Project NextGen is ignoring new COVID-19 antivirals when we need them most  

As this recent holiday surge reminds us, new dominant variants like HV.1, EG.5, and BA.2.86 are thriving despite our existing vaccines and treatments. COVID-19 remains a pressing threat, particularly for those most vulnerable to severe disease. Yet, the $5 billion initiative being administered by Biomedical Advanced Research and Development Authority (BARDA)-led Project NextGen has failed to invest in the next generation of oral COVID-19 antivirals. Next-generation oral antivirals, some of which are already in development, are likely to be the most practical and productive investment to help protect our most at-risk individuals and bring us closer to moving beyond this pandemic. However, without government/private partnerships similar to what were implemented for vaccines and monoclonal antibody development, new next-generation oral antivirals currently in development may not reach the finish line.  

To be clear, Project NextGen is an encouraging step toward delivering much-needed innovation in the ongoing response to COVID-19, having seen firsthand the pivotal role of public-private partnerships through Project Warp Speed. 

However, Project NextGen’s funding priorities have consistently neglected oral antivirals and, instead, prioritized vaccines and monoclonal antibodies (mAbs), as evidenced by each of its funding rounds for programs completed to date. While these tools have been useful in mitigating the COVID-19 pandemic, they alone cannot be a successful long-term strategy.  

We’re stuck in a perpetual game of catch-up with updated vaccines that are often outdated before they’re even available due to new SARS-CoV-2 mutations. COVID-19 mAbs have been even less reliable, as the first round of authorizations were quickly revoked due to waning efficacy. Even worse, some early mAbs may have given rise to currently circulating COVID-19 variants. Unfortunately, these limitations are inherent to mAbs, and developing an improved, universal mAb could take many years, and even then, success isn’t guaranteed. 

Project NextGen’s strategy also hinges on widespread vaccine and mAb adoption, which has been disappointingly low since they became available. Unfortunately, not enough people are getting “shots in arms,” as just ~16 percent of U.S. adults have received an updated bivalent vaccine, and previous COVID-19 mAbs, which required intravenous administration, were underutilized across the U.S. during the period they were authorized.   

The persistent reliance on updated vaccines and mABs is a shortsighted strategy akin to “pouring water into a basket” that fails to address existing and future COVID-19 treatment needs. But it’s not too late, as there are promising COVID-19 oral antivirals in late-stage clinical development, and the most successful candidates should meet these essential criteria: 

Safe and tolerable for all population groups. In the U.S., there are currently two approved COVID-19 treatments—intravenous Veklury (remdesivir) and oral Paxlovid (ritonavir-boosted nirmatrelvir)—and one authorized oral antiviral, Lagevrio (molnupiravir), each of which helps reduce severe outcomes, but also come with concerns that prevent many at-risk patients from receiving them. 

For example, Paxlovid has shown dangerous drug-drug interactions with commonly prescribed medications, which limit its use for those taking these other drugs, particularly elderly patients and those with chronic conditions. Additionally, Veklury has raised safety concerns for patients with kidney issues, and Lagevrio has potential risks to fetal health if taken during pregnancy.  

Tolerability is another concern, as several COVID-19 medications, including authorized oral antivirals, can have gastrointestinal (GI) side effects, such as nausea and abdominal pain, that can compound any GI issues caused by COVID-19 infection. 

So, we must ensure that new oral antivirals are universally safe and tolerable for everyone who needs them.  

Effective against current and future variants. This virus is accumulating mutations faster than other endemic viruses, at a rate that is 2.5 times more rapid than influenza, which can make updated vaccines and mAbs obsolete faster than the next improved product can be manufactured. For example, the EG.5 variant has shown key mutations associated with the use of specific mAbs, and recent evidence suggests that the global use of the oral antiviral Lagevrio led to new COVID-19 mutations that may compromise the effectiveness of this and similar antivirals. 

We need next-generation antivirals that target areas of the virus less prone to mutation, minimizing the likelihood that future COVID-19 variants will elude their protections. 

Prevent cross-resistance with other COVID-19 therapies. Not only can SARS-CoV-2 mutate to resist Paxlovid, but these mutations may also confer cross-resistance to other protease inhibitors. This implies that new variants could potentially evade entire classes of antiviral drugs, even those with differing chemical structures—a terrifying scenario that risks rendering our limited antiviral options ineffective. 

Our long-term strategy to address COVID-19 must include a diversified arsenal of oral antivirals with distinct mechanisms of action to ensure we maintain the long-term efficacy of as many current and future COVID-19 treatments as possible.  

The time for complacency is over. Relying solely on vaccines and mAbs isn’t a sustainable long-term solution against a virus that rapidly outpaces our current preventive and therapeutic arsenal. Project NextGen has the potential to transform our COVID-19 response. However, to realize this potential, BARDA and Project NextGen must prioritize the development of new oral antivirals to address gaps for vulnerable individuals and give us the best chance to finally turn the page on this pandemic.   

Dr. Jerome Adams MD, MPH, FASA  is a professor and executive director of health equity at Purdue University. He served as the 20th U.S. surgeon general. Adams currently serves on the board of directors for Atea Pharmaceuticals, a clinical-stage biopharmaceutical company focused on the development of medicines to treat viral diseases, including COVID-19.