EVC RESONDS TO COVID-19

EVC COVID-19 RESEARCH UPDATE

The EVC is focusing its considerable expertise to conquer COVID-19 from all angles. Our mission is to discover how to treat, cure and prevent COVID-19.Here is a brief overview of ongoing and proposed projects to combat COVID-19:

Immunology

  • Innate Immune Biomarkers Research. To identify innate immune biomarkers of SARS-CoV-2 infection in the human lung. Dr. Suthar’s research team is infecting primary and cultured human lung cells as well as human tissues with SARS-CoV-2 to understand the host response to the virus. (Suthar, Bosinger, Lowen, Anderson)

  • Antibody Response and Reagent Development Research. To understand the humoral response in humans to SARS-CoV-2. (Suthar, Ahmed, Roupael)

  • Proposing to study the immune response/pathology of COVID-19 in pregnant women. (Vijayakumar, Amara, Smith 

  • Antibody Response and Reagent Development Research. To characterize the antibody response to SARS-CoV-2 in humans and nonhuman primates (NHPs) and discover antibodies capable of viral neutralization. Dr. Bosinger and his research team have established high-throughput 10X Genomics technology in Biosafety Level 3 (BSL3) biocontainment laboratories to facilitate high-throughput characterization of antibody producing cells and accelerate discovery of human monoclonals for potential therapeutics and testing. (Bosinger, Wrammert, Suthar, Kasturi, Ahmed, Amara, Rouphael, Johnson, Rengarajan)

  • Exploring the idea of using long-read Pac-Bio sequencing to examine the variability across the genome of SARS-CoV-2 isolates in the Atlanta area. If the preliminary experiments are successful, we will look to move the technology to our research sites in Zambia and Rwanda for comparative sequencing studies. (Dilernia, Hunter)

  • Monoclonal antibodies have been used successfully by Emory experts in patients with H1N1 and Ebola. Emory Vaccine Center has begun identifying useful antibodies in patients infected with coronavirus with the goal to produce clones that can be used to help extremely ill patients and would then be licensed to a manufacturer/pharma company that produces the antibodies for trials in infected humans. Optimistically, trials could begin by the end of the summer. (Ahmed, Suthar, Johnson)

  • Production of recombinant SARS-CoV-2 proteins for serological assays. (Altman)

  • SARS-CoV-2 viral genomics, metagenomics, and transcriptomics from human clinical samples. (Piantadosi)

  • Novel Immune Diagnostics of COVID-19 for Acute Infection, Prognosis of Severe Disease, and Immune Protection.

    • Aim 1. Development of a novel MicroB-plex COVID-19 MENSA (and serum) diagnostic tests. In comparison to SARS and previously circulating strains of the coronavirus, we will select antigens that are unique to the novel COVID-19 virus

    • Aim 2. Validation of the MicroB-plex COVID-19 MENSA test in symptomatic patients under investigation (PUI). The gold standard of PCR testing is only 28-79% sensitive 4-6. As the necessary samples become available, we will develop pre-made diagnostic COVID-19 MENSA test as LDT. At the time of nasal swab, we will obtain a blood sample for the COVID-19 MENSA test.

    • Aim 3. Development of COVID-19 MENSA test for early prognosis for severe COVID-19 infections. Using the 5-color MENSA multiplex assays, we will predict patients with poor upper respiratory viral clearance who may be at risk of developing severe lower respiratory complications.

    • Aim 4. Using a combined COVID-19 MENSA and serum test to identify protection and resolution of an ongoing immune response. We propose to test healthcare workers during the widespread pandemic for history of infection and no further COVID-19 ongoing immune response. This subject would demonstrate protection with COVID-19 immunity with a positive serum and illustrate that he/she is no longer infectious with a negative MENSA, and thus is safe to be a part of our workforce. (Eun-Hyung Lee, Daiss, Sanz)

    • Effector and Memory B cell Responses to COVID19. Implications for Natural Herd Immunity and Vaccination

      • Aim 1. Characterization of SARS-CoV-2-specific B cell responses.  We will use multidimensional B cell flow cytometry with up to 25 simultaneous markers to provide a high-resolution characterization of B cell response to the SARS-CoV-2 infection.  This analysis will help identify the precise origin of viral-specific B cell responses at different time points including: acute infection at the time of known exposure and clinical and/or laboratory diagnosis of COVID-19 disease and subsequent timepoints over 12 months chosen to track different phases of memory generation, maturation and persistence. 

