2021-11-17

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Centergrid.239395.7, Harvard Medical School, Boston, Massachusetts, USA.; Department of Epidemiology, University of North Carolina at Chapel Hillgrid.10698.36, Chapel Hill, North Carolina, USA.; Department of Epidemiology, University of North Carolina at Chapel Hillgrid.10698.36, Chapel Hill, North Carolina, USA.; Department of Epidemiology, University of North Carolina at Chapel Hillgrid.10698.36, Chapel Hill, North Carolina, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Centergrid.239395.7, Harvard Medical School, Boston, Massachusetts, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Centergrid.239395.7, Harvard Medical School, Boston, Massachusetts, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Centergrid.239395.7, Harvard Medical School, Boston, Massachusetts, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Centergrid.239395.7, Harvard Medical School, Boston, Massachusetts, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Centergrid.239395.7, Harvard Medical School, Boston, Massachusetts, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Centergrid.239395.7, Harvard Medical School, Boston, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Centergrid.239395.7, Harvard Medical School, Boston, Massachusetts, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Centergrid.239395.7, Harvard Medical School, Boston, Massachusetts, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Centergrid.239395.7, Harvard Medical School, Boston, Massachusetts, USA.; Department of Epidemiology, University of North Carolina at Chapel Hillgrid.10698.36, Chapel Hill, North Carolina, USA.; Department of Epidemiology, University of North Carolina at Chapel Hillgrid.10698.36, Chapel Hill, North Carolina, USA.; Department of Epidemiology, University of North Carolina at Chapel Hillgrid.10698.36, Chapel Hill, North Carolina, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Centergrid.239395.7, Harvard Medical School, Boston, Massachusetts, USA.; Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA.; Massachusetts Consortium on Pathogen Readiness, Boston, Massachusetts, USA.

The global COVID-19 pandemic has sparked intense interest in the rapid development of vaccines as well as animal models to evaluate vaccine candidates and to define immune correlates of protection. We recently reported a mouse-adapted SARS-CoV-2 virus strain (MA10) with the potential to infect wild-type laboratory mice, driving high levels of viral replication in respiratory tract tissues as well as severe clinical and respiratory symptoms, aspects of COVID-19 disease in humans that are important to capture in model systems. We evaluated the immunogenicity and protective efficacy of novel rhesus adenovirus serotype 52 (RhAd52) vaccines against MA10 challenge in mice. Baseline seroprevalence is lower for rhesus adenovirus vectors than for human or chimpanzee adenovirus vectors, making these vectors attractive candidates for vaccine development. We observed that RhAd52 vaccines elicited robust binding and neutralizing antibody titers, which inversely correlated with viral replication

2021-11-01

Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.; Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.; Division of Pulmonary, Critical Care and Sleep Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.; Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.; Cardiovascular Research Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.; Cardiovascular Research Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.; Cardiovascular Research Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.; Cardiovascular Research Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.; Department of Obstetrics and Gynecology.; Division of Pulmonary, Critical Care and Sleep Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.; Center for Virology and Vaccine Research, and.; Department of Emergency Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.; Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.; Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.; Infectious Diseases Division, Brigham and Women's Hospital and Harvard Medical School, Massachusetts, Boston USA.CN - MGH COVID-19 Collection and Processing Team; Aerpio Pharmaceuticals, Inc., Cincinnati, Ohio, USA.; Division of Hemostasis and Thrombosis and.; Division of Nephrology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.; Division of Nephrology, University of Texas Southwestern, Dallas, Texas, USA.

