The antibody response after 2 doses of an mRNA SARS-CoV-2 vaccine is excellent in the general population but less robust in transplant patients.1 Severe breakthrough infections in SOTRs have prompted debate on how to protect these individuals.2,3 We previously reported improved antibody responses in ~50% of SOTRs after a third vaccine.4 In this series we studied antibody responses to a 4th dose of SARS-CoV-2 vaccine in 18 SOTRs from April 24, 2021, through June 16, 2021.
Participants were enrolled in an observational study of SARS-CoV-2 vaccination outcomes in SOTRs.1 18 received a 4th dose (D4) of a COVID-19 vaccine and had no known history of COVID-19 infection. Semiquantitative anti-spike antibody testing was performed using the Roche Elecsys® anti–ARS-CoV-2 S or the EUROIMMUN® IgG enzyme immunoassays 2–6 weeks after D4. We categorized titers as negative, low-positive, and high-positive: low-positive titers were >0.8 U/mL but <50 U/mL (Roche), or >1.1 but <4 arbitrary units (AU) (EUROIMMUN). High-positive titers were ≥50 U/mL (Roche), or ≥4 AU (EUROIMMUN). This study was approved by the Johns Hopkins Institutional Review Board and participants provided informed consent electronically.
The median age was 58 years (interquartile range [IQR]) 50 to 65 years). Median time from transplant was 7.1 years (IQR 2.3 to 16.2 years). Median time from D3 to D4 was 28 (IQR 21 to 30) days. Eleven (61.1%) participants received kidney transplants. Sixteen (88.9%) were on mycophenolate mofetil at the time of vaccination. Pre-D4, there were 6 participants with negative titers, 2 low-positive, and 10 high-positive. Post-D4, 5/8 (63%) participants with negative or low-positive titers showed boosting to high-positive titers (Table 1). Additionally, among 11 SOTRs serially tested on similar assays, post-D4 titers rose in 7 (63%). Most participants with high-positive pre-D4 titers showed further boosting. The 3 participants with persistently negative titers after D4 were kidney transplant recipients less than 5 years posttransplant taking tacrolimus and mycophenolate mofetil, and 2/3 were additionally taking corticosteroids. Eleven of 16 participants (69%) receiving antiproliferative agents showed antibody boosting.
Table 1.
Antibody titers after each vaccine.
| Age, y | Sex | Organ(s) | Time since transplant, y | Anti-metabolite | Initial vaccine series | Post D2 titer | D3 | Post D3 titer | Post D3 titer | D4 | Post D4 titer | Post D4 titer |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 44 | F | Kidney | 4 | Yes | Moderna | Negative | Pfizer | Negative | 0.22 E | Pfizer | Negative | 0.92 E |
| 65 | F | Kidney | 0.5 | Yes | Moderna | Negative | Moderna | Negative | 0.06 E | Moderna | Negative | 0.06 E |
| 44 | M | Kidney | 3 | Yes | Pfizer | Negative | Pfizer | Negative | 0.09 E | J&J | Negative | 0.4 R |
| 63 | M | Liver | 11 | Yes | Pfizer | Negative | J&J | Negative | 0.46 R | Pfizer | High | 54.9 R |
| 57 | M | Kidney | 15 | Yes | J&J | Negative | Moderna | Negative | 0.97 E | Moderna | High | 286.9 R |
| 53 | M | Kidney | 21 | Yes | Pfizer | Negative | Pfizer | Negative | (self-report) | J&J | High | 343 R |
| 61 | F | Kidney | 8 | Yes | Pfizer | Negative | Moderna | Low | 2.75 R | Moderna | High | >2500 R |
| 49 | F | Kidney | 1 | Yes | Moderna | Negative | Pfizer | Low | 7.3 R | Pfizer | High | 82.9 R |
| 52 | F | Kidney-Pancreas | 20 | Yes | Moderna | Negative | Pfizer | High | 504.4 R | Pfizer | High | 845 R |
| 54 | M | Liver | 1 | Yes | Pfizer | Low | Moderna | High | 125.7 R | Moderna | High | >2500 R |
| 69 | M | Heart | 16 | Yes | Pfizer | Negative | Moderna | High | 8.37 E | Moderna | High | >2500 R |
| 68 | M | Heart | 2 | Yes | Pfizer | Negative | Moderna | High | >250 R | Moderna | High | 402.9 R |
| 43 | F | Pancreas | 1 | Yes | Pfizer | Negative | Moderna | High | 4.72 E | Moderna | High | 5.27 E |
| 58 | M | Kidney | 3 | Yes | Moderna | Low | Moderna | High | 6.93 E | Moderna | High | 4.16 E |
| 42 | F | Liver | 5 | No | Moderna | Negative | Pfizer | High | 11.39 E | Pfizer | High | 8.75 E |
| 73 | F | Kidney-Liver | 18 | Yes | Pfizer | Low | Moderna | High | 4.45 E | Moderna | High | 1691 R |
| 67 | F | Kidney | 11 | Yes | Moderna | Low | Pfizer | High | 9.19 E | Pfizer | High | >2500 R |
| 64 | M | Liver | 21 | No | Moderna | Low | Pfizer | High | 7.21 E | Pfizer | High | >2500 R |
D, dose; E, EUROIMMUN assay (parameters: low-positive, ≥1.1 and <4; high-positive, ≥4 AU); F, female; J&J, Johnson & Johnson; M, male; R, Roche assay (parameters: low-positive, ≥0.8 and <50; high-positive, ≥50 U/mL).
