Abstract
This study quantifies antispike protein antibody responses to first-dose messenger RNA (mRNA) COVID-19 vaccines in solid organ transplant recipients to better understand the immunogenicity of the vaccines in immunocompromised individuals.
Immunocompromised individuals have been excluded from studies of SARS-CoV-2 messenger RNA (mRNA) vaccines. In such patients, the immune response to vaccination may be blunted. To better understand the immunogenicity of mRNA vaccines in immunocompromised individuals, we quantified the humoral response to the first dose in solid organ transplant recipients.
Methods
Transplant recipients across the US were recruited though social media to participate in this prospective cohort, and those who underwent SARS-CoV-2 vaccination between December 16, 2020, and February 5, 2021, were included. The study was approved by the Johns Hopkins University institutional review board and participants provided informed consent electronically. Participants underwent either at-home blood sampling with the TAPII blood collection device (Seventh Sense Biosystems) or standard venipuncture.
The TAPII samples were tested using an enzyme immunoassay (EUROIMMUN) that tests for antibodies to the S1 domain of the SARS-CoV-2 spike protein.1 The venipuncture samples were tested using the anti–SARS-CoV-2 S enzyme immunoassay (Roche Elecsys) that tests for antibodies against the receptor-binding domain of the SARS-CoV-2 spike protein. Both tests are semiquantitative, correspond to mRNA vaccine antigens, and are consistently correlated with neutralizing immunity.2,3,4 The sensitivity and specificity of the enzyme immunoassays are excellent for detection of the antispike humoral response to SARS-CoV-2 infection (sensitivity of 87.1% and specificity of 98.9% for EUROIMMUN3 and sensitivity of 84.0% and specificity of 100% for Roche Elecsys4) and are analogous to the antispike antibody assays used during immunogenicity assessments in mRNA vaccine clinical trials.
We assessed the proportion of patients who developed a positive antibody response with exact binomial 95% CIs. We evaluated the associations among demographic and clinical characteristics, vaccine type, and positive antibody response using modified Poisson regression with a robust variance estimator. A sensitivity analysis of vaccine type limited to those tested 14 to 21 days after vaccination was performed. All tests were 2-sided with α = .05. Analyses were performed using Stata version 16.1 (StataCorp).
Results
There were 436 transplant recipients included in the study (Table). None had a prior polymerase chain reaction–confirmed diagnosis of COVID-19. The median age was 55.9 years (interquartile range [IQR], 41.3-67.4 years), 61% were women, and 89% were White transplant recipients; 52% received the BNT162b2 vaccine (Pfizer-BioNTech) and 48% received the mRNA-1273 vaccine (Moderna). The median time since transplant was 6.2 years (IQR, 2.7-12.7 years). The maintenance immunosuppression regimen included tacrolimus (83%), corticosteroids (54%), mycophenolate (66%), azathioprine (9%), sirolimus (4%), and everolimus (2%). At a median of 20 days (IQR, 17-24 days) after the first dose of vaccine, antibody (anti-S1 or anti–receptor-binding domain) was detectable in 76 of 436 participants (17%; 95% CI, 14%-21%).
Table. Demographic and Clinical Characteristics of Study Participants, Stratified by Immune Response to the First Dose of SARS-CoV-2 Messenger RNA Vaccine, and Associations With Developing an Antibody Response (N = 436).
| Antibody, No. (%) | Bivariable IRR (95% CI) | P value | Adjusted multivariable IRR (95% CI)a | P value | ||
|---|---|---|---|---|---|---|
| Detectable (n = 76) | Undetectable (n = 360) | |||||
| Age group, y | ||||||
| 18-39 | 30 (39) | 69 (19) | 0.81 (0.71-0.93)b | .003 | 0.83 (0.73-0.93) | .002 |
| 40-59 | 18 (24) | 132 (37) | ||||
| ≥60 | 28 (37) | 159 (44) | ||||
| Sexc | ||||||
| Female | 48 (64) | 212 (59) | 1.12 (0.73-1.73)d | .60 | ||
| Male | 27 (36) | 138 (41) | ||||
| Racec,e | ||||||
| Non-Whitef | 8 (11) | 38 (11) | 0.99 (0.51-1.94)g | .99 | ||
| White | 67 (89) | 312 (89) | ||||
| Type of organ transplanth | ||||||
| Kidney | 31 (41) | 188 (53) | 0.68 (0.45-1.04)i | .07 | ||
| Liver | 28 (37) | 50 (14) | ||||
| Heart | 9 (12) | 57 (16) | ||||
| Lung | 4 (5) | 45 (13) | ||||
| Pancreas | 1 (1) | 4 (1) | ||||
| Other (multiorgan) | 2 (3) | 12 (3) | ||||
| Time since transplant, yj | ||||||
| <3 | 13 (17) | 106 (30) | 1.88 (1.21-2.93)k | .005 | 1.45 (0.96-2.20) | .08 |
| 3-6 | 12 (16) | 77 (22) | ||||
| 7-11 | 19 (25) | 82 (23) | ||||
| ≥12 | 31 (41) | 89 (25) | ||||
| Type of regimen | ||||||
| Includes anti–metabolite maintenance immunosuppressionl | 28 (37) | 292 (81) | 0.21 (0.14-0.32)m | <.001 | 0.22 (0.15-0.34) | <.001 |
| Does not include anti–metabolite maintenance immunosuppression | 48 (63) | 68 (19) | ||||
| Vaccinen | ||||||
| mRNA-1273 (Moderna) | 52 (69) | 152 (43) | 2.14 (1.24-3.69)o | .006 | 2.15 (1.29-3.57) | .003 |
| BNT162b2 (Pfizer-BioNTech) | 23 (31) | 200 (57) | ||||
| Enzyme immunoassay manufacturerp | ||||||
| Roche Elecsys | 64 (84) | 266 (74) | 1.71 (0.96-3.05)q | .07 | ||
| EUROIMMUN | 12 (16) | 94 (26) | ||||
Abbreviation: IRR, incidence rate ratio.
