatively poor SARS-CoV-2 vaccine immune responses among HSCT recipients following vaccination as compared with healthy adults. Sherman et al. and Mamez separately reported suboptimal antibody titers with a seropositivity prevalence of ∼80% among HSCT recipients when compared with healthy adults [11–14]. Before the recommendation for booster dose vaccinations, certain factors had been linked to poor sero-responsiveness including time post-transplant, presence or absence of graft-vs-host disease (GVHD), and use of anti-CD20 therapies [15, 16]. Medications such as methotrexate, sirolimus, high-dose steroids, and mycophenolate mofetil commonly used in the management of GVHD among HSCT recipients have been implicated in poor SARS-CoV-2 vaccine immunogenicity among solid organ transplant recipients [2, 5, 6, 8, 17]. In other vaccine studies (eg, with the influenza vaccine), the appropriate timing of vaccination affected immunogenicity among HSCT recipients [18].
Given the heightened risk of death and severe disease following infection with SARS-CoV-2, knowledge of SARS-CoV-2 vaccine responsiveness remains pertinent in addressing the unique needs of HSCT recipients. The goal of our study was to determine the prevalence of seropositivity and magnitude of anti-spike (S) immunoglobulin G (IgG) after SARS-CoV-2 vaccination in HSCT recipients and determine factors associated with seropositivity in this population. Insights gained from this study may aid in the development of improved vaccination strategies against SARS-CoV-2.
METHODS
Study Population
A single-center, retrospective review of electronic medical record (EMR) data was conducted among HSCT recipients who received SARS-CoV-2 vaccinations between January 2020 and August 2022 at Brigham and Women's Hospital and Dana-Farber Cancer Institute in Boston, Massachusetts. Patients were included if they were ≥18 years old and had received ≥1 dose of BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), or Ad26.COV2.S (Janssen) vaccine and had been tested at least once for anti-S IgG. Vaccines were administered intramuscularly according to their respective Emergency Use Authorizations (EUAs): BNT162b2 (30 mcg in 0.3 mL for all doses), mRNA-1273 (100 mcg in 0.5 mL for primary series, 50 mcg in 0.25 mL for booster doses), Ad26.COV2.S (5 × 1010 viral particles in 0.5 mL for all doses). All vaccines consisted of the monovalent ancestral SARS-CoV-2 spike sequence as the study period ended before the availability of bivalent variant-containing boosters. The anti-S IgG measurements occurred between January 28, 2021, and August 25, 2022. Patients were censored as of the date of SARS-CoV-2 monoclonal antibody (mAb) therapy or positive test for SARS-CoV-2 infection. Those who had anti-S IgG assays only before transplant or who relapsed and received an alternate treatment were excluded.
Patient Consent
This study was approved by the Mass General Brigham Institutional Review Board, which deemed that it was exempt from requiring participant informed consent.
Study Design
Anti-S IgG titers were quantitatively measured at the provider's discretion during routine care using the Roche Elecsys Anti-SARS-CoV-2 spike immunoassay. The assay has a cutoff defined by the manufacturer as ≥0.8 U/mL. Values below this were imputed to 0.4 U/mL; values above this were considered reactive (responder), while values below were considered nonreactive (nonresponder) [19]. Earlier anti-S IgG assays had a maximum reported titer of 2500 U/mL, while later assays had a higher maximum titer of 12 500 U/mL. For the later assays with titers >2500 U/mL, a different dilutional method was used in the lab. To ensure uniformity in reporting and facilitate appropriate comparisons, all anti-S IgG titers were adjusted to a maximum of 2500 U/mL before our analysis. Baseline demographic data, blood cell counts (CD4, WBC), and IgG levels were extracted from the EMR (starting 3 months before the first vaccination). The pretransplant conditioning regimen, type of transplant, GVHD prophylaxis, acute and chronic GVHD treatment, SARS-CoV-2 PCR result, COVID-19 treatment status, and type of vaccine received were extracted from the EMR. The study timeline for each eligible participant spanned between 3 months before the first dose of SARS-CoV-2 vaccination and the date of their last anti-S IgG antibody assay. To determine the time from the last vaccine dose after transplant, we used the results of the anti-S IgG assay that were collected after the last dose for all patient groups.
