What you need to know about the next generation of COVID vaccines

Despite calls to speed more powerful shots, they are still likely years away.

A vial of the AstraZeneca COVID-19 vaccine at a vaccination drive hosed by Indonesian Retail Merchants Association in Jakarta, Indonesia, in 2021.Dimas Ardian/Bloomberg

For more than a year, some scientists have called on companies and the Biden administration to speed the development of more powerful COVID-19 vaccines. That message received a long-awaited acknowledgment last month at a White House meeting.

“Our job is not done,” said Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases and chief medical adviser to the president.

Moderna and Pfizer are making booster shots for this fall to protect against the recent Omicron subvariants BA.4 and BA.5. But many scientists caution that playing catchup to variants is not a good long-term strategy. Next-generation vaccines, they say, could help protect people even as the virus continues to evolve.

“We’re in this for the long haul, and we have to figure out what are our long-haul vaccines going to be,” said Michael T. Osterholm, a professor at the University of Minnesota and director of the Center for Infectious Disease Research and Policy.

What exactly are next-generation vaccines?

There’s no shortage of ideas for new COVID shots that could provide broader or longer-lasting protection.

Many groups are designing pan-coronavirus vaccines to stay a step ahead of future variants so we don’t need boosters as often. Some of the shots aim to protect against the larger virus family that SARS-CoV-2 belongs to — the betacoronaviruses.

Others are making intranasal vaccines, given as a squirt up the nose, that recruit immune cells in airways to stop the virus at its point of entry. The approach could reduce mild infections and maybe even cut off transmission of the virus — all without a needle.

Another idea is to design shots that are better at recruiting T cells, soldiers of the immune system, to nip infections in the bud. The Moderna and Pfizer vaccines largely spur antibodies to protect us, but T cell immunity may hold its own even as the virus continues to evolve.

How badly do we need them?

Scientists agree that second-generation vaccines could be useful, but opinions diverge on how urgently we need them.

“The current vaccines are not sufficient,” said Dr. Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center. Although the existing vaccines are “very good at preventing severe disease,” he said, protection against infection wanes very quickly.

The White House meeting convened experts to discuss the advantages of developing new vaccines, but didn’t outline any plans for how to get them. Rick Bright, chief executive of the Pandemic Prevention Institute at the Rockefeller Foundation, said the meeting “should have happened a year ago.”

“It’s taken way too long to get to this point,” Bright added. “We don’t need a 10-year research agenda on a next-generation vaccine for COVID. We really need to cut to the chase.”

Operation Warp Speed, the US government’s $12 billion effort to rapidly make and test COVID shots in 12 to 18 months, may have set unrealistic expectations for how quickly future vaccines can be made.

“It’s not moving at that pace. And there isn’t the same urgency probably because we don’t necessarily need to have the same urgency,” said Dr. Gaurav Gaiha, a scientist working on next-gen vaccines at the Ragon Institute of MGH, MIT, and Harvard.

So how quickly can they be ready?

Some experts bemoan that money and willpower are the only things stopping us from having the new vaccines within a year. Others say that designing, testing, and producing them will take at least two or three years, and maybe longer, since the vaccines are largely based on unproven ideas and technologies.

Most funding for next-gen COVID vaccines comes from the Coalition for Epidemic Preparedness Innovations, a nonprofit backed by dozens of governments globally. CEPI has already committed $185 million to 11 groups designing broadly protective coronavirus vaccines. Many of those vaccines are entering clinical trials later this year or in early 2023.

Dr. Melanie Saville, CEPI’s executive director of vaccine research and development, expects early clinical data on some of the “variant-proof” vaccines in the summer of 2023 and on pan-betacoronavirus vaccines in 2024 or 2025. Testing the vaccines, ramping up manufacturing, and authorizing the shots could take another year or two, she said.

The most advanced intranasal vaccines for COVID are being developed by companies in China, India, and Iran and they have shared little to no data. Intranasal vaccines developed by small companies in the United States and United Kingdom are still in animal studies or early-stage clinical trials.

Many experts say that without funding, intranasal vaccines may remain nothing more than a promising idea. But “if we put the funds behind them to support large clinical trials, I think in 6 to 12 months we would have the data we need to show that they work or they don’t work and move on,” Bright said.

Do we need another Operation Warp Speed?

Early in the pandemic, Bright helped select the roster of vaccines included in Operation Warp Speed when he was director of the Biomedical Advanced Research and Development Authority, a division of the Department of Health & Human Services that funds work on diagnostics, drugs, and vaccines. Bright believes that a sequel operation could speed up development of new vaccines.

“We would have no problem finding another six or so candidates and moving those forward. And I bet in the same period of time we’d have three additional vaccines authorized at least,” Bright said.

Yet other experts doubt that we’re ready for another Operation Warp Speed.

Saville said that CEPI-funded vaccines will need more funding to eventually get them over the finish line, but she doesn’t believe it’s time to hit the gas yet. “I don’t think we’re at a phase where we can say, if we gave these people $2 billion, that they could do it in six months. The science is not at that level.”

Even if the money was available, picking the best vaccines to prioritize would be a difficult task.

“We need to find a way of examining things head-to-head, otherwise everybody lobbies for their own product,” said Erica Ollmann Saphire, president and chief executive of the La Jolla Institute for Immunology. “And we need to make sure that we are investing in improvements and not just pouring a lot of money into things that are shovel-ready.”

Why are next-generation vaccines harder to develop than the first COVID shots?

There are many unanswered questions about what it will take to make vaccines that provide longer lasting and broader immunity against coronaviruses. Scientists for decades have unsuccessfully tried to develop universal flu vaccines. Making a broadly protective coronavirus vaccine could present a similar challenge.

“A vaccine works like a wanted poster. We have to faithfully show what the bad guy looks like,” Saphire said. That means a pan-coronavirus vaccine must somehow teach the immune system to target not only the bad guys that we know about, but ones that we’ve never seen before.

Many of the ideas for how to do that are based on technologies that have never been tested in people or only tested in small studies. Even if they prove to be safe and effective, Saville said, it will take time to learn how to make them in larger quantities and at prices affordable for low- and middle-income countries.

Intranasal vaccines have their own challenges. Measuring the special immune cells and antibodies that live in the mucous membranes of the nose and upper airways is more difficult than measuring antibodies collected from blood. That makes it hard to know if the vaccine is working and complicates comparisons with existing COVID vaccines.

There’s only one approved intranasal vaccine in the United States: FluMist, a flu vaccine for children that uses live but weakened flu viruses. No one knows if the technologies used in the commercial COVID shots — mRNA, protein nanoparticles, and viral vectors — would be safe and effective as intranasal vaccines.

And since many Americans still haven’t gotten booster shots and few children have received any COVID shots, Osterholm cautions that the public’s interest in a new-and-improved vaccine could be lackluster. “It has to be a much better product for it to be successful,” he said.