What It Will Take to Get a Next-Generation COVID Vaccine

Nearly 4 years since the first messenger RNA (mRNA) COVID-19 vaccines were developed, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is evolving more quickly than tailored boosters can be made ready and continues to kill hundreds of Americans every week. There is a pressing need for more durable and lasting protection, but there is no “Operation Warp Speed” working to create new and better vaccines, only pandemic fatigue, experts said.

While existing vaccines remain one of the most important tools in combating severe disease and long COVID, research suggests that current protections wane significantly within 4-6 months. Scientists around the world have been trying to break new ground with the next generation of vaccines, but the unprecedented speed and collaboration with which those first mRNA shots were developed and made available to the public have not been replicated.

Critics point to a lack of urgency, national strategy and policy, and funding hampering progress. Overall spending on public health had already been decreasing for more than two decades, and funding for emergency preparedness programs has been cut again and again, according to Trust for America’s Health, a nonprofit, nonpartisan public health policy organization.

“It’s certainly disappointing, as someone who’s still actively working on improving vaccines for respiratory pathogen,” said David Martinez, PhD, an assistant professor of immunobiology at the Yale School of Medicine, New Haven, Connecticut. “There’s no doubt in my mind, if we’re able to even devote half of the resources that we did for something like Operation Warp Speed — and resources and personnel and funding — then we could certainly achieve something great in the form of more quickly being able to develop these next-generation booster vaccines.

“But that’s unfortunately not reality right now.”

Experts are encouraged by initiatives like the $5 billion investment in Project NextGen, aimed at accelerating the development of the next generation of vaccines and treatments through public-private partnerships. Yet they also want to see more funding and better communication from policymakers, similar to what made Operation Warp Speed, which had a budget as high as $18 billion as of October 2020, possible.

“The virus is still evolving, and it’s still causing hospitalization and death. It’s causing long COVID. So, we’re still going to need that investment,” said Sabrina Assoumou, MD, MPH, an infectious disease physician at Boston Medical Center, Boston.

Eric Topol, MD, wrote in his Ground Truths newsletter that vaccines have “sat in stagnation since the miracle of their appearance and potency in late 2020” with little progress toward developing a more durable shot. Newer vaccines approved abroad are not yet available in the United States, he noted, while efforts to create a universal coronavirus vaccine remain firmly in the realm of research.

“We’re essentially in standstill mode with little investment in moving forward. How shortsighted this is,” Topol wrote. “The variants will keep coming, and we’ll just keep chasing them, being months behind.”

A Cycle of ‘Panic and Neglect’

Many had hoped SARS-CoV-2 would eventually become a seasonal virus, but COVID experts say it is not like the flu. New variants, including a group of Omicron subvariants called FLiRT and the LB.1 variant, were among the major drivers of a summer surge, with the Centers for Disease Control and Prevention (CDC) reporting a substantial rise in cases across several states, based on wastewater testing and emergency room visits. Nationally, viral activity in wastewater was still deemed “high” as of mid-September, and nearly a thousand people died of COVID in a single week as recently as mid-August, according to provisional data from the CDC.

Taken together, the notion of a once-a-year booster like fall flu shots, or even a twice-a-year immunization routine, is not a solution for controlling COVID, experts said, particularly when the percentage of people receiving booster shots is already significantly lower than those opting for flu vaccines.

A national strategy on how to manage COVID going forward is important, said Bruce Y. Lee, MD, MBA, a professor at CUNY Graduate School of Public Health & Health Policy, New York City.

“That panic and neglect cycle, that’s been the situation with epidemics, outbreaks, and pandemics for a while. There’s panic when it happens, but then there’s neglect when it doesn’t seem to be the same level of emergency,” said Lee, executive director of PHICOR, which focuses on computational systems and models to help address complex health and public health decision-making.