Statistical Analysis
Patients were categorized based on the number of doses of the vaccine(s) received before their last anti-S IgG titer. We analyzed these data using descriptive statistics to assess the quantitative difference in anti-S IgG titer and a Kruskal-Wallis or Mann-Whitney U test to assess for statistical significance between groups. Univariable and multivariable models were used to assess the relationship between key patient demographics, vaccine and treatment characteristics, and their association with vaccine response among HSCT recipients. A logistic regression model was used to calculate odds ratios (ORs) and 95% CIs for factors potentially associated with a dichotomous response status to SARS-CoV-2 vaccination (responders vs nonresponders). P values ≤.05 were considered statistically significant. Only variables with P values ≤.25 and certain clinically relevant variables regardless of statistical significance were included in the multivariable analysis. Factors evaluated included age, sex, neutrophil count, lymphocyte count, platelet counts, IgG level, prophylaxis and treatment for GVHD (eg, mycophenolate mofetil, sirolimus, systemic corticosteroids [≥20 mg], tacrolimus, and cyclophosphamide), receipt of anti-CD20 therapy (eg, rituximab, ocrelizumab, veltuzumab, obinutuzumab), type of transplant, type of conditioning regimen, time from transplant to first vaccination, time from first vaccination to first anti-S IgG titer assay, time from last dose to last antibody titer, and number of vaccine doses received. Stata, version 17.0, and GraphPad Prism 9 were used to analyze the study data and render figures.
RESULTS
Sociodemographic Characteristics and Magnitude of Antispike Response
A total of 871 HSCT recipients were screened, and 152 patient records met the study inclusion criteria (Supplementary Figure 1). Of these, 82 (54%) were male, and the median age (interquartile range [IQR]) was 62 (50–68.0) years. Participants were predominantly White (n = 139, 91.5%). The majority of patients, 124 (81.6%), received an allogeneic transplant, and 28 (18.4%) received an autologous transplant. Patients received anywhere from 1 to 5 SARS-CoV-2 vaccinations, with most patients receiving ≥3 vaccines (98/152, 64.5%) (Supplementary Table 1). Other characteristics such as underlying disease, preparation intensity, transplant type, and medications used in the prophylaxis and treatment of acute and chronic GVHD are described in Table 1.
Table 1.
Demographic, Treatment, and SARS-CoV-2 Vaccination Characteristics of Hematopoietic Stem Cell Transplant Recipients
| Total (n = 152) | Responders (n = 141) | Nonresponders (n = 11) | P Value | |
|---|---|---|---|---|
| Anti-S IgG Antibody ≥0.8 U/mL | Anti-S IgG Antibody <0.8 U/mL | |||
| Demographic characteristics | ||||
| Age, median (IQR), y | 62 (50–68) | 62 (50–68) | 65 (36–68) | .57 |
| Sex | .011 | |||
| Female | 70 (46.1) | 69 (48.9) | 1 (9.1) | |
| Male | 82 (53.9) | 72 (51.1) | 10 (90.9) | |
| Race | .24 | |||
| Non-White | 13 (8.6) | 11 (7.8) | 2 (18.2) | |
| White | 139 (91.5) | 130 (92.2) | 9 (81.8) | |
| Clinical characteristics | ||||
| Disease type | .32 | |||
| AML/other acute leukemias | 41 (27) | 38 (27.0) | 3 (27.3) | |
| CML/other chronic leukemias | 9 (5.9) | 8 (5.7) | 1 (9.1) | |
| ALL | 15 (9.9) | 14 (9.9) | 1 (9.1) | |
| Lymphomas (HL/NHL) | 26 (17.1) | 23 (16.3) | 3 (27.3) | |
| Anemias/hemoglobinopathies | 8 (5.3) | 6 (4.3) | 2 (18.2) | |
| Myelodysplastic Syndrome/myelofibrosis | 41 (27) | 40 (28.4) | 1 (9.1) | |
| Multiple myelomas | 12 (7.9) | 12 (8.5) | 0 (0.0) | |
| Baseline WBC count, median (IQR), cells × 109/L | 4.6 (3.5–6.0) | 4.7 (3.5–6.0) | 4.6 (3.2–6.2) | .72 |
| Baseline lymphocyte count, median (IQR), cells × 109/L | 1 (0.6–1.5) | 1 (0.6–1.5) | 1 (0.8–1.1) | .34 |
