Warp speed isn’t fast enough: the need for variant-proof therapeutics

Broad-spectrum vaccines and therapies are needed to get ahead of the next pandemic, and stay ahead of viral variants

This month marks three years since the global pandemic officially reached our shores. More than 1 million Americans have now died. Today, mRNA vaccines and therapeutics enable many of us to live near-normal lives, and the worst may be over. But the question remains: how long until the next untreatable variant emerges?

For decades, the U.S. prided itself on its ability to contain novel viral epidemics that, in part, resolved themselves due to a lack of lethality (2009 H1N1) or a lack of transmissibility (Anthrax, SARS-CoV-1, MERS, Zika and Ebola). When a new virus that was both lethal and highly transmissible entered our borders, the country was unprepared. And today, three years later, we are still unprepared. 

The primary barrier to pandemic preparedness isn’t political will and it isn’t insufficient spending. Republican and Democratic administrations have devoted tens of billions of dollars to develop and stockpile countermeasures to “prevent the next pandemic.” And yet, none of these countermeasures is likely to protect us from another novel viral threat.

Viruses adapt quickly, while we spend years developing precision vaccines and therapeutics that only target specific viral protein variants. When viral proteins evolve sufficiently or when novel viruses emerge, our arsenal of narrow-spectrum countermeasures becomes obsolete.

Already, the dominant SARS-CoV-2 variants in the country (XBB.1.5 and BQ.1.1) are resistant to treatment by every single previously authorized mAb. As a result, FDA has now pulled all mAbs against SARS-CoV-2 off the shelves. The small molecule Paxlovid is still a therapeutic option, but there are multiple published reports of resistance-conferring mutations.

Resistance is not limited to SARS-CoV-2 antivirals. The country’s Strategic National Stockpile (SNS) was built to serve as a last line of defense stocked with life-saving countermeasures in the event of an unforeseen pandemic. Instead, it may be lined with billions of dollars of medicines designed to fight last year’s wars.

As obvious as it sounds, we should only stockpile countermeasures today that have a possibility of protecting the country tomorrow. We also can’t wait until resistance emerges. There is no way to design, develop, clinically translate, FDA-review, manufacture and distribute a new countermeasure faster than a highly transmissible, aerosolized virus can spread. Within two weeks of its detection, Omicron was a global pandemic.

We need to alter the rules of the game, by investing in variant-proof countermeasures that can maintain efficacy even as viruses evolve.

Synthetic biology and immunology now enable us to target regions of viral genomes that are less mutable than the proteins that current antivirals attack. Using these techniques to target a region common to a wide array of known coronaviruses could, for example, lead to a drug that would work against a future coronavirus.

It may also now be possible to develop plug-and-play platform technologies that are resistance-proof and rapidly adaptable to any viral threat. And the regulatory process for applying these platforms to new viral indications may soon be streamlined — due to the new advanced platform technology designation provided by the PREVENT Pandemics Act, passed by Congress in the recent 2023 omnibus appropriations bill.

One example of a pan-viral platform technology is a new class of RNA, known as encrypted RNA. This next-generation RNA, which we aim to advance at Autonomous Therapeutics Inc., is designed to encode an artificial immune system that can detect and eliminate every variant of a viral family. We have developed encrypted RNA candidates with potential variant-proof efficacy against a wide range of pathogens, from coronaviruses to influenza and RSV. These can be made inhalable and shielded from human immune systems to enable safe and long-term prophylaxis. As a result, encrypted RNA offers the possibility of population-scale protection against mutating viral threats, including variants never seen before.

Other technologies are also on the horizon. An example is combination therapy, where cocktails of multiple antivirals are developed to simultaneously attack multiple viral proteins, offering the virus fewer avenues of escape. Additional strategies involve targeting human proteins rather than evolving viral proteins. We should explore these and other potential pan-variant approaches to get ahead of the viral variants of the future.

For nearly a century, the U.S. has led the world in scientific innovation — much of it driven by organizations that took the risk and initially invested in mRNA vaccines, including NIH, DARPA and venture capital. The country’s vaccines, therapeutics, and Warp Speed initiative averted millions of deaths. But these countermeasures had no chance of being ready in time to save hundreds of thousands of lives in early 2020.

When the next deadly variant emerges, the only available countermeasure could again be a shutdown of the country’s economy, schools and way of life, to flatten the curve. An alternative strategy would be to get ahead of the curve by developing broad-spectrum therapeutics and vaccines that are now in the realm of possibility. 

The mRNA vaccine platforms that came to the rescue for COVID-19 shortened the process of vaccine development and FDA approval to one year, through a combination of scientific and regulatory innovation. The next round of innovative technologies could again shorten that process with a little help from regulators.

For example, if FDA were to approve a broad-spectrum vaccine or therapy that demonstrates efficacy and safety against any known SARS-CoV-1 and SARS-CoV-2 variant, the agency could then dramatically speed the process of responding to a new threat — e.g., SARS-CoV-3 — by extending the product’s label to SARS-CoV-3 without requiring a large, lengthy efficacy trial. The decision could instead be based on a smaller, faster clinical study demonstrating the product induces immune correlates of protection against the new virus, plus supportive data in cellular and animal models of SARS-CoV-3 and other coronavirus family members.

Such an approach could shave months off an economic shutdown. To get from here to there we need to change the existing playbook and embrace this alternative approach, before it’s too late.

Tevi Troy is a former HHS deputy secretary and the author of the 2016 book: Shall We Wake the President? Two Centuries of Disaster Management from the Oval Office. He is on the board of Autonomous Therapeutics Inc. Ariel Weinberger is the founder and CEO of Autonomous Therapeutics, which developed encrypted RNA.

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