What will the next generation of COVID-19 vaccines look like?

As the coronavirus continues to evolve into newer and more contagious variants — capable of evading immunity from infection or vaccination — public health experts are trying to develop the next generation of vaccines that can outsmart the novel virus.

The federal government’s unprecedented effort to develop and distribute a COVID-19 vaccine — Operation Warp Speed — produced several jabs capable of preventing severe illness and death from the disease, and an estimated 1.9 million lives have been saved in the U.S. in the first year vaccines were made available. 

But variants of concern continue to emerge with enhanced transmissibility, and people who are fully vaccinated are experiencing breakthrough infections and spreading the virus to others. In the U.S., daily new cases are still hovering around the 100,000 mark and most counties still have a “medium” or “high” level of COVID-19, although hospitalizations and deaths have fallen dramatically from the early days of the pandemic. 

A sub lineage of the omicron variant, BA.5, is dominant in the U.S. and is causing reinfections in people who already had COVID-19. The variant is believed to be the most contagious version of COVID-19, but is generally milder than previous strains.  

New infections give the virus the opportunity to mutate, and thus, COVID-19 vaccines can wane in efficacy. That’s why during a White House summit last month, federal health officials, public health experts and vaccine manufacturers stressed the need to develop innovative new vaccines to help induce broad and durable protection against coronaviruses. 

Here are some of the next generation vaccines under development:

Universal COVID-19 vaccine

Vaccines are generally tailored to protect against one or a handful of versions of a virus. Current COVID-19 vaccines target the spike protein of the SARS-CoV-2 virus, which is used to penetrate host cells and cause infection. But the spike protein can mutate quickly, making it a moving target for vaccines. 

To combat this, researchers are working on a universal COVID-19 vaccine that would ideally protect against all current and future strains of SARS-CoV-2. Such a vaccine could significantly slow the transmission of the virus. The Coalition for Epidemic Preparedness Innovations (CEPI) and the National Institute of Allergy and Infectious Diseases (NIAID) have committed $200 million and $43 million, respectively, for research and development of several pancoronavirus vaccine programs. Some universal vaccines under development aim not only to protect against multiple types of COVID-19, but against a variety of coronaviruses. 

“The current vaccine is highly effective against the original virus, but the virus has moved on and there’s several new variants. Lab studies show the effectiveness of the neutralizing ability against new variants has decreased substantially,” Wan Yang, assistant professor of epidemiology at Columbia University Mailman School of Public Health, said in an interview. 

“It is crucial to prevent severe disease and the vaccine has been so important in terms of saving so many people. But if we’re going to get ahead of the game in terms of preventing large pandemic waves in the future, I think we really need a universal vaccine that works against future variants and is able to block infection,” Yang said. 

Work in this area is in its early stages. The Walter Reed Army Institute of Research is currently conducting a phase 1 clinical trial of a vaccine to target multiple variants of SARS-CoV-2 and potentially other coronaviruses as well. Pre-clinical research showed the vaccine produced “highly potent and broad neutralizing” antibody responses against  several SARS-CoV-2 variants and SARS-CoV-1 virus. Several entities including CalTech, Duke University, Pfizer and BioNTech and other biotech companies are in early testing of a range of universal coronavirus vaccines. 

Nasal vaccine

A vaccine in the form of a nasal spray could be another weapon in the arsenal against COVID-19 as early research has shown interesting results in animal studies. 

While current mRNA vaccines induce robust immunity in the blood, preventing severe disease, the antibody response in the nose and airways, the body’s first line of defense against respiratory infection, are lacking. This is particularly true of the omicron sublineage. Recent research published in Science Immunology suggests coupling mRNA vaccines with a nasal booster vaccine could provide much stronger protection where the virus enters the body, thus preventing infection. 

Researchers showed that mice given an mRNA vaccine experienced a good antibody response in the blood but not very good mucosal immunity. However, when given a nasal booster, researchers observed a “very robust” mucosal immunity response against all SARS-CoV-2 variants tested.

“We think the robust antibody responses in the respiratory tract would neutralize the virus immediately upon viral entry when the individual contracts the virus, preventing the establishment of viral infection and subsequent passing of the infection to others,” Jie Sun, a professor of medicine at the University of Virginia and co-author of the study said. 

Akiko Iwasaki, an immunobiologist at Yale University working to commercialize a nasal booster, said during last month’s White House COVID-19 vaccine summit the only way to stop the emergence of new variants is with transmission-blocking vaccines. 

Plenty of nasal vaccine candidates are being tested, but most studies are in the early phase and few have been tested on humans. Researchers say it will likely be a couple of years before a viable nasal vaccine is made available to the public. 

Oral vaccine

Biotechnology company Vaxart is currently testing a COVID-19 adenovirus vaccine that comes in the form of a small tablet and induces antibodies in the mucosal tissues in the nose and lungs. Sean Tucker, Vaxart’s senior vice president chief scientific officer, kicked off research on an oral vaccine for influenza more than 12 years ago to make a flu vaccine more convenient and accessible than traditional injections. 

Preliminary phase 1 clinical data released last month showed Vaxart’s oral COVID-19 vaccine induced long-lasting mucosal antibodies against SARS-CoV-2. Most of the 35 vaccine recipients in the trial experienced an increase in mucosal antibodies which were highly cross-reactive against all coronaviruses tested and persisted up to a year. The vaccine also appeared to be safe and well tolerated. 

In addition, results showed the participants had higher antibody levels than people whose antibodies were produced by past COVID-19 infections. 

“We think our technology would pair pretty well with an mRNA vaccine. Those do really well from the standpoint of antibodies in the serum, our vaccine will add to that because they are going to be able to do a mucosal response. And it could be that we’ll be able to boost their serum responses as well. We just don’t know that yet,” Tucker said in an interview. 

A phase 2 trial with nearly 900 participants is currently underway. 

Limitations

The success of Operation Warp Speed was the result of huge investments into research and development and a sense of urgency to tame the coronavirus that has killed millions globally. But as deaths and hospitalizations have subsided and Congress gridlocks on new rounds of COVID-19 funding, the path to bringing innovative new vaccines to the market is uncertain. 

“The question is will Congress act to fund,” Mark Herr, a communications representative for Vaxart, said. “If there was substantial effort and money put into it, we could certainly get to the finish line within a year, 18 months, and have a vaccine available.” 

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