| Baseline CD4 lymphocyte count, median (IQR), cells × 106/L | 281.5 (183–405) | 305.5 (183–420) | 225 (171–324) | .45 |
| Baseline IgG level, median (IQR), mg/dL | 652 (498.5–1020.5) | 652 (507–1023) | 436 (367–756) | .18 |
| Preparation intensity | .74 | |||
| Myeloablative | 63 (41.5) | 59 (41.8) | 4 (36.4) | |
| Nonmyeloablative | 7 (4.6) | 6 (4.3) | 1 (9.1) | |
| Reduced-intensity conditioning | 82 (54) | 76 (53.9) | 6 (54.5) | |
| Transplant type | .43 | |||
| Autologous | 28 (18.4) | 25 (17.7) | 3 (27.3) | |
| Allogeneic | 124 (81.6) | 116 (82.3) | 8 (72.7) | |
| Acute GVHD | .62 | |||
| Yes | 32 (15.5) | 21 (15.9) | 1 (10) | |
| No | 120 (84.5) | 111 (84.1) | 9 (90) | |
| Chronic GVHD | .57 | |||
| Yes | 57 (37.5) | 52 (36.9) | 5 (45.5) | |
| No | 95 (62.5) | 89 (63.1) | 6 (54.5) | |
| Pharmacotherapy around the time of vaccination | ||||
| GVHD prophylaxis (tacrolimus) | <.001 | |||
| Yes | 77 (50.7) | 77 (54.6) | 0 (0) | |
| No | 75 (49.3) | 64 (45.4) | 11 (100) | |
| Acute GVHD treatment (tacrolimus) | .73 | |||
| Yes | 10 (6.6) | 9 (6.4) | 1 (9.1) | |
| No | 142 (93.4) | 132 (93.6) | 10 (90.9) | |
| Chronic GVHD treatment (tacrolimus) | .66 | |||
| Yes | 36 (23.7) | 34 (24.1) | 2 (18.2) | |
| No | 116 (76.3) | 107 (75.9) | 9 (81.8) | |
| Systemic corticosteroids | .85 | |||
| Yes | 65 (42.8) | 60 (42.6) | 5 (45.5) | |
| No | 87 (57.2) | 81 (57.4) | 6 (54.5) | |
| Anti-CD20 therapy | .004 | |||
| Yes | 16 (10.5) | 12 (8.5) | 4 (36.4) | |
| No | 136 (89.5) | 129 (91.5) | 7 (63.6) | |
| Vaccination characteristics | ||||
| Time from transplant to first vaccine dose, median (IQR),a d | 140.5 (−48 to 254) | 136 (−56 to 253) | 217 (174–330) | .096 |
| No. of vaccine doses | .28 | |||
| 1 | 11 (7.8) | 11 (0) | 0 (0) | |
| 2 | 66 (44.0) | 62 (31.9) | 4 (27.3) | |
| 3 | 55 (34.0) | 48 (44.7) | 7 (72.7) | |
| 4 | 10 (7.1) | 10 (7.8) | 0 (0) | |
| 5 | 10 (7.1) | 10 (11.3) | 0(0) | |
P values ≤ .05 are indicated in boldface.
Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myelogenous leukemia; CML, chronic myelogenous leukemia; GVHD, graft-vs-host disease; HL, Hodgkin lymphoma; IQR, interquartile range; NHL, non-Hodgkin lymphoma; WBC, white blood cells.
Negative time means patient had first vaccine dose before transplant.
Descriptive Analysis Comparing Anti-S IgG Levels in Various Categories
The results comparing anti-S IgG titers between HSCT recipients stratified by number of vaccines received are shown in Figure 1. In addition, there was no statistically significant difference in the anti-S IgG assay time between the different patient strata (Figure 1B). Furthermore, the median anti-S IgG titers among HSCT patients stratified by concurrent receipt of high-dose steroid, tacrolimus, anti-CD20 therapy, and type of transplant are shown in Figure 2. Of these, patients who had concurrent anti-CD20 therapy had the lowest antibody titers. More descriptive analysis comparing the median anti-S IgG titers of other subgroups can be found in the Supplementary Data. Eleven (7.2%) HSCT recipients could not mount a positive response, regardless of the number of vaccines received. Of these nonresponders, 4 (27.3%) received 2 doses of the vaccine and 7 (72.7%) received 3 doses.
Figure 1.
Anti-SARS-CoV-2 spike antibody titers among HSCT recipients. The result of the multivariate analysis shows an association between the number of vaccine doses received and the magnitude of anti-S IgG response. A, Anti-spike IgG responses on the y-axis and the number of vaccine doses received on the x-axis. B, The corresponding median time between anti-S IgG assay and the last dose received. A Mann-Whitney U test shows no significant difference in the last dose to assay time between the various dose categories. Abbreviations: HSCT, hematopoietic stem cell transplant; IgG, immunoglobulin G; S, spike; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Figure 2.