Endothelial dysfunction accompanies the microvascular thrombosis commonly observed in severe COVID-19. Constitutively, the endothelial surface is anticoagulant, a property maintained at least in part via signaling through the Tie2 receptor. During inflammation, the Tie2 antagonist angiopoietin-2 (Angpt-2) is released from endothelial cells and inhibits Tie2, promoting a prothrombotic phenotypic shift. We sought to assess whether severe COVID-19 is associated with procoagulant endothelial dysfunction and alterations in the Tie2/angiopoietin axis. Primary HUVECs treated with plasma from patients with severe COVID-19 upregulated the expression of thromboinflammatory genes, inhibited the expression of antithrombotic genes, and promoted coagulation on the endothelial surface. Pharmacologic activation of Tie2 with the small molecule AKB-9778 reversed the prothrombotic state induced by COVID-19 plasma in primary endothelial cells. Lung autopsies from patients with COVID-19 demonstrated a

2021-07-04

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.; Division of Infectious Diseases, Massachusetts General Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.; Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.; Harvard Medical School, Boston, Massachusetts, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.; Program in Immunology, Harvard Medical School, Boston, Massachusetts, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.; Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.; Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.; Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.; Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.; Massachusetts Consortium on Pathogen Readiness, Boston, Massachusetts, USA.

Emerging SARS-CoV-2 variants of concern that overcome natural and vaccine-induced immunity threaten to exacerbate the COVID-19 pandemic. Increasing evidence suggests that neutralizing antibody (NAb) responses are a primary mechanism of protection against infection. However, little is known about the extent and mechanisms by which natural immunity acquired during the early COVID-19 pandemic confers cross-neutralization of emerging variants. In this study, we investigated cross-neutralization of the B.1.1.7 and B.1.351 SARS-CoV-2 variants in a well-characterized cohort of early pandemic convalescent subjects. We observed modestly decreased cross-neutralization of B.1.1.7 but a substantial 4.8-fold reduction in cross-neutralization of B.1.351. Correlates of cross-neutralization included receptor binding domain (RBD) and N-terminal domain (NTD) binding antibodies, homologous NAb titers, and membrane-directed T cell responses. These data shed light on the cross-neutralization of emerging

2021-11-18

Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.; Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, 02138, USA.; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02115, USA.; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.; Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02115, USA.; Harvard Medical School, Boston, MA, 02115, USA.; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02115, USA.; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.; Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02115, USA.; Harvard Medical School, Boston, MA, 02115, USA.; Department of Microbiology, Boston University School of Medicine and National Emerging Infectious Diseases Laboratories, Boston, MA, 02118, USA.; Department of Microbiology, Boston University School of Medicine and National Emerging Infectious Diseases Laboratories, Boston, MA, 02118, USA.; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.; Harvard Program in Biophysics, Harvard University, Cambridge, MA, 02138, USA.; Harvard-MIT Division in Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.; Department of Microbiology, Boston University School of Medicine and National Emerging Infectious Diseases Laboratories, Boston, MA, 02118, USA.; Department of Microbiology, Boston University School of Medicine and National Emerging Infectious Diseases Laboratories, Boston, MA, 02118, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02115, USA.; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, 02139, USA.; Massachusetts Consortium on Pathogen Readiness, Boston, MA, 02215, USA.; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.; Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02115, USA.; Harvard Medical School, Boston, MA, 02115, USA.; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.; Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, 02138, USA.

The coronavirus disease 2019 (COVID-19) pandemic demonstrates the importance of generating safe and efficacious vaccines that can be rapidly deployed against emerging pathogens. Subunit vaccines are considered among the safest, but proteins used in these typically lack strong immunogenicity, leading to poor immune responses. Here, a biomaterial COVID-19 vaccine based on a mesoporous silica rods (MSRs) platform is described. MSRs loaded with granulocyte-macrophage colony-stimulating factor (GM-CSF), the toll-like receptor 4 (TLR-4) agonist monophosphoryl lipid A (MPLA), and SARS-CoV-2 viral protein antigens slowly release their cargo and form subcutaneous scaffolds that locally recruit and activate antigen-presenting cells (APCs) for the generation of adaptive immunity. MSR-based vaccines generate robust and durable cellular and humoral responses against SARS-CoV-2 antigens, including the poorly immunogenic receptor binding domain (RBD) of the spike (S) protein. Persistent antibodies

2021-04-04

Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.; Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.; PhD program in Immunology and Virology, University of Duisburg-Essen, Essen, Germany.; Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.; Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.; PhD program in Virology, Division of Medical Sciences, Harvard University, Boston, Massachusetts, USA.; Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.; Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.; Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.; Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.; Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.; Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.; Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.; Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.; Providence Medical Group, Everett, Washington, USA.; Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.; Department of Epidemiology and.; Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, Washington, USA.; Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.; Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.; Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.; Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, Washington, USA.; Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.; Department of Global Health, University of Washington, Seattle, Washington, USA.; Benaroya Research Institute, Seattle, Washington, USA.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.; Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.; Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA.; Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.

