Developing therapeutic approaches for twenty-first-century emerging infectious viral diseases

FOCUS | Review Article FOCUS | Review Article https://doi.org/10.1038/s41591-021-01282-0 Developing therapeutic approaches for twenty-first-century emerging infectious viral diseases Rita M. Meganck and Ralph S. Baric ✉ The twenty-first century has already recorded more than ten major epidemic or pandemic virus emergence events, including the ongoing and devastating coronavirus disease 2019 (COVID-19) pandemic. As viral disease emergence is expected to accelerate, these data dictate a need for proactive approaches to develop broadly active family-specific and cross-family therapeutics for use in future disease outbreaks. Emphasis should focus not only on the development of broad-spectrum small-molecule and antibody direct-acting antivirals, but also on host-factor therapeutics, including repurposing previously approved or in-pipeline drugs. Another new class of therapeutics with great antiviral therapeutic potential is RNA-based therapeutics. Rather than only focusing on known risks, dedicated efforts must be made toward pre-emptive research focused on outbreak-prone virus families, ultimately offering a strategy to shorten the gap between outbreak and response. Emphasis should also focus on orally available drugs for outpatient use, if possible, and on identifying combination therapies that combat viral and immune-mediated pathologies, extend the effectiveness of therapeutic windows and reduce drug resistance. While such an undertaking will require new vision, dedicated funding and private, federal and academic partnerships, this approach offers hope that global populations need never experience future pandemics such as COVID-19. I n December 2019, a novel virus was identified in a cluster of human cases in Wuhan, China. The virus, identified as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; a coronavirus related to the virus that caused the 2003 SARS epidemic), quickly spread throughout China and then globally1. COVID-19, the disease caused by SARS-CoV-2, has raged across the world, causing more than 100 million reported cases and greater than 2 million deaths. As of early 2021, the COVID-19 pandemic is still ongoing, causing enormous economic losses, closing of uncountable numbers of businesses and loss of employment for millions. As with the deadly 1918 influenza outbreak almost exactly 100 years prior, the world was unprepared for SARS-CoV-2—despite the 2003 SARS-CoV pandemic, an ongoing Middle East respiratory syndrome coronavirus (MERS-CoV) outbreak since 2012 and warnings of high-risk coronavirus strains circulating in bats2. In the first months of the COVID-19 pandemic, initial responses included public health measures such as business closings, stay-at-home orders, mask wearing and social distancing, which were effective against earlier outbreaks. However, SARS-CoV-2 was capable of community and asymptomatic spread, circumventing classic control strategies in most nations globally. Revolutionary advances in fundamental virology, immunology, biochemistry and cell biology research led to novel vaccines and antiviral products in record time, yet distribution of these products to 7 billion individuals across the globe remains a daunting challenge. In parallel, the rapid spread of misinformation on social media continues to sow confusion and erode public confidence in medical interventions and heighten anxiety and confusion. In the year since SARS-CoV-2 emerged, the scientific community has made incredible progress in developing therapeutic regimens. One of the most well-known SARS-CoV-2 antivirals is remdesivir, previously shown to be a potent inhibitor of a panel of contemporary epidemic and zoonotic coronaviruses both in vitro and in vivo3. It was quickly shown that remdesivir also possessed robust antiviral activity against SARS-CoV-2 (ref. 4), and successful clinical trials rapidly led to its approval for emergency use by the Food and Drug Administration (FDA) in May 2020 in the USA and elsewhere. In August, convalescent plasma from individuals who have recovered from COVID-19 was approved for use in the USA under emergency authorization. The European Medicines Agency endorsed use of the corticosteroid dexamethasone for late-stage COVID-19 disease in September5. Soon thereafter, in November, the FDA approved the arthritis drug baricitinib (in combination with remdesivir) for emergency use. Two novel monoclonal antibody therapeutics were approved for COVID-19 emergency use by the FDA in November of 2020: bamlanivimab6 and a combination of casirivimab and imdevimab7. Thus far, these therapeutics have been associated with reduced viral load in patients, reduced time to recovery and/or reduced progression to severe disease5–9. Although a great success, these novel therapeutics were not developed, tested and approved until nearly a full year after the outbreak emerged. More recently, the first broadly cross-neutralizing human monoclonal antibodies have been described that target many different sarbecoviruses10. Finally, in December 2020, the adenovirus-based AstraZeneca–Oxford vaccine and two mRNA-based vaccines (Pfizer–BioNTech and Moderna) were approved for COVID-19 emergency use in England, the USA and elsewhere11–13. A wide portfolio of repurposed drugs, therapeutic antibodies and antiviral drugs are currently in clinical trials, providing novel opportunities for identifying SARS-CoV-2 and broadly active pan-coronavirus intervention strategies. The SARS-CoV-2 pandemic has highlighted a critical need for investment in preparedness for global outbreaks by infectious agents of the future, including systemic investment in public health preparedness, diagnostics and intervention technologies. As highlighted by the cases of remdesivir3, molnupiravir (a nucleoside analog developed for influenza and repurposed for SARS-CoV-2)4 and the human monoclonal antibody ADG2 (an antibody therapeutic active against multiple coronavirus family members)14, it is vital to develop and identify family-wide or group-specific therapeutics and vaccines that can treat highly heterogeneous unknown zoonotic viruses that may emerge in the future. By having broad-based Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. ✉e-mail: Nature Medicine | VOL 27 | March 2021 | 401–410 | www.nature.com/naturemedicine 401 Review Article | FOCUS NATuRE MEDICInE a 21st century viral disease outbreaks MERS-CoV Middle East Dengue Americas Dengue Americas Ebola virus West Africa SARS-CoV Worldwide 2000 2002 CHIKV India 2004 H1N1 influenza Worldwide Rift Valley fever East Africa 2006 2008 2010 Dengue Americas Dengue Zika virus Southeast Asia Pan-Americas CHIKV Americas 2012 2014 Ebola virus Africa Yellow fever Africa Nipah virus India SARS-CoV-2 Worldwide 2016 2018 2020 b Zoonotic reservoirs and vectors Alphaviruses (CHIKV, VEEV) Filoviruses (EBOV, MARV) Bunyaviruses (RVFV, CCHFV LASV) Influenza viruses Corona (...truncated)