Climate change and infectious disease: A prologue on multidisciplinary cooperation and predictive analytics.

Climate change impacts global ecosystems at the interface of infectious disease agents and hosts and vectors for animals, humans, and plants. The climate is changing, and the impacts are complex, with multifaceted effects. In addition to connecting climate change and infectious diseases, we aim to draw attention to the challenges of working across multiple disciplines. Doing this requires concentrated efforts in a variety of areas to advance the technological state of the art and at the same time implement ideas and explain to the everyday citizen what is happening. The world's experience with COVID-19 has revealed many gaps in our past approaches to anticipating emerging infectious diseases. Most approaches to predicting outbreaks and identifying emerging microbes of major consequence have been with those causing high morbidity and mortality in humans and animals. These lagging indicators offer limited ability to prevent disease spillover and amplifications in new hosts. Leading indicators and novel approaches are more valuable and now feasible, with multidisciplinary approaches also within our grasp to provide links to disease predictions through holistic monitoring of micro and macro ecological changes. In this commentary, we describe niches for climate change and infectious diseases as well as overarching themes for the important role of collaborative team science, predictive analytics, and biosecurity. With a multidisciplinary cooperative "all call," we can enhance our ability to engage and resolve current and emerging problems.

Climate change and infectious disease: A prologue on multidisciplinary cooperation and predictive analytics

Climate change impacts global ecosystems at the interface of infectious disease agents and hosts and vectors for animals, humans, and plants. The climate is changing, and the impacts are complex, with multifaceted effects. In addition to connecting climate change and infectious diseases, we aim to draw attention to the challenges of working across multiple disciplines. Doing this requires concentrated efforts in a variety of areas to advance the technological state of the art and at the same time implement ideas and explain to the everyday citizen what is happening. The world's experience with COVID-19 has revealed many gaps in our past approaches to anticipating emerging infectious diseases. Most approaches to predicting outbreaks and identifying emerging microbes of major consequence have been with those causing high morbidity and mortality in humans and animals. These lagging indicators offer limited ability to prevent disease spillover and amplifications in new hosts. Leading indicators and novel approaches are more valuable and now feasible, with multidisciplinary approaches also within our grasp to provide links to disease predictions through holistic monitoring of micro and macro ecological changes. In this commentary, we describe niches for climate change and infectious diseases as well as overarching themes for the important role of collaborative team science, predictive analytics, and biosecurity. With a multidisciplinary cooperative "all call,” we can enhance our ability to engage and resolve current and emerging problems.

Drug Combinations as a First Line of Defense against Coronaviruses and Other Emerging Viruses.

The world was unprepared for coronavirus disease 2019 (COVID-19) and remains ill-equipped for future pandemics. While unprecedented strides have been made developing vaccines and treatments for COVID-19, there remains a need for highly effective and widely available regimens for ambulatory use for novel coronaviruses and other viral pathogens. We posit that a priority is to develop pan-family drug cocktails to enhance potency, limit toxicity, and avoid drug resistance. We urge cocktail development for all viruses with pandemic potential both in the short term (<1 to 2 years) and longer term with pairs of drugs in advanced clinical testing or repurposed agents approved for other indications. While significant efforts were launched against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in vitro and in the clinic, many studies employed solo drugs and had disappointing results. Here, we review drug combination studies against SARS-CoV-2 and other viruses and introduce a model-driven approach to assess drug pairs with the highest likelihood of clinical efficacy. Where component agents lack sufficient potency, we advocate for synergistic combinations to achieve therapeutic levels. We also discuss issues that stymied therapeutic progress against COVID-19, including testing of agents with low likelihood of efficacy late in clinical disease and lack of focus on developing virologic surrogate endpoints. There is a need to expedite efficient clinical trials testing drug combinations that could be taken at home by recently infected individuals and exposed contacts as early as possible during the next pandemic, whether caused by a coronavirus or another viral pathogen. The approach herein represents a proactive plan for global viral pandemic preparedness.