Comorbid medical illnesses, such as obesity and diabetes, are associated with more severe COVID-19, hospitalization, and death. However, the role of the immune system in mediating these clinical outcomes has not been determined. We used multiparameter flow cytometry and systems serology to comprehensively profile the functions of T cells and antibodies targeting spike, nucleocapsid, and envelope proteins in a convalescent cohort of COVID-19 subjects who were either hospitalized (n = 20) or not hospitalized (n = 40). To avoid confounding, subjects were matched by age, sex, ethnicity, and date of symptom onset. Surprisingly, we found that the magnitude and functional breadth of virus-specific CD4+ T cell and antibody responses were consistently higher among hospitalized subjects, particularly those with medical comorbidities. However, an integrated analysis identified more coordination between polyfunctional CD4+ T cells and antibodies targeting the S1 domain of spike among subjects who

2021-06-30

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.; Janssen Vaccines & Prevention BV, Leiden, the Netherlands.; Janssen Vaccines & Prevention BV, Leiden, the Netherlands.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.; Tufts University Cummings School of Veterinary Medicine, North Grafton, MA 01536, USA.; Tufts University Cummings School of Veterinary Medicine, North Grafton, MA 01536, USA.; Tufts University Cummings School of Veterinary Medicine, North Grafton, MA 01536, USA.; Tufts University Cummings School of Veterinary Medicine, North Grafton, MA 01536, USA.; Janssen Vaccines & Prevention BV, Leiden, the Netherlands.; Janssen Vaccines & Prevention BV, Leiden, the Netherlands.; Janssen Vaccines & Prevention BV, Leiden, the Netherlands.; Janssen Vaccines & Prevention BV, Leiden, the Netherlands.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.; Bioqual, Rockville, MD 20852, USA.; Bioqual, Rockville, MD 20852, USA.; Bioqual, Rockville, MD 20852, USA.; Bioqual, Rockville, MD 20852, USA.; Bioqual, Rockville, MD 20852, USA.; Bioqual, Rockville, MD 20852, USA.; Bioqual, Rockville, MD 20852, USA.; Bioqual, Rockville, MD 20852, USA.; Bioqual, Rockville, MD 20852, USA.; Janssen Vaccines & Prevention BV, Leiden, the Netherlands.; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA; Massachusetts Consortium on Pathogen Readiness, Boston, MA 02215, USA. Electronic address: dbarouch@bidmc.harvard.edu.

We previously reported that a single immunization with an adenovirus serotype 26 (Ad26)-vector-based vaccine expressing an optimized SARS-CoV-2 spike (Ad26.COV2.S) protected rhesus macaques against SARS-CoV-2 challenge. To evaluate reduced doses of Ad26.COV2.S, 30 rhesus macaques were immunized once with 1 × 10(11), 5 × 10(10), 1.125 × 10(10), or 2 × 10(9) viral particles (vp) Ad26.COV2.S or sham and were challenged with SARS-CoV-2. Vaccine doses as low as 2 × 10(9) vp provided robust protection in bronchoalveolar lavage, whereas doses of 1.125 × 10(10) vp were required for protection in nasal swabs. Activated memory B cells and binding or neutralizing antibody titers following vaccination correlated with protective efficacy. At suboptimal vaccine doses, viral breakthrough was observed but did not show enhancement of disease. These data demonstrate that a single immunization with relatively low dose of Ad26.COV2.S effectively protected against SARS-CoV-2 challenge in rhesus macaques