Anti-S IgG responses among various categories of HSCT recipients. Titers were compared between patients who were on concurrent immunosuppression therapy vs those who were not. A, High-dose (≥20 mg prednisone equivalent per day) steroid treatment. B, Tacrolimus treatment. C, Anti-CD20 monoclonal antibody treatment. D, Autologous HSCT vs allogeneic HSCT. All panels show a Mann-Whitney U test unadjusted analysis between the groups. Abbreviations: HSCT, hematopoietic stem cell transplant; IgG, immunoglobulin G; S, spike.
Autologous and Allogeneic Transplant Recipients
Autologous transplant patients had a median (IQR) anti-S IgG of 2303.5 (25.3–2500) U/mL measured at a median time (IQR) of 132 (83–181) days from the last vaccine dose. Allogeneic transplant patients had a median anti-S IgG (IQR) of 2500 (25.3–2500) U/mL at a median time (IQR) of 63 (36–145) days from the last vaccine dose (Supplementary Table 6).
Patients who had concurrent treatments for acute GVHD with tacrolimus had a median anti-S IgG (IQR) of 156.7 (3.53–1556) U/mL at a median time (IQR) of 107 (50–148) days from the last vaccine dose. Those who did not have tacrolimus treatment had a higher median anti-S IgG (IQR) of 2500 (153.5–2500) U/mL at a median time (IQR) of 80.5 (153.5–2500) days from the last vaccine dose (Supplementary Table 7).
HSCT Recipients Aged <65 vs ≥65 Years
Patients aged 65 years and older had a lower median anti-S IgG (IQR) of 1786 (62–2500) U/mL at a median time (IQR) of 84 (49–148) days from the last vaccine dose. Patients aged <65 years had a higher median titer (IQR) of 2500 (249.8–2500) U/mL at a median time (IQR) of 63 (34–154) days from the last vaccine dose.
Correlates of Seropositivity (Multivariable Analysis)
The results of the multivariable linear regression analysis indicated a positive correlation between the number of vaccine doses received and the quantitative anti-S IgG titer (Table 2). Specifically, as the number of doses increased, the anti-S IgG titer also increased correspondingly (coeff, 205; 95% CI, 30.1 to 381.5; P = .022). Being female (coeff, 343.5; 95% CI, −682.6 to −4.4; P = .047) was also associated with having a higher anti-S IgG titer compared with being male. Being age <65 years had a positive correlation with the quantitative anti-S IgG titer when compared with those aged 65 years or older (coeff, 365.2; 95% CI, −711.3 to −19.1; P = .039). Patients on concurrent anti-CD20 therapy had a statistically significant negative correlation with the quantitative anti-S IgG titer when compared with those who were not receiving the therapy (coeff, −1163.7; 95% CI, −1717.7 to −609.7; P = .001) (Table 2). The results of the regression analysis indicated that being on treatment for acute GVHD with steroids and tacrolimus and having chronic GVHD did not have a significant effect on the quantitative anti-S IgG titer (Table 2).
Table 2.
Linear and Logistic Regression Table
| Table of Linear Regression Analysis | ||||
|---|---|---|---|---|
| Univariable Analysis | Multivariable Analysis | |||
| Coefficient (95% CI) | P Value | Coefficient (95% CI) | P Value | |
| Doses of vaccine received | 154.20 (−35.36 to 343.77) | .110 | 205.79 (30.10 to 381.47) | .022 |
| Age | ||||
| ≥65 y | −293.60 (−664.22 to 77.03) | .120 | −365.20 (−711.32 to 19.09) | .039 |
| <65 y (ref.) | ||||
| Sex | ||||
| Male | −451.00 (−808.98 to −92.99) | .014 | −343.51 (−682.58 to 4.45) | .047 |
| Female (ref.) | ||||
| Anti-CD20 therapy | ||||
| Yes | −1256.10 (−1813.74 to −698.45) | .000 | −1163.67 (−1717.69 to −609.66) | .000 |
| No (ref.) | ||||
| Systemic corticosteroids | ||||
| Yes | −157.58 (−524.75 to 209.59) | .398 | −28.21 (−399.54 to 343.13) | .881 |
| No (ref.) | ||||
| Acute GVHD treatment (tacrolimus) | ||||
| Yes | −769.09 (−1493.01 to −45.17) | .037 | −531.75 (−1212.76 to 149.26) | .125 |
| No (ref.) | ||||
| Chronic GVHD | ||||
| Yes | 200.31 (−174.42 to 575.03) | .293 | 242.66 (−128.21 to 613.53) | .198 |
| No (ref.) | ||||
| Table of Logistic Regression Analysis | ||||
|---|---|---|---|---|
| Univariable Analysis | Multivariable Analysis | |||
| Odds Ratio (95% CI) | P Value | Odds Ratio (95% CI) | P Value | |
| Doses of vaccine received | 0.98 (0.52 to 1.86) | .948 | 1.16 (0.59 to 2.31) | .664 |
| Age | ||||