Model adjusted for age, years since transplant, antimetabolite maintenance immunosuppression, days since vaccination, and vaccine type.
Per 10-year increase in age.
Missing data for 11 participants (1 in detectable category and 10 in undetectable category).
Comparison of female vs male.
The options were defined by the investigators and classified by the participants. Race/ethnicity was assessed to evaluate potential race/ethnicity differences in immune response.
Includes Black or African American, Asian, American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, Arab or Middle Eastern, and multiracial.
Comparison of non-White vs White.
Missing data for 5 participants (1 in detectable category and 4 in undetectable category).
Comparison of kidney transplant recipient vs non–kidney transplant recipient.
Missing data for 7 participants (1 in detectable category and 6 in undetectable category).
Comparison of 6 or more years since transplant vs less than 6 years since transplant. This was used as a cutoff since it was the median time since transplant.
Includes mycophenolate mofetil, mycophenolic acid, or azathioprine.
Comparison of other maintenance immunosuppression vs anti–metabolite maintenance immunosuppression.
Missing data for 9 participants (1 in detectable category and 8 in undetectable category).
Comparison of mRNA-1273 vs BNT162b2. Also adjusted for number of days between vaccination and antibody testing (median of 21 days for mRNA-1273 and 20 days for BNT162b2).
The antibody-positive cutoffs (determined by the manufacturer) were 0.80 U/mL or greater for Roche Elecsys and 1.1 or greater arbitrary units for EUROIMMUN.
Comparison of Roche Elecsys vs EUROIMMUN.
Transplant recipients receiving anti–metabolite maintenance immunosuppression therapy were less likely to develop an antibody response than those not receiving such immunosuppression therapy (37% vs 63%, respectively; adjusted incidence rate ratio [IRR], 0.22 [95% CI, 0.15-0.34]; P < .001) (Table). Older transplant recipients were less likely to develop an antibody response (adjusted IRR, 0.83 [95% CI, 0.73-0.93] per 10 years; P = .002). Those who received mRNA-1273 were more likely to develop an antibody response than those receiving BNT162b2 (69% vs 31%, respectively; adjusted IRR, 2.15 [95% CI, 1.29-3.57]; P = .003). This association was similar in a sensitivity analysis limited to those tested 14 to 21 days after vaccination (n = 245; adjusted IRR, 2.29 [95% CI, 1.32-3.94]; P = .003).
Discussion
In this study of immunogenicity of the first dose of the mRNA SARS-CoV-2 vaccine among solid organ transplant recipients, the majority of participants did not mount appreciable antispike antibody responses. However, younger participants, those not receiving anti–metabolite maintenance immunosuppression, and those who received the mRNA-1273 vaccine were more likely to develop antibody responses. These results contrast with the robust early immunogenicity observed in mRNA vaccine trials, including 100% antispike seroconversion by day 15 following vaccination with mRNA-12735 and by day 21 following vaccination with BNT162b2.6
Limitations include a convenience sample that may lack generalizability, lack of serial measurements after vaccination, and lack of a concurrent control group without immunosuppression. In addition, these data represent the humoral response to the first dose of a 2-dose series.
These findings of poor antispike antibody responses in organ transplant recipients after the first dose of mRNA vaccines suggest that such patients may remain at higher early risk for COVID-19 despite vaccination. Deeper immunophenotyping of transplant recipients after vaccination, including characterization of memory B-cell and T-cell responses, will be important in determining vaccination strategies as well as immunologic responses after the second dose.
Section Editor: Jody W. Zylke, MD, Deputy Editor.
References
- 1.Boyarsky BJ, Ou MT, Werbel WA, et al. Early development and durability of SARS-CoV-2 antibodies among solid organ transplant recipients: a pilot study. Transplantation. Published online January 19, 2021. doi: 10.1097/tp.0000000000003637 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Klein SL, Pekosz A, Park HS, et al. Sex, age, and hospitalization drive antibody responses in a COVID-19 convalescent plasma donor population. J Clin Invest. 2020;130(11):6141-6150. doi: 10.1172/JCI142004 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Patel EU, Bloch EM, Clarke W, et al. Comparative performance of five commercially available serologic assays to detect antibodies to SARS-CoV-2 and identify individuals with high neutralizing titers. J Clin Microbiol. 2021;59(2):e02257-20. doi: 10.1128/JCM.02257-20 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Higgins V, Fabros A, Kulasingam V. Quantitative measurement of anti-SARS-CoV-2 antibodies: analytical and clinical evaluation. J Clin Microbiol. Published online March 19, 2021. doi: 10.1128/JCM.03149-20 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Jackson LA, Anderson EJ, Rouphael NG, et al. ; mRNA-1273 Study Group . An mRNA vaccine against SARS-CoV-2—preliminary report. N Engl J Med. 2020;383(20):1920-1931. doi: 10.1056/NEJMoa2022483 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Walsh EE, Frenck RW Jr, Falsey AR, et al. Safety and immunogenicity of two RNA-based Covid-19 vaccine candidates. N Engl J Med. 2020;383(25):2439-2450. doi: 10.1056/NEJMoa2027906 [DOI] [PMC free article] [PubMed] [Google Scholar]