Abstract
SARS-CoV-2 infection during the Omicron period was frequent amongst a cohort of vaccinated pediatric solid organ transplant recipients (pSOTRs) despite robust anti-receptor-binding domain (anti-RBD) antibody response, suggesting poor neutralizing capacity against Omicron subvariants. Breakthrough infections among pSOTRs were overall limited in severity.
Keywords: breakthrough, COVID-19, mRNA vaccination, Omicron variant, pediatrics, solid organ transplant
During severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariant waves, breakthrough pediatric infections following vaccination occurred in part to viral antibody escape [1, 2]. Immunosuppressed persons such as solid organ transplant recipients (SOTRs) are at higher risk for suboptimal vaccine response and consequent breakthrough yet data are not available for pediatric SOTRs (pSOTRs) [3]. We therefore investigated the prevalence and severity of SARS-CoV-2 infections amongst vaccinated pSOTRs during the US Omicron wave (BA.1 through BA.4/5). We additionally assessed the impact of preceding antibody levels on risk of breakthrough infection.
METHODS
After approval by the Johns Hopkins Institutional Review Board, pSOTRs (5–18 years of age) were recruited at 7 sites across the United States between April and August 2021 to study antibody responses to the mRNA COVID-19 vaccine. pSOTRs who received one or more solid organs (liver, kidney, heart, small intestine, and lung) were eligible. Samples were drawn 1, 3, 6, and 12 months after each dose and were processed through different US LabCorp laboratories. The Roche Elecsys anti-SARS-CoV-2 S enzyme immunoassay was used to measure antibodies against the spike protein receptor-binding domain (anti-RBD; positive: ≥0.8, maximum: >2500 U/mL) [4].
pSOTRs between the ages 5 and 18 years reporting ≥1 mRNA vaccination were surveyed every 2 weeks to identify breakthrough infection during a period of Omicron variant circulation. Participants were surveyed regarding COVID-19 diagnoses and related symptoms/treatment, transplant complications, and hospitalizations. A participant with breakthrough COVID-19 infection reported type/duration of symptoms, diagnostic test used, associated rejection, and treatment obtained. Breakthrough infection was defined as a positive COVID-19 test between December 1, 2021 and February 9, 2022. Predefined indications for testing included exposure to a positive case, recent travel, or COVID-19 symptoms. Testing was otherwise at the primary transplant team’s discretion. Survey results were not corroborated with their transplant centers. Negative testing was not captured and infection prior to the defined study period was identified through self-report. At-home COVID-19 antigen tests were accepted. Demographic and transplant factors for those with and without breakthrough were recorded, as was preceding anti-RBD level. For participants with breakthrough, the most recent available anti-RBD level preinfection was used; for those without, the first recorded anti-RBD level on or after December 1, 2021 was used. Participants who received a vaccine between the most recent antibody level and infection were excluded from antibody analysis (n = 8). A date of December 1, 2021 was chosen to standardize comparisons when analyzing time since the latest vaccination. Fisher’s exact test was used to compare demographics, transplant characteristics, antibody levels, and immunosuppressive regimens between patients who developed breakthrough infection and those who did not. All analyses used Stata 15.1 (StataCorp).
RESULTS
A total of 32/54 (59%) respondents had completed the primary series for immunocompromised children (defined as a minimum of 3 vaccine doses). Of these, 18/32 (56%) reported breakthrough infection during the study period. Median anti-RBD were similar between those with and without breakthrough (>2500 U/mL [IQR: 853,>2500] vs >2500 U/ml [IQR: 72,>2500]), P = .82; negative preceding anti-RBD was recorded for 2/19 (10.5%) pSOTRs with breakthrough vs 3/27 (11%) without (P = .28). Demographic and transplant factors did not differ by breakthrough status (Table 1).
Table 1.
