First-in-human immunoPET imaging of COVID-19 convalescent patients using dynamic total-body PET and a CD8-targeted minibody

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Abstract

With most of the T cells residing in the tissue, not the blood, developing noninvasive methods for in vivo quantification of their biodistribution and kinetics is important for studying their role in immune response and memory. This study presents the first use of dynamic positron emission tomography (PET) and kinetic modeling for in vivo measurement of CD8 ⁺ T cell biodistribution in humans. A ⁸⁹Zr-labeled CD8-targeted minibody ( ⁸⁹Zr-Df-Crefmirlimab) was used with total-body PET in healthy individuals ( N = 3) and coronavirus disease 2019 (COVID-19) convalescent patients ( N = 5). Kinetic modeling results aligned with T cell–trafficking effects expected in lymphoid organs. Tissue-to-blood ratios from the first 7 hours of imaging were higher in bone marrow of COVID-19 convalescent patients compared to controls, with an increasing trend between 2 and 6 months after infection, consistent with modeled net influx rates and peripheral blood flow cytometry analysis. These results provide a promising platform for using dynamic PET to study the total-body immune response and memory.

Abstract

Total-body dynamic imaging of a radiolabeled minibody enables measurements of distribution and kinetics of targeted immune cells.

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Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections

Quan-Xin Long, Xiao-Jun Tang, Qiu-Lin Shi … (2020)

The clinical features and immune responses of asymptomatic individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have not been well described. We studied 37 asymptomatic individuals in the Wanzhou District who were diagnosed with RT-PCR-confirmed SARS-CoV-2 infections but without any relevant clinical symptoms in the preceding 14 d and during hospitalization. Asymptomatic individuals were admitted to the government-designated Wanzhou People's Hospital for centralized isolation in accordance with policy1. The median duration of viral shedding in the asymptomatic group was 19 d (interquartile range (IQR), 15-26 d). The asymptomatic group had a significantly longer duration of viral shedding than the symptomatic group (log-rank P = 0.028). The virus-specific IgG levels in the asymptomatic group (median S/CO, 3.4; IQR, 1.6-10.7) were significantly lower (P = 0.005) relative to the symptomatic group (median S/CO, 20.5; IQR, 5.8-38.2) in the acute phase. Of asymptomatic individuals, 93.3% (28/30) and 81.1% (30/37) had reduction in IgG and neutralizing antibody levels, respectively, during the early convalescent phase, as compared to 96.8% (30/31) and 62.2% (23/37) of symptomatic patients. Forty percent of asymptomatic individuals became seronegative and 12.9% of the symptomatic group became negative for IgG in the early convalescent phase. In addition, asymptomatic individuals exhibited lower levels of 18 pro- and anti-inflammatory cytokines. These data suggest that asymptomatic individuals had a weaker immune response to SARS-CoV-2 infection. The reduction in IgG and neutralizing antibody levels in the early convalescent phase might have implications for immunity strategy and serological surveys.

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Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection

Jennifer M. Dan, Jose Mateus, Yu Kato … (2021)

Understanding immune memory to SARS-CoV-2 is critical for improving diagnostics and vaccines, and for assessing the likely future course of the COVID-19 pandemic. We analyzed multiple compartments of circulating immune memory to SARS-CoV-2 in 254 samples from 188 COVID-19 cases, including 43 samples at ≥ 6 months post-infection. IgG to the Spike protein was relatively stable over 6+ months. Spike-specific memory B cells were more abundant at 6 months than at 1 month post symptom onset. SARS-CoV-2-specific CD4+ T cells and CD8+ T cells declined with a half-life of 3-5 months. By studying antibody, memory B cell, CD4+ T cell, and CD8+ T cell memory to SARS-CoV-2 in an integrated manner, we observed that each component of SARS-CoV-2 immune memory exhibited distinct kinetics.

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Multiorgan and Renal Tropism of SARS-CoV-2

Victor G. Puelles, Marc Lütgehetmann, Maja T Lindenmeyer … (2020)