Global health security threats and related risks in Latin America

The costs of responding and mitigating the COVID-19 pandemic is a critical example of the need for continual investment for global health security (GHS) preparedness in today’s inter-connected world as exemplified earlier with Ebola, Zika, and H1N1. Microbial diversity including endemic and emerging infectious diseases unique to Latin America are well known. When combined with geopolitical, socioeconomic, and environmental factors, especially climate change and human migration, which are expanding the range of disease vectors and pathogens, the risk for infectious disease outbreaks greatly increases. Enhancing GHS requires a greater awareness and cooperation within the region as well as more effective infectious disease surveillance systems. Frameworks such as the International Health Regulations and Global Health Security Agenda underpin policies to strengthen health systems. Greater international cooperation aimed to effectively enhance infectious disease surveillance are pivotal to increasing trust among partner countries and strengthen health security systems and best practices to respond and mitigate infectious disease outbreaks. Here we discuss infectious disease threats and risks associated with the current socioeconomic and political climate that influence GHS in order to demonstrate the need for further investment.

SARS-CoV-2 Supply Shortages and Tuberculosis Diagnostics: Current Issues Requiring Immediate Solutions.

The SARS-CoV-2 pandemic has strained manufacturing capacity worldwide, resulting in significant shortages of laboratory supplies both directly and indirectly. Such shortages include probe-based kits for detection of the Mycobacterium tuberculosis complex from positive liquid broth cultures. These shortages and possible loss of this particular assay have consequences for laboratory testing algorithms and public health in the United States. As there are no FDA-approved, commercially available options that currently exist which could immediately fill this gap, laboratories must identify alternatives and plan for modifying current testing algorithms to accommodate this change.

Significance of High-Containment Biological Laboratories Performing Work During the COVID-19 Pandemic: Biosafety Level-3 and -4 Labs.

High containment biological laboratories (HCBL) are required for work on Risk Group 3 and 4 agents across the spectrum of basic, applied, and translational research. These laboratories include biosafety level (BSL)-3, BSL-4, animal BSL (ABSL)-3, BSL-3-Ag (agriculture livestock), and ABSL-4 laboratories. While SARS-CoV-2 is classified as a Risk Group 3 biological agent, routine diagnostic can be handled at BSL-2. Scenarios involving virus culture, potential exposure to aerosols, divergent high transmissible variants, and zoonosis from laboratory animals require higher BSL-3 measures. Establishing HCBLs especially those at BSL-4 is costly and needs continual investments of resources and funding to sustain labor, equipment, infrastructure, certifications, and operational needs. There are now over 50 BSL-4 laboratories and numerous BSL-3 laboratories worldwide. Besides technical and funding challenges, there are biosecurity and dual-use risks, and local community issues to contend with in order to sustain operations. Here, we describe case histories for distinct HCBLs: representative national centers for diagnostic and reference, nonprofit organizations. Case histories describe capabilities and assess activities during COVID-19 and include capacities, gaps, successes, and summary of lessons learned for future practice.

First Movers in Molecular Detection: Case Comparison on Harnessing Research and Development, Industry, and Entrepreneurship.

The current unprecedented COVID-19 pandemic underscores the importance of diagnostic assays in health security preparedness and readiness. Advancing new technologies for rapid molecular detection of high consequence infectious pathogens is an ongoing challenge that requires ingenuity and vision. Sustainment of a robust supply chain for materials and the logistics of timely product delivery further challenge diagnostic kit and device manufacturers. Business economists often characterize technology companies that discover unique breakthroughs in their field and are first to bring related products to market as first movers. From a market perspective, three first mover characteristics include: having the knowledge and capability to address a unique breakthrough, excellent technological leadership, and the ability to capitalize on the opportunity. Current mainstays for molecular detection include using Taq DNA Polymerase enzyme and fluorescent chemistry for quantitative PCR (qPCR). A newer and promising technology uses CRISPR-Cas proteins for nucleic acid detection. Our panel discussion from the 2020 ASM Biothreats conference, which included members from two prototypical first mover companies, explored their respective corporate experiences. Both companies were selected for the discussion based on their revolutionary innovations and similarities in their research and development, corporate culture and trajectory. One company, established over 20 years ago, became a market leader in the biothreat detection market by advancing air thermocycling qPCR across multiple product families. The second company is a rapidly growing start-up and a scientific pioneer in establishing next generation CRISPR technologies. Here we discuss their technology development, product deployment, and customer markets to draw lessons learned for researchers, end users, and funders.