Demographic and Transplant Characteristics of Pediatric SOT Recipients, by Breakthrough Infection Status
| n (%) | Breakthrough 27 (50%) |
No breakthrough 27 (50%) |
P Valuea |
|---|---|---|---|
| Demographics | |||
| Age group, years | 0.84 | ||
| 5–11 | 10 (37.0) | 10 (37.0) | |
| 12–15 | 10 (37.0) | 13 (48.1) | |
| 16+ | 7 (25.9) | 4 (14.9) | |
| Sex, male | 14 (48.1) | 12 (42.9) | 0.79 |
| Race, White | 25 (92.6) | 19 (67.8) | 0.08 |
| Hispanic or Latino | 0 (0.0) | 2 (7.1) | 0.49 |
| Transplant characteristics | |||
| Organ | 0.77 | ||
| Liver | 13 (48.1) | 15 (53.5) | |
| Kidney | 5 (18.5) | 7 (25.0) | |
| Heart | 8 (29.6) | 6 (21.4) | |
| Liver–Kidney | 1 (3.7) | 0 (0) | |
| Time since transplant, years | 0.79 | ||
| <3 | 4 (14.8) | 2 (7.1) | |
| 3–11 | 15 (55.5) | 17 (60.7) | |
| ≥12 | 8 (29.6) | 9 (32.1) | |
| Immunosuppression regimenb | |||
| Number of agents | 0.81 | ||
| 1 | 13 (48.1) | 12 (42.9) | |
| 2 | 8 (29.6) | 12 (42.9) | |
| 3+ | 6 (22.2) | 4 (14.2) | |
| Agents used | |||
| Tacrolimus | 22 (81.5) | 24 (85.7) | >0.99 |
| Cyclosporine | 1 (3.7) | 1 (3.6) | >0.99 |
| Antimetabolite | 10 (37.0) | 11 (39.3) | >0.99 |
| Sirolimus | 7 (25.9) | 6 (21.4) | >0.99 |
| Corticosteroids | 6 (22.2) | 4 (14.3) | >0.99 |
| SARS-CoV-2 infection prior to defined period | 2 (7.4) | 0 (0.0) | >0.99 |
| Vaccine doses (at time of infection/antibody analysis) | 0.05 | ||
| 1 | 0 (0.0) | 5 (17.8) | |
| 2 | 9 (32.1) | 9 (32.1) | |
| 3 | 11 (40.7) | 12 (42.9) | |
| 4 | 7 (25.9) | 2 (7.1) | |
| Days since last vaccine at time of infection (stratified by number of doses at time of infection) Median IQR | |||
| 1 | |||
| 2 | 42 (33,115) | ||
| 3 | 121 (75,185) | ||
| 4 | 64 (22,124) | ||
| Most recent antibody titer median (IQR)c | >2500 (853,>2500) | >2500 (72,>2500) | 0.82 |
| Negative antibody titers Antibody titers > 2500 U/mL |
2 (7.4) 13 (48.1) |
3 (11.1) 14 (51.9) |
|
| Days between sampling for antibody titer and last vaccine (stratified by number of doses) Median (IQR) | 0.86 | ||
| 1 | 19 (16,27) | ||
| 2 | 97 (33,135) | 30 (27,31) | |
| 3 | 132 (93,190) | 141 (113,182) | |
| 4 | 62 (32,100) | 144 (114,174) | |
aAll univariable statistical comparisons performed using the Fisher’s exact test.
bImmunosuppressants reported at start of the study. Categories are not mutually exclusive. No participants were taking rituximab or lymphodepleting agents.
c8 Participants who had a vaccination between most recent titer and infection were excluded.
Symptomatic infection was reported by 89% (24/27) of the surveyed cohort, including those who did not complete the primary series. Of these, 12.5% (3/24) reported upper respiratory symptoms and 83% (20/24) had constitutional symptoms (fever, headache, fatigue, pharyngitis, and myalgias). One patient reported loss of taste and/or smell. The most common symptoms were cough (12/24, 50%), fever (11/24, 46%), myalgias (11/24, 46%), and pharyngitis (11/24, 46%). Monoclonal antibody was given to 21% (5/24) of symptomatic participants. No participants reported myocarditis, multisystem inflammatory syndrome in children (MIS-C), rejection, or hospitalization related to infection during the Omicron period.
DISCUSSION
Breakthrough infection among pSOTRs during the Omicron era was common despite robust anti-RBD response, suggesting that pSOTRs may not have developed sufficient neutralizing capacity against Omicron subvariants. These results align with studies in immunocompetent populations demonstrating that the presence of neutralizing antibodies against the SARS-CoV-2 Omicron variant cannot be reliably inferred from anti-RBD IgG levels [5, 6]. Reduced neutralizing antibody titers against the Omicron variant compared with both ancestral and Beta variants have been recognized in vaccinated immunocompetent pediatric patients, but not fully described in vaccinated pSOTRs [7]. While protection was suboptimal, breakthrough infections were limited in their severity and no participants experienced hospitalization, death, organ rejection, or severe complications such as MIS-C. Among this cohort, there was no clear association between immunosuppressive regimen and development of breakthrough infection. Limitations related to observational design include reliance on self-reported COVID-19 diagnoses, lower survey response rate, and variation in vaccines received and time since vaccination between groups which may confound comparisons.