      • Aim 2. Measurement of SARS-CoV-2-specific B cell memory and herd immunity Phenotypic features and antigen-specific flow cytometry assays established in aim 1, will be applied to intermediate and late post-infection time points in order to understand:  a) the cellular compartments in which SARS-CoV-2-specific B cell memory resides; b) its quality, magnitude and distribution within the population; c) its provenance (whether from early of late cellular precursors); and d) its concordance or conversely, uncoupling from serological responses and the generation of long-lived plasma cells (LLPC). (Sanz, Boss, Scharer, Eun-Hyung Lee, Tipton, Gibson)

  • Memory B cell identification from recovered patients to generate panels of human monoclonal antibodies. This work, if successful, is expected to offer novel avenues towards prophylaxis and therapy for Covid-19.

    • The ICGEB-Emory Vaccine Center lab are working in collaboration with a large consortium in India that includes Translational health science and technology institute (THSTI), National Institute of Immunology (NII), Delhi University South Campus (DUSC) and Clinical Development Services Agency (CDSA) to understand quality, quantity and longevity of the human B and T cell response in Covid-19 recovered individuals. This knowledge will help provide baseline information for future vaccine design, testing and evaluation.  (Kaja, Ahmed, Chandele, Wrammert, Suthar, Davis)

  • Propose to produce and characterize monoclonal lamprey VLRB antibodies against the SARS-Cov-2 S protein.

    • Specific Aim 1. Generation of SARS-Cov-2 S-specific VLRB antibodies

    • Specific Aim 2. Assessment of their domain/epitope specificities and functionality (Hirano, Cooper)

 Virology & Pathogenesis

  • Studies of biomarkers of pathogenesis and immuno-pathogenesis in autopsy samples from deceased COVID-19 patients. (Silvestri, Mosunjac) 

  • Pathogenesis and Virology Research. To characterize viral pathogenesis, the early antiviral responses of the immune system and viral evolution. (Paiardini, Piantadosi, Bosinger)

  • In Vivo Dr. Bosinger’s genomics laboratory is supporting studies of pathogenesis in human samples and NHPs conducted by collaborators. (Bosinger, Paiardini, Kasturi, Barouch, Pulendran).

  • The Genomics Core, led by Dr. Boginger, is planning to run genomics to discover biomarkers that predict COVID severe disease vs. convalescence (mild). This is part of the IMPACC consortium, which will analyze markers of 1,000 COVID patients from acute infection through convalescence. (Bosinger)

  • Pathogenesis and Virology Research: To characterize viral pathogenesis, the early antiviral responses of the immune system and viral evolution. (Paiardini, Piantadosi, Bosinger)

  • Proposed study of prevalence of secondary bacterial infections in COVID patients and determine if this leads to worse outcomes. We will be studying the isolates to determine how antibiotic resistant they are and how virulent they are. (Weiss) 

Animal Models

  • Effects of ACE inhibitors on SARS-CoV-2 infection in nonhuman primates. Individuals with hypertension and cardiovascular disease are at a higher risk for severe COVID-19 clinical manifestations. Treatment of hypertension and cardiovascular disease typically involves the use of ACE inhibitors, which has been linked with increased expression of ACE2, the receptor used for cell entry by SARS-CoV-2, in the lung and heart. We are proposing nonhuman primate experiments to investigate if treatment with ACE inhibitors results in increased COVID-19 related morbidity and mortality. (Paiardini, Levit) 

  • Safety and Efficacy Research: To test, in the relevant nonhuman primate (NHP) model, the safety and efficacy of novel compounds that may directly block the replication of the "new" coronavirus SARS-CoV-2 or reduce the disease burden of the new disease COVID-19. This work is an essential first step to rapidly move these candidate drugs to clinical studies in humans. (Silvestri, Schinazi)

  • Non-human primate model development. We have the infrastructure and scientific and technical expertise to develop a validated non-human primate model to study the virology, immunology, and immuno-pathogenesis of COVID-19 and to test specific antibodies, vaccines, and antiviral compounds. We also have the scientific track record to conduct detailed, cutting-edge studies, in both humans and animal models, of the specific features of the immune response to coronavirus disease. This research will require sophisticated equipment to be available in our biosafety facility. (Paiardini, Vanderford, Piantadosi, Bosinger, Schinazi, Silvestri)

Diagnostics

  • Serological Testing Development. Emory Vaccine Center faculty collaborated in the development of a serological test that is highly specific, sensitive and continuously improving. It separately detects both immunoglobulin G (IgG) and immunoglobulin M (IgM) to accurately categorize the status of immunity. In development are various forms of commercialization to better protect against supply chain risk and with the hope of scaling up to testing 5,000 specimens per say, as an initial goal. (Wrammert, Ahmed, Roback and others)

  • Nucleic Acid Diagnostic Research. To develop new diagnostics for SARS-CoV2. (Suthar, Ahmed, Kraft, Waggoner)

Anti-Virals and Immune Therapies

  • Antiviral-Related Research: To screen a few antivirals against SARS-CoV-2 by using in vitro human cell model systems. (Suthar, Serafianos, Mainou)