| ≥65 y | 0.74 (0.22 to 2.56) | .640 | 0.58 (0.15 to 2.26) | .436 |
| <65 y (ref.) | ||||
| Sex | ||||
| Male | 0.10 (0.01 to 0.84) | .033 | 0.11 (0.01 to 0.93) | .042 |
| Female (ref.) | ||||
| Anti-CD20 therapy | ||||
| Yes | 0.16 (0.04 to 0.64) | .009 | 0.16 (0.03 to 0.70) | .016 |
| No (ref.) | ||||
| Systemic corticosteroids | ||||
| Yes | 0.89 (0.26 to 3.05) | .851 | 1.75 (0.38 to 8.01) | .472 |
| No (ref.) | ||||
| Acute GVHD treatment (tacrolimus) | ||||
| Yes | 0.68 (0.08 to 5.93) | .729 | 1.20 (0.12 to 11.69) | .878 |
| No (ref.) | ||||
| Chronic GVHD | ||||
| Yes | 0.70 (0.20 to 2.41) | .573 | 0.45 (0.10 to 2.09) | .311 |
| No (ref.) | ||||
P values ≤ .05 are indicated in boldface.
Abbreviation: GVHD, graft-vs-host disease.
Additionally, receiving anti-CD20 therapy and being male were significantly associated with not mounting a positive vaccine response (OR, 0.16; 95% CI, 0.03 to 0.70; P = .016; and OR, 0.11; 95% CI, 0.01 to 0.93; P = .04, respectively). Other factors, such as the number of doses, age, treatment of acute GVHD using systemic steroids or tacrolimus, and the presence of chronic GVHD, were not found to be statistically significant (Table 2).
DISCUSSION
Our results demonstrated that HSCT recipients had overall high seropositivity rates, defined as having detectable anti-S IgG titers, but the quantitative median anti-S IgG titers were generally lower than reported among healthy participants who received COVID vaccines which were granted EUAs [20, 21]. In the phase 3 registrational studies, healthy adults had almost a 100% seropositivity rate and high quantitative titers after the first dose of SARS-CoV-2 vaccines [11, 22]. While antibody levels are a clear correlate of protection against SARS-CoV-2 infection, there are likely other mechanisms of protection [1, 23–28]. Therefore, the results of the quantitative anti-S IgG titers and seropositivity in particular must be interpreted with caution and should not be taken as the sole indicator of immune-protectiveness among HSCT recipients.
Our results depicted that the use of anti-CD20 therapy was associated with being a non-responder and having significantly lower anti-S IgG titers. This supports previous findings in the literature that anti-CD20 therapies inhibit B-cell antibody production and deplete peripheral B cells, leading to a decrease in vaccine-elicited IgG titers [22–24]. To ensure that HSCT recipients benefit optimally from SARS-CoV-2 vaccination, it may be important to consider the timing of vaccine administration in regards to anti-CD20 therapy if feasible. Furthermore, clinicians should be aware that these patients remain at risk despite vaccination and should be counseled on the need for additional layers of protection known to supplement vaccination and reduce transmissibility of SARS-CoV-2 infection as recommended by the US Centers for Disease Control and Prevention (CDC) [29].
This study found no significant difference in the response to SARS-CoV-2 vaccines between HSCT recipients receiving concurrent GVHD treatment (tacrolimus, steroids) and those not receiving treatment, after adjusting for confounding factors. However, another study showed that ongoing GVHD and treatment negatively impact the anti-S IgG response in HSCT recipients compared with healthy adults [30, 31]. One study among Japanese patients showed that allogeneic transplant patients, some of whom had treatment for GVHD, showed a better overall anti-S IgG response compared with autologous transplant patients in the cohort [32].
Immunosuppression in other contexts has also been found to lead to blunted vaccine-elicited immune responses. In a recent prospective study, Griessbach and colleagues offered a third dose of either the Moderna or Pfizer/BioNTech SARS-CoV-2 vaccine to a cohort of patients either living with HIV or who had had kidney or lung transplants [33]. They found that while the majority of participants had a serologic response, the response rate was higher among persons with HIV compared with solid organ transplant recipients (100% vs 73% using the same cutoff value as we used for the Roche Elecsys assay) [33]. Further research is needed to fully elucidate the complex relationship between GVHD, immunosuppressive medications, and vaccine efficacy in HSCT patients.