The Next Generation of Vaccines

Existing vaccines target the variable parts of the spike protein that is found on the surface of the SARS-CoV-2 virus. During the replication process, copying “errors” are made, creating variants. Coronaviruses have a very high mutation rate, but there are portions of the virus that stay the same when they replicate. Current vaccines and boosters target the part that mutates, so it is a constant race to keep up. Scientists are looking into longer-term solutions that target the unique parts of the virus that remain unchanged, with the hope that these so-called “universal” or “pan-coronavirus” vaccines would have the potential to last longer, reducing the need for frequent boosters.

Experts agree the next pandemic is not a question of if, but when. Rather than scrambling to develop a vaccine during a crisis, proponents of universal vaccines say these types of shots could help combat emerging new viruses, saving not only lives but also tens of billions of dollars in direct medical costs alone. While these vaccines still seem like far-off, lofty goals, several candidates are making some headway. Even so, much of the work is still very much at a preclinical stage — promising concepts that have only been researched in animal models like mice, not humans, explained Martinez.

Meanwhile, the world’s first self-amplifying mRNA vaccine (saRNA or sa-mRNA) was approved in Japan in late 2023, yet is still unavailable in the United States. The saRNA vaccine uses a smaller dose than standard mRNA shots because the technology allows the vaccine to replicate inside a patient’s cells. It provides a greater level of immune response and lasts longer, according to clinical trials. The benefits of this technology include the possibility that manufacturers could produce vaccines faster using less material and potentially reduce side effects for patients who react to larger doses. While research indicates it is much more durable than existing COVID shots, saRNA vaccines still eventually degrade in the body similar to their mRNA counterparts and do not produce new viruses.

Despite the sluggish progress, experts are not without hope. “What makes me optimistic is the fact that there are a lot of very bright and talented scientists who, even in the face of not getting enough funding, they’re still pursuing work,” said Lee, but added that the work is not sustainable without proper funding and support. “That’s what’s happening right now.”

The next generation of vaccines that are furthest along are the nasal and oral versions. Current vaccines are intramuscular injections, but COVID is a respiratory virus that enters through the nose and mouth and begins its invasion somewhere along the respiratory tract. Scientists are hoping that a mucosal version will give better and longer protection by stimulating the immune response closer to the virus’s point of entry, along the upper and lower airways.

“I think within the next 12-24 months, you could start talking about phase 2 efficacy trials,” said Robert Seder, acting chief medical officer and acting associate director of NIAID’s Vaccine Research Center.

“The 12– to 36–month timeframe is reasonable for the first generation…I’m optimistic and hopeful that we’ll be able to develop a mucosal vaccine safely.”

Up to $500 million in Project NextGen funding has been earmarked for three Phase 2b clinical trials evaluating an oral pill and two nasal spray vaccines for COVID-19, but the initiative has made no investment yet in many other nasal vaccines from academic labs like Washington University, Yale, and elsewhere. Washington University researchers found that infected hamsters that had been inoculated with their nasal vaccine — already approved for emergency use in India in late 2022 — actually halted the transmission process by not passing the virus on.

Building Trust for Future Vaccines

While the wait continues for more effective and longer-lasting vaccines, Assoumou said doctors should talk to their patients, build trust, and encourage them — especially those who are vulnerable — to stay up-to-date on their shots.

“Let’s start by talking about how remarkable the current [COVID] vaccines that we have are,” she said. Immunization not only helps minimize severe disease, hospitalization, and long COVID risks, she said, it could potentially help slow down new variants.

While the mRNA vaccines were developed with unprecedented speed, it was only possible because of fundamental discoveries made through decades of prior research. Experts say there is also a need to continue to invest in similar types of basic research, which could have a broad and significant impact for a variety of respiratory viral pathogens and future vaccines.

“The reality is that for a large majority of problems, if you want a solution faster, one of the ways to do that is to throw money at the problem in the form of resources and the form of grant support, the form of policy,” said Martinez.

“These investments are not just economic. They’re also investments in extending human life expectancy.”