Solid organ transplant recipients (SOTRs) have suboptimal antibody responses to 2-dose severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination, with some improvement after receiving a third dose.1,2 Further boosting with a fourth dose (D4) has been suggested in small cohorts of SOTRs, but the evidence remains limited and restricted to kidney recipients with poor preceding seroresponse.3-5 To expand on these early observations, we updated our original case series of 18 participants to a more granular evaluation of 128 participants, diverse in organ type and pre-D4 vaccine response.
One-hundred twenty-eight SOTRs without prior reported SARS-CoV-2 infection who reported 4 doses of SARS-CoV-2 vaccine were identified from a previously described national, prospective observational cohort.1 Semiquantitative anti-spike (anti-S) serologic testing was performed using the Roche Elecsys anti-SARS-CoV-2 S enzyme immunoassay, which tests for the receptor-binding domain (RBD), or the EUROIMMUN Anti-SARS-CoV-2 enzyme immunoassay, which tests for the S1 domain of the SARS-CoV-2 spike protein, 2–4 wk after D4. Using the pre-D4 antibody response (defined as most recent titer before D4), participants were stratified into 3 groups (negative [anti-RBD<0.8 or anti-S<1.1], low [anti-RBD <250 U/mL or anti-S <4 AU/mL], or high [anti-RBD ≥250 U/mL or anti-S ≥4 AU/mL] titer) based on levels associated with in vitro neutralization.1 Clinical characteristics were compared between the 3 groups using the Kruskal–Wallis test for continuous and Fisher exact test for categorical variables. This study was approved by the Johns Hopkins Institutional Review Board (IRB00248540), and participants provided informed consent electronically.
The median (interquartile range [IQR]) age of participants at D4 was 62 y (49–69 y), 55% (n = 70) were female, and 59% (n = 75) were kidney transplant recipients. Pre-D4, 27% (n = 35) of SOTRs had negative titers, whereas 34% (n = 43) had low and 39% (n = 50) had high titers. The median (IQR) pre-D4 titers were 207.0 U/mL (11.6–1500.0 U/mL) (anti-RBD) and 2.1 AU/mL (0.5–6.0 AU/mL) (anti-S). Post-D4, 11% of SOTRs had persistently negative titers (nonresponders), whereas 14% had low and 75% had high titers (responders). The median (IQR) post-D4 titers were 2132.5 U/mL (96.9 to ≥2500.0 U/mL) (anti-RBD) and 8.8 AU/mL (5.3 to ≥8.94 AU/mL) (anti-S). Stratifying by pre-D4 antibody status, 61% (n = 21) of seronegative participants seroconverted and 84% (n = 36) of pre-D4 seroresponders boosted from low to high antibody titers post-D4 (Table 1). When stratified by post-D4 response, there were no statistically significant differences in any clinical factors between responders and nonresponders.
TABLE 1.
Demographics and antibody responses of solid organ transplant recipients who received 4 doses of SARS-CoV-2 vaccine, stratified by pre-dose 4 anti-spike antibody response
| Factor | Pre-dose 4 antibody levelsa | P | ||
|---|---|---|---|---|
| Negative | Low | High | ||
| N | 35 | 43 | 50 | |
| Age, median (IQR) | 63.5 (54.2–71.6) (n = 35) | 62.3 (49.6–69.5) (n = 43) | 58.4 (48.4–68.0) (n = 50) | 0.54 |
| Female, n (%) | 20 (57) | 24 (56) | 26 (52) | 0.90 |
| Years since transplant, median (IQR) | 4.6 (1.1–11.3) | 4.9 (1.5–11.5) | 7.2 (3.4–14.9) | 0.11 |
| Organ transplanted, n (%) | 0.052 | |||
| Kidney | 27 (77) | 23 (53) | 25 (50) | |
| Liver | 2 (6) | 6 (14) | 6 (12) | |
| Pancreas | 0 (0) | 0 (0) | 2 (4) | |
| Lung | 4 (11) | 4 (9) | 2 (4) | |
| Heart | 1 (3) | 4 (9) | 11 (22) | |
| Multiorgan | 1 (3) | 6 (14) | 4 (8) | |
| MMF, n (%) | 30 (86) | 31 (72) | 37 (74) | 0.33 |
| Triple immunosuppression, n (%) | 22 (63) | 18 (42) | 20 (40) | 0.090 |
| Initial vaccine series, n (%) | 0.21 | |||
| BNT162b2 | 22 (63) | 28 (65) | 24 (48) | |
| mRNA-1273 | 13 (37) | 15 (35) | 26 (52) | |
| Dose 3 vaccine type, n (%) | 0.31 | |||
| BNT162b2 | 16 (46) | 15 (35) | 17 (34) | |
| mRNA-1273 | 12 (34) | 13 (30) | 23 (46) | |
| Ad.26.CoV2.S | 7 (20) | 15 (35) | 10 (20) | |