Patients who received a higher number of SARS-CoV-2 vaccinations had a significantly higher quantitative anti-S IgG response. This result is consistent with other studies among healthy individuals and HSCT recipients [14, 34]. These data, therefore, generally support the recommendation for booster doses as recommended by the CDC [29], particularly for transplant patients who have lower antibody levels and are more vulnerable to severe illness [12]. However, the optimal timing of booster doses should be further explored in future prospective studies.
Our results show that women had a significantly higher anti-S antibody level compared with men, consistent with other reports in healthy individuals [30, 35]. Ongoing research suggests that hormones such as estrogen may have an immunomodulatory function [36]. Environmental and genetic factors may also play a role [37]. Further studies are needed to elucidate the underlying mechanisms.
Additionally, being age <65 years was associated with a stronger quantitative antibody response compared with older patients age ≥65. This observation is consistent with what has been described in other studies among allogeneic HSCT recipients and healthy participants who had SARS-CoV-2 vaccinations [2, 38, 39]. While an age-related decline in immune responses, known as immunosenescence, has been observed in older individuals compared with their younger counterparts [40–42], the mechanisms underlying this phenomenon are an area of active research [43–45].
Our study has several limitations that should be taken into account when interpreting the findings. The study was conducted retrospectively, meaning that a causal relationship cannot be established from the results. Additionally, the clinical significance of the findings remains unknown, as correlates of protection may vary between immunocompromised hosts and healthy clinical trial participants. It is also worth noting that our study participants had not had variant-containing bivalent booster vaccines during the observation period, and treatment records were censored on the date of a positive SARS-CoV-2 infection. In addition, circulating viral variants complicate the correlates analyses. The study's population was predominantly White, limiting the generalizability of the findings to other racial or ethnic groups. Furthermore, only a small proportion of the sampled population had the complete vaccine series and serial anti-S IgG titer measurements, which prevented us from assessing vaccination responses longitudinally. Moreover, while the heterogeneity of vaccine types may have influenced the results, most patients received mRNA vaccines. The study also did not consider the duration of prophylaxis or treatment against GVHD, only whether recipients had treatment or not. Lastly, the results of this study may be challenging to compare with other studies that used different antibody assay techniques, as the reference range and assay limits may vary. These limitations indicate the need for larger prospective studies to confirm the results and gain a better understanding of the optimal vaccination strategy for HSCT patients.
CONCLUSIONS
The FDA-authorized SARS-CoV-2 vaccine series produced an immunogenic response among the majority of HSCT patients, but the response was suboptimal for certain subsets of the cohort, such as older patients and those who had received anti-CD20 therapy. The number of vaccine doses administered correlated with the magnitude of the anti-S IgG response, and quantitative anti-S IgG assays could therefore be conducted for early identification of patients who fail to respond to vaccination. The findings support the current recommendations for HSCT patients to receive a 3-dose primary series followed by serial booster COVID vaccines to optimize protection against SARS-CoV-2 infection.
Supplementary Material
Acknowledgments
We wish to thank the dedicated staff at the BWH Vaccine Trials Unit who helped make this study possible. We would like to acknowledge Kristen Rizza for her assistance with the Dana-Farber Cancer Institute HSCT database. We also wish to thank Brian Claggett for assistance with the statistical analyses.
Financial support. National Institute of Allergy and Infectious Diseases / National Institutes of Health (grant UM1AI069412 to SRW and LRB).
Disclaimer. The views expressed are those of the authors and should not be construed to represent the positions of the US Army, Department of Defense, Henry M. Jackson Foundation for the Advancement of Military Medicine, Brigham and Women's Hospital, Dana-Farber Cancer Institute, or Harvard Medical School.
Contributor Information
Afoke Kokogho, Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA.
Trevor A Crowell, Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA; US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.
Muneerah Aleissa, Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA.
Ana-Mihaela Lupan, Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA.
Sonya Davey, Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA; Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Jun Bai Park Chang, Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA; Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Lindsey R Baden, Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA.
Stephen R Walsh, Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA.
Amy C Sherman, Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA.
