College of Pharmacy COVID-19 Research Initiatives

Research Team:

• Neil MacKinnon, PhD, MSc (Pharm), Dean and Professor, College of Pharmacy
• Ana Hincapie, PhD, MS, Assistant Professor, College of Pharmacy
• Diego Cuadros, PhD, Assistant Professor, Department of Geography, College of Arts and Sciences
• Yanyu Xiao, PhD, Assistant Professor, Department of Mathematical Sciences, College of Arts and Sciences

Project Description
The identification of areas in Ohio that will be more impacted by the novel coronavirus SARS-CoV-2 regarding numbers of admissions to intensive care unit, invasive ventilation or death related to COVID-19 play a critical role for the effective allocation of resources to reduce the potential saturation and failure of the health care system. To accomplish this goal, this project aims to: 1) identify the current spatial distribution of the COVID-19 outbreak, and to predict the potential spatial dispersion of the infection in Ohio; and 2) identify the counties at high-risk of the COVID-19 outbreak, where vulnerable populations at high-risk of health complications due to COVID-19 infections are located. This project will use geo-spatial techniques and mathematical models with district-level data of comorbidities to identify the areas that would experience the highest burden of COVID-19 infection.

The primary and short-term outcome of our study will be the preparation of a policy-analytic report (policy brief) specifically developed for Dr. Amy Acton, Director of the Ohio Department of Health. Our analysis will provide valuable new information, unavailable elsewhere, about the spread of COVID-19 in Ohio and the relationship of this spread to the availability of scarce healthcare resources such as hospital beds, including ICU beds.

Research Team: Georg F. Weber, MD, PhD
Our mission is the boosting of a coronavirus vaccine by conjugating it to an adjuvant that will stimulate both arms of the immune response, comprising antibody-based as well as cellular immunity.

Background Vaccination is the most efficient public health measure to address viral threats, including coronavirus. Unfortunately, anti-viral vaccination efficiency is variable, depending on pathogen factors (such as the virus strain) and host factors (such as the potential for impaired immune responsiveness in the most susceptible populations of the elderly and those with preexisting conditions). In the host, the cytokine profile (the pattern of soluble mediators) accompanying an immunotherapeutic regimen is an important early determinant for outcome. While traditional vaccines aim at generating a high antibody titer, both arms of the immune system, Type I (cellular) and Type II (humoral, antibody-based) responses, can contribute to an efficient anti-viral reaction.

It has become increasingly clear that the outcome of vaccination in general is decisively determined by the type of immune response induced. Immunization with inactivated virus generates a type II response (antibody-driven) and does not lead to broad immunity against viral subtypes. This can be remedied by the generation of a type I priming environment (to also activate the cellular immunity). Yet, a cytokine-based modulation of existing vaccination strategies that efficiently directs the immune system to induce a combined cellular and humoral reaction is currently not at hand. The critical decision between the induction of type I and type II responses is made on the molecular level by one cytokine (OPN), which has been the research focus of the Weber laboratory for more than two decades. Dr. Weber has published several landmark observations on this molecule, including its role as an essential upstream determinant of the type I/type II decision [Ashkar/Weber et al. Science 2000, this paper has been cited ~1150 times].

Objective The cytokine OPN regulates type I and type II immunity at a more proximal level than most other cytokines. It may be utilized to direct the phenotype of an immune response. We hypothesize that its functional domains may serve as potent adjuvants for various vaccines, such as an inactivated coronavirus vaccine but potentially also for a vaccine based on a single coronavirus antigen. A unique opportunity is provided by the existence of distinct immunoregulatory domains of OPN (discovered by Dr. Weber and colleagues). We will engineer the important domains of OPN, so that they can be attached to a coronavirus vaccine. This conjugation will enhance the immune response by activating both arms, thus yielding a more potent resistance to infection than could be accomplished with either type I or type II alone.

Research team:

• Bingfang Yan, DVM, PhD, Professor
• Zhanquan Shi, DVM, PhD, Research Associate
• William Abplanalp, BS, Senior Research Assistant
• Yue Shen, BS, PhD, Graduate student

Project Description
Dr. Yan’s research laboratory is focused on therapy on COVID-19 related to drugs, genetic determination and delivery routes. The priority is placed on remdesivir, a promising medicine for COVID-19. SARS-CoV-2, the pathogen of COVID-19, shares with many viruses the replicative machinery and pathogenesis process. The rationale of our research is to verify and optimize existing antiviral agents for the potential against SARS-CoV-2.

The experimental approaches:

• To ascertain drug interactions
• To investigate genetic factors for the interactions
• To optimize delivery routes for maximum efficacy and minimum toxicity

The currently focused drugs and delivery:

• Lopinavir/ritonavir, designed to treat HIV infection
• Remdesivir (GS-5734), designed to treat Ebola infection
• Nasal and pulmonary delivery system formulated with nanotechnology

 Research Team:
Pankaj B. Desai, Ph.D (Professor of Pharmacokinetics)
Gary Gudelsky, PhD (Professor of Neuropharmacology)
Soma Sengupta, MD, PhD (Neurology/Oncology)

Project Description:

The novel coronavirus outbreak (Covid-19), the pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is among the worst worldwide crises with approximately 4,000,000 confirmed cases of infection and 275,00 fatalities as of May 8, 2020. Similar to other enveloped RNA coronaviruses such as SARS-CoV (discovered in 2002) and Middle East Respiratory Syndrome (MERS)-CoV (discovered in 2012), the SARS-CoV-2 primarily infects the pulmonary system and causes severe respiratory distress. However, there is growing evidence that this virus also gains access to the Central Nervous System (CNS) and causes serious neurological complications. Many patients complain of headache and anosmia (loss of smell and taste) as initial symptoms, and patients who go on to develop severe disease, exhibit serious neurologic sequelae including stroke, impaired consciousness and seizures. The entry of the virus into the CNS could be from the nasal route (olfactory mucosa) or may be from within the systemic circulation. The viral brain infection is particularly concerning given that most drugs have restricted passage across the blood-brain barrier (BBB), and CNS may serve as a potential “sanctuary” for SARS-CoV-2, similar to what is observed with other viral infection including that with the HIV.

Thus, for effective drug therapy for Covid-19, there is an urgent need to identify anti-viral agents that penetrate BBB and accumulate to provide brain-specific levels required for anti-viral efficacy. Accordingly, the primary goal of our research is to identify drugs and investigational agents that not only have the requisite efficacy to treat the pulmonary infection but have the ability to penetrate BBB and accumulate within CNS spaces to effectively treat the viral infection of the brain. Following careful analyses of ongoing clinical trials, we wish to include some of the most promising agents in our studies such as remdesivir (or GS5734; Gilead Sciences), faripiravir (Avigan, Fujifilm) and other small molecular weight drugs. We will employ several in vitro and in vivo (mice and rats) and advanced pharmacokinetic (PK) modeling to comprehensively evaluate the systemic (plasma) and brain PK of these compounds. Where possible, we will employ brain microdialysis that facilitates serial collection of both brain extracellular fluid (ECF) and blood samples and quantitative characterization of plasma to brain drug partitioning. Collectively, these studies will delineate effective drug combination and dosing strategy most likely to be clinically effective in treating not only pulmonary but also the brain infection of SARS-CoV-2. Therefore, our proposed approach will be effective in reducing morbidity and mortality associated with CNS complications of this dreadful viral infection.