ACKNOWLEDGMENTS
This research was made possible with the generous support of the Ben-Dov family. The authors would like to acknowledge database management and data acquisition support from Benjamin L Salazar (Johns Hopkins University). JM is funded by a National Institutes of Health grant (T32-AI052071).
Contributor Information
John McAteer, Division of Infectious Diseases, Department of Pediatrics, Johns Hopkins Children’s Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Division of Nephrology, Department of Pediatrics, Johns Hopkins Children’s Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Divya D Kalluri, Department of Surgery, The Johns Hopkins Hospital, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Rivka R Abedon, Department of Surgery, The Johns Hopkins Hospital, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Caroline X Qin, Division of Nephrology, Department of Pediatrics, Johns Hopkins Children’s Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Department of Surgery, The Johns Hopkins Hospital, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Scott R Auerbach, Division of Cardiology, Department of Pediatrics, Children’s Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
Olga Charnaya, Division of Nephrology, Department of Pediatrics, Johns Hopkins Children’s Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Lara A Danziger-Isakov, Division of Infectious Diseases, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
Noelle H Ebel, Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Lucile Packard Children’s Hospital Stanford, Stanford University School of Medicine, Palo Alto, California, USA.
Amy G Feldman, Section of Gastroenterology, Hepatology and Nutrition, Digestive Health Institute, Children’s Hospital Colorado, University of Colorado Denver School of Medicine, Aurora, Colorado, USA.
Evelyn K Hsu, Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Seattle Children’s Hospital, University of Washington School of Medicine, Seattle, Washington, USA.
Saeed Mohammad, Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee, USA.
Emily R Perito, Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of California San Francisco Benioff Children’s Hospital, University of California San Francisco, San Francisco, California, USA.
Ashley M Thomas, Section of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Johns Hopkins Children’s Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Teresa P Y Chiang, Department of Surgery, The Johns Hopkins Hospital, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Jacqueline M Garonzik-Wang, Department of Surgery, NYU Grossman School of Medicine, New York City, New York, USA.
Dorry L Segev, Division of Transplant Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Milwaukee, Wisconsin, USA.
William A Werbel, Department of Surgery, The Johns Hopkins Hospital, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Douglas B Mogul, Section of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Johns Hopkins Children’s Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Notes
Financial support . This work was supported by the National Institute of Allergy and Infectious Diseases (K24AI144954 to D. L. S.) and the Agency for Healthcare Research and Quality (K08 H2026510-01A1 to A. G. F.).
Potential conflicts of interest . L. A. D.-I. has the following financial disclosures: Consulting and/or DMSB member: Takeda, Merck, GSK, Roche. Contracted clinical research agreements paid to her institution: Ansun Bio-Pharma, Astellas, Merck, Pfizer, Takeda, Viracor. N. H. E. has the following financial disclosures: consulting for Mirum. E. K. H. has the following financial disclosures: contracted clinical research agreements paid to her institution: Gilead, Mirum, Albireo. E. R. P. has the following financial disclosures: contracted clinical research agreements paid to her institution: Gilead, Albireo. D. L. S. has the following financial disclosures: consulting and/or speaking honoraria from Sanofi, Novartis, CSL Behring, Jazz Pharmaceuticals, Veloxis, Mallinckrodt, Thermo Fisher Scientific. W. A. W. has the following financial disclosures: consulting and/or speaking honoraria from AstraZeneca, GlobalData, the CDC/IDSA COVID-19 Real Time Learning Network, and advisory board fees from Novavax. D. B. M. has the following financial disclosures: consulting for Mirum. All other authors report no potential conflicts.
Authors’ contributions
J. M., D. D. K., R. R. A., C. X. Q., S. R. A., O. C., L. A. D.-I., N. H. E., A. G. F., E. K. H., S. M., E. R. P., A. M. T., T. P. Y. C., J. M G.-W., D. L. S., W. A. W., and D. B. M.: Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work. Drafting the work or revising it critically for important intellectual content. Final approval of the version to be published. J. M., D. B. M., and W. A. W.: 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.
Data availability
Deidentified data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
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Data Availability Statement
Deidentified data that support the findings of this study are available from the corresponding author upon reasonable request.