Supplementary Data
Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
References
- 1. Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med 2020; 384:403–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. N Engl J Med 2020; 383:2603–15. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Stephenson KE, Le Gars M, Sadoff J, et al. Immunogenicity of the Ad26.COV2.S vaccine for COVID-19. JAMA 2021; 325:1535–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Malard F, Gaugler B, Gozlan J, et al. Weak immunogenicity of SARS-CoV-2 vaccine in patients with hematologic malignancies. Blood Cancer J 2021; 11:142. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Eberhardt CS, Balletto E, Cornberg M, Mikulska M. Coronavirus disease 2019 vaccination in transplant recipients. Curr Opin Infect Dis 2021; 34:275–87. [DOI] [PubMed] [Google Scholar]
- 6. Sharma A, Bhatt NS, St Martin A, et al. Clinical characteristics and outcomes of COVID-19 in haematopoietic stem-cell transplantation recipients: an observational cohort study. Lancet Haematol 2021; 8:e185–93. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Sonani B, Aslam F, Goyal A, Patel J, Bansal P. COVID-19 vaccination in immunocompromised patients. Clin Rheumatol 2021; 40:797–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Madan A, Siglin J, Khan A. Comprehensive review of implications of COVID-19 on clinical outcomes of cancer patients and management of solid tumors during the pandemic. Cancer Med 2020; 9:9205–18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Loconsole D, Stea ED, Sallustio A, et al. Severe COVID-19 by SARS-CoV-2 lineage B.1.1.7 in vaccinated solid-organ transplant recipients: new preventive strategies needed to protect immunocompromised patients. Vaccines (Basel) 2021; 9:806. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Mena Lora AJ, Long JE, Huang Y, et al. Rapid development of an integrated network infrastructure to conduct phase 3 COVID-19 vaccine trials. JAMA Netw Open 2023; 6:e2251974. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Sherman AC, Desjardins M, Cheng CA, et al. Severe acute respiratory syndrome coronavirus 2 messenger RNA vaccines in allogeneic hematopoietic stem cell transplant recipients: immunogenicity and reactogenicity. Clin Infect Dis 2022; 75:e920–3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Mamez AC, Pradier A, Giannotti F, et al. Antibody responses to SARS-CoV2 vaccination in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant 2021; 56:3094–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Wu X, Wang L, Shen L, He L, Tang K. Immune response to vaccination against SARS-CoV-2 in hematopoietic stem cell transplantation and CAR T-cell therapy recipients. J Hematol Oncol 2022; 15:81. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Ge C, Du K, Luo M, et al. Serologic response and safety of COVID-19 vaccination in HSCT or CAR T-cell recipients: a systematic review and meta-analysis. Exp Hematol Oncol 2022; 11:46. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Kyong CO, Gomez-Arteaga A, Chen Z, et al. Predictors of COVID-19 vaccination response after in-vivo T-cell–depleted stem cell transplantation. Transplant Cell Ther 2022; 28:618.e1–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Redjoul R, Le Bouter A, Beckerich F, Fourati S, Maury S. Antibody response after second BNT162b2 dose in allogeneic HSCT recipients. Lancet 2021; 398:298–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Korth J, Jahn M, Dorsch O, et al. Impaired humoral response in renal transplant recipients to SARS-CoV-2 vaccination with BNT162b2 (Pfizer-BioNTech). Viruses 2021; 13:756. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Park JK, Lee YJ, Shin K, et al. Impact of temporary methotrexate discontinuation for 2 weeks on immunogenicity of seasonal influenza vaccination in patients with rheumatoid arthritis: a randomised clinical trial. Ann Rheum Dis 2018; 77:898–904. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Elecsys Anti-SARS-CoV-2 S. Diagnostics. Available at: https://diagnostics.roche.com/global/en/products/params/elecsys-anti-sars-cov-2-s.html. Accessed December 15, 2022.