To the Editor: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) preferentially infects cells in the respiratory tract, 1,2 but its direct affinity for organs other than the lungs remains poorly defined. Here, we present data from an autopsy series of 27 patients (see the clinical data in Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org) that show that SARS-CoV-2 can be detected in multiple organs, including the lungs, pharynx, heart, liver, brain, and kidneys. We first quantified the SARS-CoV-2 viral load in autopsy tissue samples obtained from 22 patients who had died from Covid-19. Seventeen patients (77%) had more than two coexisting conditions (Figure 1A), and a greater number of coexisting conditions was associated with SARS-CoV-2 tropism for the kidneys (Table S2), even in patients without a history of chronic kidney disease (Table S3). The highest levels of SARS-CoV-2 copies per cell were detected in the respiratory tract, and lower levels were detected the kidneys, liver, heart, brain, and blood (Figure 1B). These findings indicate a broad organotropism of SARS-CoV-2. Since the kidneys are among the most common targets of SARS-CoV-2, we performed in silico analysis of publicly available data sets of single-cell RNA sequencing. This analysis revealed that RNA for angiotensin-converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2), and cathepsin L (CTSL) — RNA of genes that are considered to facilitate SARS-CoV-2 infection 3 — is enriched in multiple kidney-cell types from fetal development through adulthood (Fig. S1). This enrichment may facilitate SARS-CoV-2–associated kidney injury, as previously suggested. 4 We also quantified the SARS-CoV-2 viral load in precisely defined kidney compartments obtained with the use of tissue microdissection from 6 patients who underwent autopsy (1 patient who was included in the previously mentioned 22 patients as an internal negative control, plus 5 additional patients). Three of these 6 patients had a detectable SARS-CoV-2 viral load in all kidney compartments examined, with preferential targeting of glomerular cells (Fig. S2). We also detected viral RNA and protein with high spatial resolution using in situ hybridization and indirect immunofluorescence with confocal microscopy (Figure 1C). Data on additional controls are provided in Figures S3 and S4. On the basis of these findings, renal tropism is a potential explanation of commonly reported new clinical signs of kidney injury in patients with Covid-19, 5 even in patients with SARS-CoV-2 infection who are not critically ill. Our results indicate that SARS-CoV-2 has an organotropism beyond the respiratory tract, including the kidneys, liver, heart, and brain, and we speculate that organotropism influences the course of Covid-19 disease and, possibly, aggravates preexisting conditions.

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Author and article information

Contributors

Negar Omidvari:

ORCID: https://orcid.org/0000-0002-7589-4745

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Terry Jones:

ORCID: https://orcid.org/0000-0002-8852-6837

Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Pat M. Price:

ORCID: https://orcid.org/0000-0003-4709-3323

Role: ConceptualizationRole: MethodologyRole: SupervisionRole: ValidationRole: Writing - review & editing

April L. Ferre:

ORCID: https://orcid.org/0009-0003-5963-1309

Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Jacqueline Lu: Role: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing - review & editing

Yasser G. Abdelhafez:

ORCID: https://orcid.org/0000-0002-1989-3094

Role: Data curationRole: Formal analysisRole: MethodologyRole: Writing - review & editing

Fatma Sen: Role: ConceptualizationRole: MethodologyRole: Project administrationRole: Resources

Stuart H. Cohen: Role: ResourcesRole: Validation

Kristin Schmiedehausen: Role: VisualizationRole: Writing - review & editing

Ramsey D. Badawi:

ORCID: https://orcid.org/0000-0002-9769-0292

Role: ConceptualizationRole: Funding acquisitionRole: ResourcesRole: Writing - review & editing

Barbara L. Shacklett:

ORCID: https://orcid.org/0000-0002-7067-732X

Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Validation

Ian Wilson: Role: ConceptualizationRole: MethodologyRole: ResourcesRole: Writing - review & editing

Simon R. Cherry:

ORCID: https://orcid.org/0000-0002-0155-5644

Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing - review & editing

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): sciadv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: 13 October 2023

Publication date (Electronic, pub): 12 October 2023

Volume: 9

Issue: 41

Electronic Location Identifier: eadh7968

Affiliations

[ ¹ ]Department of Biomedical Engineering, University of California Davis, Davis, CA, USA.

[ ² ]Department of Radiology, University of California Davis Medical Center, Sacramento, CA, USA.

[ ³ ]Department of Surgery and Cancer, Imperial College London, London, UK.

[ ⁴ ]Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, CA, USA.

[ ⁵ ]Radiotherapy and Nuclear Medicine Department, South Egypt Cancer Institute, Assiut University, Assiut, Egypt.

[ ⁶ ]Division of Infectious Diseases, Department of Internal Medicine, University of California Davis Medical Center, Sacramento, CA, USA.

[ ⁷ ]ImaginAb Inc., Inglewood, CA, USA.

Author notes

[* ]Corresponding author. Email: nomidvari@ 123456ucdavis.edu

Author information

Negar Omidvari https://orcid.org/0000-0002-7589-4745

Terry Jones https://orcid.org/0000-0002-8852-6837

Pat M. Price https://orcid.org/0000-0003-4709-3323

April L. Ferre https://orcid.org/0009-0003-5963-1309

Yasser G. Abdelhafez https://orcid.org/0000-0002-1989-3094

Ramsey D. Badawi https://orcid.org/0000-0002-9769-0292

Barbara L. Shacklett https://orcid.org/0000-0002-7067-732X

Simon R. Cherry https://orcid.org/0000-0002-0155-5644

Article

Publisher ID: adh7968

DOI: 10.1126/sciadv.adh7968

PMC ID: 10569706

PubMed ID: 37824612

SO-VID: e3aeccf4-1e4e-484a-8a4d-462af7682f15

Copyright © Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.