| Dose 4 vaccine type, n (%) | 0.75 | |||
| BNT162b2 | 15 (43) | 14 (33) | 17 (34) | |
| mRNA-1273 | 17 (49) | 27 (63) | 30 (60) | |
| Ad.26.CoV2.S | 3 (9) | 2 (5) | 3 (6) | |
| Post-D4 antibody response category,a n (%) | <0.001 | |||
| Negative | 14 (40) | 0 (0) | 0 (0) | |
| Low | 11 (31) | 7 (16) | 0 (0) | |
| High | 10 (29) | 36 (84) | 50 (100) | |
| Pre-D4 anti-RBD titer, median (IQR) | <0.8 (<0.8 to <0.8) (n = 17) | 103.3 (46.4–197.9) (n = 32) | 1945.5 (1035.0 to >2500.0) (n = 34) | <0.001 |
| Post-D4 anti-RBD titer, median (IQR)b | 2.0 (<0.8 to 54.9) (n = 26) | 2027.0 (475.0 to >2500.0) (n = 37) | >2500.0 (>2500.0 to >2500.0) (n = 35) | <0.001 |
| Pre-D4 anti-S titer, median (IQR) | 0.3 (0.1–0.6) (n = 18) | 2.3 (2.0–2.9) (n = 11) | 7.0 (5.4–8.8) (n = 16) | <0.001 |
| Post-D4 anti-S titer, median (IQR)b | 5.1 (2.0–8.2) (n = 9) | 7.1 (5.1–8.9) (n = 6) | 8.9 (8.6 to ≥8.94) (n = 15) | 0.023 |
aNegative: Anti-RBD <0.8 U/mL anti-S <1.1 AU, low: anti-RBD <250 U/mL anti-S <4 AU high: anti-RBD ≥250 U/mL anti-S ≥4 AU.
bTiters were collected at a median (IQR) 28.5 d (17.0–32.0 d) post-D4.
anti-RBD, anti-receptor binding domain; anti-S, anti-spike; D4, dose 4; IQR, interquartile range; MMF, mycophenolate mofetil; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
In this cohort of SOTRs receiving a D4 of SARS-CoV-2 vaccine, 89% of participants had positive anti-spike antibody post-D4 with a high rate of seroconversion among prior nonresponders. Additionally, titers were boosted in 75% to levels consistent with live virus neutralization. This is the largest study of SOTRs receiving 4 doses of SARS-CoV-2 vaccine, encompassing a breadth of organ recipients, and demonstrates the immunogenic potential of booster vaccination.3-5 Limitations include the observational nature of the cohort, lack of formal neutralization against variants of concern including omicron, and the lack of cellular analyses.
These findings support recommendations for booster vaccination in SOTRs, with post-booster antibody testing to identify individuals who remain seronegative and may be targeted for additional vaccination or passive immunoprophylactic interventions.
ACKNOWLEDGMENTS
The authors thank the participants of the Johns Hopkins COVID-19 Transplant Vaccine Study, without whom this research could not be possible. The authors also thank the members of the study team, including Brian J. Boyarsky, MD, PhD; Alexa Jefferis, BS; Nicole Fortune Hernandez, BS; Letitia Thomas; Rivka Abedon; Chunyi Xia; Kim Hall; Mary Sears, BA; and Alex Alex; Jonathan Susilo. The authors also thank Andrew H. Karaba, MD, PhD and Ms. Yolanda Eby for project support and guidance.
Footnotes
All authors were involved in substantial contributions to the conception or design of the work or the acquisition, analysis, or interpretation of data for the work; drafting the work and revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
This research was made possible with the generous support of the Ben-Dov family. This work was supported by The ASTS Fryer Resident Scientist Award (J.M.), grants T32DK007713 (J.L.A.), T32DK007732 (A.C.), K01DK101677 (A.B.M.), and K23DK115908 (J.M.G.-W.) from the National Institute of Diabetes and Digestive and Kidney Diseases; grant K24AI144954 (D.L.S.) from the National Institute of Allergy and Infectious Disease; and grants K23AI157893 and U01AI138897 from the National Institute of Allergy and Infectious Disease (W.A.W.).
D.L.S. has the following financial disclosures: consulting and speaking honoraria from Sanofi, Novartis, CLS Behring, Jazz Pharmaceuticals, Veloxis, Mallinckrodt, Thermo Fisher Scientific, Regeneron, and AstraZeneca. R.K.A. has study/grant support from Aicuris, Astellas, Chimerix, Merck, Oxford Immunotec, Qiagen, Regeneron, Takeda/Shire, and Vir/GSK and is an Associate Reviewer for Transplantation. M.L.L. is the Social Media Editor for Transplantation. The other authors declare no conflicts of interest.
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