- 20. Tolan NV, Sherman AC, Zhou G, et al. The effect of vaccine type and SARS-CoV-2 lineage on commercial SARS-CoV-2 serologic and pseudotype neutralization assays in mRNA vaccine recipients. Microbiol Spectr 2022; 10:e0021122. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Jochum S, Kirste I, Hortsch S, et al. Clinical utility of Elecsys anti-SARS-CoV-2 S assay in COVID-19 vaccination: an exploratory analysis of the mRNA-1273 phase 1 trial. Front Immunol 2021; 12:798117. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Vijenthira A, Gong I, Betschel SD, Cheung M, Hicks LK. Vaccine response following anti-CD20 therapy: a systematic review and meta-analysis of 905 patients. Blood Advances 2021; 5:2624–43. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Ciotti JR, Valtcheva MV, Cross AH. Effects of MS disease-modifying therapies on responses to vaccinations: a review. Mult Scler Relat Disord 2020; 45:102439. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Wei X, Xie Y, Jiang R, et al. The impact of rituximab administered before transplantation in patients undergoing allogeneic hematopoietic stem cell transplantation: a real-world study. Front Immunol 2022; 13:967026. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Fong Y, McDermott AB, Benkeser D, et al. Immune correlates analysis of the ENSEMBLE single Ad26.COV2.S dose vaccine efficacy clinical trial. Nat Microbiol 2022; 7:1996–2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Benkeser D, Fong Y, Janes HE, et al. Immune correlates analysis of a phase 3 trial of the AZD1222 (ChAdOx1 nCoV-19) vaccine. NPJ Vaccines 2023; 8:36. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Fong Y, Huang Y, Benkeser D, et al. Immune correlates analysis of the PREVENT-19 COVID-19 vaccine efficacy clinical trial. Nat Commun 2023; 14:331. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Gilbert PB, Montefiori DC, McDermott AB, et al. Immune correlates analysis of the mRNA-1273 COVID-19 vaccine efficacy clinical trial. Science 2022; 375:43–50. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Patel P, Twentyman E, Koumans E, et al. Information for persons who are immunocompromised regarding prevention and treatment of SARS-CoV-2 infection in the context of currently circulating Omicron sublineages—United States, January 2023. MMWR Morb Mortal Wkly Rep 2023; 72:128–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Majcherek M, Matkowska-Kocjan A, Szymczak D, et al. Two doses of BNT162b2 mRNA vaccine in patients after hematopoietic stem cell transplantation: humoral response and serological conversion predictors. Cancers (Basel) 2022; 14:325. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Mohty B, Bel M, Vukicevic M, et al. Graft-versus-host disease is the major determinant of humoral responses to the AS03-adjuvanted influenza A/09/H1N1 vaccine in allogeneic hematopoietic stem cell transplant recipients. Haematologica 2011; 96:896–904. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Tsushima T, Terao T, Narita K, et al. Antibody response to COVID-19 vaccine in 130 recipients of hematopoietic stem cell transplantation. Int J Hematol 2022; 115:611–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Griessbach A, Chammartin F, Abela IA, et al. Antibody response after third vaccination with mRNA-1273 or BNT162b2: extension of a randomized controlled SARS-CoV-2 noninferiority vaccine trial in patients with different levels of immunosuppression (COVERALL-2). Open Forum Infect Dis 2023; 10:XXX–XX. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Lindemann M, Klisanin V, Thümmler L, et al. Humoral and cellular vaccination responses against SARS-CoV-2 in hematopoietic stem cell transplant recipients. Vaccines (Basel) 2021; 9:1075. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35. Abid MB, Rubin M, Ledeboer N, et al. Efficacy of a third SARS-CoV-2 mRNA vaccine dose among hematopoietic cell transplantation, CAR T cell, and BiTE recipients. Cancer Cell 2022; 40:340–2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. Lang TJ. Estrogen as an immunomodulator. Clinical Immunology 2004; 113:224–30. [DOI] [PubMed] [Google Scholar]
- 37. Ovsyannikova IG, Haralambieva IH, Crooke SN, Poland GA, Kennedy RB. The role of host genetics in the immune response to SARS-CoV-2 and COVID-19 susceptibility and severity. Immunol Rev 2020; 296:205–19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38. Huang A, Cicin-Sain C, Pasin C, et al. Antibody response to SARS-CoV-2 vaccination in patients following allogeneic hematopoietic cell transplantation. Transplant Cell Ther 2022; 28:214.e1–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39. El Sahly HM, Baden LR, Essink B, et al. Efficacy of the mRNA-1273 SARS-CoV-2 vaccine at completion of blinded phase. N Engl J Med 2021; 385:1774–85. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40. Pawelec G, Larbi A, Derhovanessian E. Senescence of the human immune system. J Comp Pathol 2010; 142:S39–44. [DOI] [PubMed] [Google Scholar]
- 41. Aw D, Silva AB, Palmer DB. Immunosenescence: emerging challenges for an ageing population. Immunology 2007; 120:435–46. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42. Gruver A, Hudson L, Sempowski G. Immunosenescence of ageing. J Pathol 2007; 211:144–56. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43. Pawelec G, Larbi A, Derhovanessian E. Senescence of the human immune system. J Comp Pathol 2010; 142:S39–44. [DOI] [PubMed] [Google Scholar]
- 44. Goronzy JJ, Weyand CM. Understanding immunosenescence to improve responses to vaccines. Nat Immunol 2013; 14:428–36. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45. Frasca D, Blomberg BB, Paganelli R. Aging, obesity, and inflammatory age-related diseases. Front Immunol 2017; 8:1745. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.