To our knowledge this is the first series describing the antibody response among SOTRs after 4 doses of vaccine against COVID-19. Given neutralizing antibody level may be the best correlate of vaccine-associated immunoprotection to date, it is encouraging that 50% of participants with negative and all with low-positive titers pre-D4 showed boosting to high-positivity post-D4.5 This echoes previous findings that one-third of negative and all low-positive patients after 2 doses were boosted to high-positive after receiving a third vaccine dose.4 These findings suggest immunogenic potential exists for these poor responders.
Limitations include small sample size, lack of formal neutralizing antibody, B-cell, or T-cell assays, durability of antibody levels, or safety information regarding the 4th dose given limited time to follow-up. We also lacked CD4 counts or hypogammaglobulinemia information in persistent suboptimal responders.
Though some patients may require additional measures such as immunosuppression modulation to achieve immunity, these data support continued exploration of subsequent vaccine doses in SOTRs.
ACKNOWLEDGEMENTS
The authors thank the participants of the study, without whom this work would be impossible, as well as the Johns Hopkins Transplant Vaccine study team, including Michael T. Ou, BS; Ross S. Greenberg, BA; Jake A. Ruddy, BS; Muhammad Asad Munir, MBBS; Michelle R. Krach, MS; Iulia Barbur, BSE. They also thank Andrew H. Karaba, MD, PhD; and Ms. Yolanda Eby for project support and guidance.
FUNDING/GRANT/AWARD INFORMATION
This research was made possible with the generous support of the Ben-Dov family. This work was supported by grants 5T32DK007713 (J.L.A.), The ASTS Fryer Resident Scientist Award (J.M.), F32DK124941 (B.J.B.), K01DK114388-03 (M.L.L.), 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.
ABBREVIATIONS
- D4
Dose 4
- mRNA
messenger RNA
- SOTRs
Solid Organ Transplant Recipients
Footnotes
DISCLOSURES
D.L.S. has the following financial disclosures: consulting and speaking honoraria from Sanofi, Novartis, CLS Behring, Jazz Pharmaceuticals, Veloxis, Mallinckrodt, Thermo Fisher Scientific. M.L.L. is the Social Media Editor for Transplantation. The remaining authors of this manuscript have no financial disclosures or conflicts of interest to disclose as described by Transplantation.
References:
- 1.Boyarsky BJ, Werbel WA, Avery RK, et al. Antibody response to 2-dose SARS-CoV-2 mRNA vaccine series in solid organ transplant recipients. JAMA. 2021;325(21):2204–2206. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Tau N, Yahav D, Schneider S, et al. Severe consequences of COVID-19 infection among vaccinated kidney transplant recipients. Am J Transplant. 2021;21:2910–2912. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Qin CX, Moore LW, Anjan S, et al. Risk of breakthrough SARS-CoV-2 infections in adult transplant recipients. Transplantation. 2021. IN PRESS. doi: 10.1097/TP.0000000000003907 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Werbel WA, Boyarsky BJ, Ou MT, et al. Safety and immunogenicity of a third dose of SARS-CoV-2 vaccine in solid organ transplant recipients: a case series. Ann Intern Med. 2021. IN PRESS. doi: 10.7326/L21-0282 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Khoury DS, Cromer D, Reynaldi A, et al. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat Med. 2021;27(7):1205–1211. [DOI] [PubMed] [Google Scholar]