  • Therapeutics Research: To test therapeutics, including some already clinically approved for other conditions, for their safety and efficacy in blocking SARS-CoV-2 replication and disease progression to inform the care of infected patients. (Paiardini, Schinazi, Silvestri)

  • Identified anti-viral peptides derived from amphibians that are viricidal for Influenza, Zika and Dengue viruses. Currently screening their peptide library to identify peptides that can neutralize the SARS CoV-2 virus. (Jacobs)

  • Immunomodulator agents prevent the pulmonary immunopathology of this infection. We are working with Eli Lilly to study baracitinib, which is already approved for rheumatoid arthritis, and other immunotherapy approaches that have generated positive reports from Italy for seriously ill patients. These agents may be studied separately or in combination with antiviral drugs. (Schinazi, Marconi, Rouphael)

  • Drug repurposing. A handful of marketed drugs show antiviral activity in cell culture for COVID-19 and antiviral activity in animals infected with MERS and SARS, which are coronaviruses similar to COVID-19. Since the drugs work at different points in the viral life cycle, it is reasonable to test these drugs in combinations to see which combinations might be particularly effective. Data on effective combinations could be immediately translated to treating humans infected with COVID-19 because the drugs are already on the market, widely available, and inexpensive. (Jacobs, Sukhatme)

  • Other drug discovery. Emory is developing a test to screen millions of compounds (including FDA approved drugs) and identify those that could block viral entry. We have a high-throughput facility for such screens already in place and can test candidates in a functional, cell-based antiviral assay. (Fu, Jacobs)

Prevention & Vaccines

  • Vaccine-Related Research: To evaluate MVA-based vaccines against SARS-CoV to prevent infection. (Suthar, Amara, Kasturi)

  • Developing MVA-based vaccines that are designed to induce homologous and heterologous neutralizing antibodies against SARS-CoV2. The researchers are making different versions of MVA vaccines and will test the immunogenicity and efficacy in mice and monkeys. A single MVA vaccination has been shown to provide protection against SARS-CoV1, Ebola and Zika. (Amara)

  • Developing the probiotic Lactococcus lactis-based vaccine for oral delivery. The researchers will use their patented technology. The vaccine will be very easy to produce and can be administered in the form of yogurt. (Amara)

  • Vaccine-Related Research: To comprehensively characterize and rapidly test vaccines against the SARS-COV-2 mediated COVID-19 to identify a suitable vaccine for human use; this research will include rhesus macaques (RMs) as a relevant nonhuman primate (NHP) model. (Kasturi, Suthar, Fox, Hotez, Bottazi) 

Clinical Trials

  • Convalescent Plasma Clinical Trial. Serology assays to detect antibodies against COVID-19 was developed in the Vaccine Center and transitioned to Emory Medical Laboratories. By identifying people who have mounted an immune response to COVID-19, we may not only determine who is immune to COVID-19, but also who could donate plasma ("convalescent plasma") which can be transfused to patients to prevent COVID-19 infections, or to treat ongoing infections.  (Ahmed, Wrammert, Neish, Roback, Edupuganti)

  • Clinical Trials on Remdesivir and mRNA. Remdesivir (Gilead) is the most promising of the currently available experimental drugs. Emory started our first COVID-19 patient on a clinical trial evaluating this drug. While the costs of the study are covered through the NIH, there are a number of research questions, both virologic and immunologic, that are not covered. (Mehta, Roupael and others)

  • mRNA vaccine (Moderna) is part of a vaccine trial sponsored by the National Institute for Allergy and Infectious Diseases scheduled to begin in Seattle. Emory will be the second site, enrolling patients later this month. Again, while the costs of the study are covered through the NIH, there are a number of research questions that are not covered. (Anderson, Roupael and others)

  • Use of lung cancer database to record clinical outcomes for COVID patients (Ramalingam, Ahmed)

  • Collecting blood samples on cancer patients with COVID (Ramalingam, Ahmed)

  • The Emory Vaccine Center Hope Clinic is working to collect blood and saliva samples from people who have recovered from COVID-19 through an existing investigator-initiated study called, Phlebotomy for Emerging Infectious Diseases. (Edupuganti)

  • Existing clinical trial sites in Rwanda and Zambia are readying themselves for COVID-19 vaccine clinical trials. Sites in Zambia (now participating in HVTN-705 HIV vaccine trials with Janssen products) and Rwanda (implementing Ebola vaccinations and preparing for a safety trial in pregnant women with Janssen products) are actively thinking and preparing to be ready for COVID-19 vaccine trials as they become available. (Allen, Hunter) 

Epidemiology

  • Preparing for a Rollins School of Public Health pilot grant to conduct population-level surveys using online panels, regarding social distancing, vaccine readiness, etc. Along with working with graduate students to develop summer practicum opportunities related to COVID research, specifically in the areas of health communication and vaccine planning. (Bednarczyk)