Preparing for future pandemics, today with broad-spectrum antivirals
The current emerging coronavirus outbreak in Wuhan demonstrates that we need drugs for emerging viruses and especially for emerging coronaviruses. Below, we tell the story behind our recent paper on a broad-spectrum antiviral which may be able to fill this very important public health need.
Are we prepared for the next viral pandemic?
A new coronavirus is believed to be the cause of an outbreak of viral pneumonia in Wuhan China (#WuHanPneumonia) with potential spread to Hong Kong 1. Since the initial case reported on December 12th 2019, there have been at least 44 cases 11 of which are severely ill 2. Unfortunately, with the ease of global travel, increased human contact with wild and domestic animals, land use changes, and development etc., novel disease emergence is no longer unusual. In the past 20 years, we have seen the two largest Ebola virus outbreaks on record, Zika virus spread to the Americas, and the emergence of now three new human coronaviruses including SARS in 2002 and MERS in 2012.
How do we prepare for future pandemics, today?
Rather than develop “one drug for one bug” we want to create “one drug for many bugs.” Broad-spectrum therapies effective against known epidemic strains of virus as well as zoonotic strains likely to seed future emergence, have greater potential to diminish current and future epidemic disease than drugs with single pathogen specificity. Like most papers, completing this story was not without many hours of hard work from a team of scientists and liters upon liters of coffee. Since 2015, we have been collaborating with Gilead Sciences and Mark Denison’s Lab at Vanderbilt University (@DenisonLab) to accelerate the preclinical development remdesivir (GS-5734), an antiviral nucleoside analog3. Our recent paper in Nature Communications (DOI: 10.1038/s41467-019-13940-6) details the in vitro and in vivo efficacy of remdesivir against MERS coronavirus and its superior antiviral efficacy as compared to a combination therapy currently under evaluation in human clinical trial in the Kingdom of Saudi Arabia4. Since remdesivir works against many genetically distinct CoV encompassing family-wide genetic diversity including zoonotic viruses poised for emergence, the drug is likely to work against currently emerging CoV like MERS and the newly identified virus in Wuhan as well as those of the future5.
Working with killer viruses at biosafety level three (BSL3)
As a scientist, I was born in the BSL3 lab. In 2003, I (@timothysheahan) joined the lab of Dr. Ralph Baric (@Baric_Lab) as a graduate student at UNC Chapel Hill just after SARS emerged. Since SARS can kill you, it must be worked with in a special lab, wearing special protective equipment by highly trained scientists. My guitar toting hard core punk rock loving younger self would never have imagined my adult self wearing a full protective suit with an air purifying respirator in order to study deadly viral diseases but my youth was brimming with myopathy. After a postdoc on HCV and a stint at GlaxoSmithKline developing antiviral drugs, I am back working in the same BSL3 lab I was born in studying coronavirus while waiting for the inevitable emergence of a new coronavirus to study.
Peer review is painful but always makes your paper better
This paper was a labor of love and I love the finished product but it was not without the pains of peer review. After submitting what we thought were two solid and improved drafts, our paper was rejected. We had apparently failed to provide convincing evidence to a reviewer that remdesivir was better than other treatment regimens. We were having a communication problem. Our editor mentioned Nature Communications does entertain appeals to rejections but only rarely and only if very compelling. My pathologist friend, Dr. Stephanie Montgomery, and I came up with a plan for our perplexing pathology problems to blindly quantitate features of lung pathology rather than just qualitatively describe them. After scoring hundreds of fields, we definitively showed only therapeutic remdesivir improved MERS-induced lung pathology in mice. On December 7, 2019, our paper was accepted. This was a good day. The peer review process, though painful and protracted, forced us to develop tools to quantitate pathology in a way that made our final draft much better. The tools developed in response to peer review, will become part of our analytical repertoire and will surely elevate future papers as they did this paper.
See the full paper here: https://www.nature.com/articles/s41467-019-13940-6
1. Kahn, N. New Virus Discovered by Chinese Scientists Investigating Pneumonia Outbreak. Wall Street Journal (2020).
2. Disease, I.S.f.I. PRO/AH/EDR> Undiagnosed pneumonia - China (HU) (03): updates, SARS, MERS ruled out, WHO, RFI. Promed (2020).
3. Sheahan, T.P., et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med 9(2017).
4. Arabi, Y.M., et al. Treatment of Middle East Respiratory Syndrome with a combination of lopinavir-ritonavir and interferon-beta1b (MIRACLE trial): study protocol for a randomized controlled trial. Trials 19, 81 (2018).
5. Brown, A.J., et al. Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase. Antiviral Res 169, 104541 (2019).