COVID-19 vaccines: Global challenges and prospects forum recommendations.

The 11th KAIMRC Annual Research Forum Themed "COVID-19 Vaccine: Global Challenges and Prospects Forum" discussed COVID19 Vaccines. The Forum was a vital event as it provided a hub for leading COVID-19 vaccine scientists, regulators, developers, and distributors to learn about COVID-19 vaccines in development, make decisions about the best vaccines to use, and develop appropriate plans for global distribution and pricing. The COVID-19: Global Efforts for Development, Clinical Trials and Distribution Symposium brought together leading scientists, clinicians, pharma, decision makers, academic institutions and businesses to present and discuss the vaccines that are being currently developed for the COVID19. This event was held to shed light on these vaccines as many are at the late stage of Phase III clinical trials and ready to be marketed. This follows the confusion that few vaccines were produced and pushed into phase III without sharing all the necessary data preventing the scientific and clinical community to judge its efficacy and safety. This event allowed a discussion into the challenges in the distribution, pricing and accessibility of the vaccines. Moreover, the symposium discussed the importance to invest in Biotech-Pharma to combat and overcome any future health crisis. The discussion focused on Saudi Arabia leading initiatives as front runner in the field among G20 members.

MHC class II transactivator CIITA induces cell resistance to Ebola virus and SARS-like coronaviruses.

Recent outbreaks of Ebola virus (EBOV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have exposed our limited therapeutic options for such diseases and our poor understanding of the cellular mechanisms that block viral infections. Using a transposon-mediated gene-activation screen in human cells, we identify that the major histocompatibility complex (MHC) class II transactivator (CIITA) has antiviral activity against EBOV. CIITA induces resistance by activating expression of the p41 isoform of invariant chain CD74, which inhibits viral entry by blocking cathepsin-mediated processing of the Ebola glycoprotein. We further show that CD74 p41 can block the endosomal entry pathway of coronaviruses, including SARS-CoV-2. These data therefore implicate CIITA and CD74 in host defense against a range of viruses, and they identify an additional function of these proteins beyond their canonical roles in antigen presentation.

Project IDentif.AI: Harnessing Artificial Intelligence to Rapidly Optimize Combination Therapy Development for Infectious Disease Intervention.

In 2019/2020, the emergence of coronavirus disease 2019 (COVID-19) resulted in rapid increases in infection rates as well as patient mortality. Treatment options addressing COVID-19 included drug repurposing, investigational therapies such as remdesivir, and vaccine development. Combination therapy based on drug repurposing is among the most widely pursued of these efforts. Multi-drug regimens are traditionally designed by selecting drugs based on their mechanism of action. This is followed by dose-finding to achieve drug synergy. This approach is widely-used for drug development and repurposing. Realizing synergistic combinations, however, is a substantially different outcome compared to globally optimizing combination therapy, which realizes the best possible treatment outcome by a set of candidate therapies and doses toward a disease indication. To address this challenge, the results of Project IDentif.AI (Identifying Infectious Disease Combination Therapy with Artificial Intelligence) are reported. An AI-based platform is used to interrogate a massive 12 drug/dose parameter space, rapidly identifying actionable combination therapies that optimally inhibit A549 lung cell infection by vesicular stomatitis virus within three days of project start. Importantly, a sevenfold difference in efficacy is observed between the top-ranked combination being optimally and sub-optimally dosed, demonstrating the critical importance of ideal drug and dose identification. This platform is disease indication and disease mechanism-agnostic, and potentially applicable to the systematic N-of-1 and population-wide design of highly efficacious and tolerable clinical regimens. This work also discusses key factors ranging from healthcare economics to global health policy that may serve to drive the broader deployment of this platform to address COVID-19 and future pandemics.