Human Leukocyte Antigen Susceptibility Map for Severe Acute Respiratory Syndrome Coronavirus 2

Nguyen, Austin; David, Julianne K.; Maden, Sean K.; Wood, M. C.; Weeder, Benjamin R.; Nellore, Abhinav; Thompson, Reid F.

doi:10.1128/jvi.00510-20

Cited by 468 publications

(505 citation statements)

References 78 publications

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“…Human leukocyte antigen (HLA) is a critical component of the viral antigen presentation pathway and plays essential roles in conferring differential viral susceptibility and severity of diseases 6‐9 6,7 . Importantly, polymorphisms in the HLA have been shown to impact susceptibility to SARS‐CoV introduced to humans earlier in the 21st century 6,7 .…”

Section: Introductionmentioning

confidence: 99%

Association between HLA gene polymorphisms and mortality of COVID‐19: An in silico analysis

Tomita

Ikeda

Sato

et al. 2020

Immunity Inflam & Disease

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Introduction The emergence of SARS‐CoV‐2 has caused global public health and economic crisis. Human leukocyte antigen (HLA) is a critical component of the viral antigen presentation pathway and plays essential roles in conferring differential viral susceptibility and severity of diseases. However, the association between HLA gene polymorphisms and risk for COVID‐19 has not been fully elucidated. We hypothesized that HLA genotypes might impact on the differences in morbidity and mortality of COVID‐19 across countries. Methods We conducted in silico analyses and examined an association of HLA gene polymorphisms with prevalence and mortality of COVID‐19 by using publicly available databases. Results We found that a possible association between HLA‐A*02:01 and an increased risk for COVID‐19. HLA‐A*02:01 had a relatively lower capacity to present SARS‐CoV‐2 antigens compared with other frequent HLA class I molecules, HLA‐A*11:01 or HLA‐A*24:02. Conclusion This study suggests that individuals with HLA‐A*11:01 or HLA‐A*24:02 genotypes may generate efficiently T‐cell‐mediated antiviral responses to SARS‐CoV‐2 compared with HLA‐A*02:01. The differences in HLA genotypes may potentially alter the course of the disease and its transmission.

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Section: Introductionmentioning

confidence: 99%

Association between HLA gene polymorphisms and mortality of COVID‐19: An in silico analysis

Tomita

Ikeda

Sato

et al. 2020

Immunity Inflam & Disease

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“…36,37 Furthermore, patients with various HLA genotypes form MHC-I mediated responses to varying SARS-CoV-2 epitopes, and this can be predicted with bioinformatics approaches. 38 While bioinformatic predictions of MHC loading corresponding to various HLA genotypes do not predictively reveal which peptide sequences will or will not be loaded, they do create a comprehensive overview of the possible state-spaces for empirical validation. SARS-BLOCK™ peptides are designed to display modular motifs for priming clonal expansion of selective TCR repertoires, which can be facilitated by sequencing of recovered patient TCR repertoires, insertion into these scaffolds, and finally assessing HLA genotypes of target populations, which we aim to assess in future studies.…”

Section: Discussionmentioning

confidence: 99%

Peptide Antidotes to SARS-CoV-2 (COVID-19)

Watson

Ferreira

Hwang

et al. 2020

Preprint

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The design of an immunogenic scaffold that serves a role in treating a pathogen, and can be rapidly and predictively modeled, has remained an elusive feat. Here, we demonstrate that SARS-BLOCK™ synthetic peptide scaffolds act as antidotes to SARS-CoV-2 spike protein-mediated infection of human ACE2-expressing cells. Critically, SARS-BLOCK™ peptides are able to potently and competitively inhibit SARS-CoV-2 S1 spike protein receptor binding domain (RBD) binding to ACE2, the main cellular entry pathway for SARS-CoV-2, while also binding to neutralizing antibodies against SARS-CoV-2. In order to create this potential therapeutic antidote-vaccine, we designed, simulated, synthesized, modeled epitopes, predicted peptide folding, and characterized behavior of a novel set of synthetic peptides. The biomimetic technology is modeled off the receptor binding motif of the SARS-CoV-2 coronavirus, and modified to provide enhanced stability and folding versus the truncated wildtype sequence. These novel peptides attain single-micromolar binding affinities for ACE2 and a neutralizing antibody against the SARS-CoV-2 receptor binding domain (RBD), and demonstrate significant reduction of infection in nanomolar doses. We also demonstrate that soluble ACE2 abrogates binding of RBD to neutralizing antibodies, which we posit is an essential immune-evasive mechanism of the virus. SARS-BLOCK™ is designed to “uncloak” the viral ACE2 coating mechanism, while also binding to neutralizing antibodies with the intention of stimulating a specific neutralizing antibody response. Our peptide scaffolds demonstrate promise for future studies evaluating specificity and sensitivity of immune responses to our antidote-vaccine. In summary, SARS-BLOCK™ peptides are a promising COVID-19 antidote designed to combine the benefits of a therapeutic and vaccine, effectively creating a new generation of prophylactic and reactive antiviral therapeutics whereby immune responses can be enhanced rather than blunted.

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“…Thus, with the use of leukapheresis instead of buffy coats, fully-closed isolation and expansion using CliniMACS Prodigy cell processing and G-Rex culture flasks we could generate sufficient material to treat multiple patients from a single suitably HLA-matched donor, with or without a second expansion phase. HLA matching is important for effective function of adoptive T cell therapies, and it is clear that some HLA types have increased susceptibility to COVID-19 (37), so supplementation of immune response with donor T cells from a matched donor could be a therapeutic option where few others exist.…”

Section: Discussionmentioning

confidence: 99%

Rapid GMP-compliant expansion of SARS-CoV-2-specific T cells from convalescent donors for use as an allogeneic cell therapy for COVID-19

Cooper

Fraser

Smith

et al. 2020

Preprint

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COVID-19 disease caused by the SARS-CoV-2 virus is characterized by dysregulation of effector T cells and accumulation of exhausted T cells. T cell responses to viruses can be corrected by adoptive cellular therapy using donor-derived virus-specific T cells. Here we show that SARS-CoV-2-exposed blood donations contain CD4 and CD8 memory T cells specific for SARS-CoV-2 spike, nucleocapsid and membrane antigens. These peptides can be used to isolate virus-specific T cells in a GMP-compliant process. These T cells can be rapidly expanded using GMP-compliant reagents for use as a therapeutic product. Memory and effector phenotypes are present in the selected virus-specific T cells, but our method rapidly expands the desirable central memory phenotype. A manufacturing yield ranging from 1010 to 1011 T cells can be obtained within 21 days culture. Thus, multiple therapeutic doses of virus-specific T cells can be rapidly generated from convalescent donors for treatment of COVID-19 patientsOne Sentence SummaryCD4+ and CD8+ T cells specific for SARS-CoV-2 can be isolated from convalescent donors and rapidly expanded to therapeutic doses at GMP standard, maintaining the desired central memory phenotype required for protective immune responses against severe COVID-19 infections.

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Human Leukocyte Antigen Susceptibility Map for Severe Acute Respiratory Syndrome Coronavirus 2

Abstract: 22

Cited by 468 publications

References 78 publications

Association between HLA gene polymorphisms and mortality of COVID‐19: An in silico analysis

Association between HLA gene polymorphisms and mortality of COVID‐19: An in silico analysis

Peptide Antidotes to SARS-CoV-2 (COVID-19)

Rapid GMP-compliant expansion of SARS-CoV-2-specific T cells from convalescent donors for use as an allogeneic cell therapy for COVID-19

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