Next-Generation COVID Vaccines Have Many Different Targets

Emily Willingham

April 19, 2021

Vaccine developers are monitoring the durability of the immune response of current COVID vaccines while racing against variants to provide more options for protection, no matter what happens next in the pandemic.

Vaccine research, which used to be on the back burner, making only slow progress, has been fast-tracked in the past year, pushing the field of vaccinology forward, says Deborah Fuller, PhD, professor of microbiology and vaccine developer at the University of Washington School of Medicine in Seattle.

The emergence of dozens of vaccine candidates in less than a year has been nothing short of extraordinary, and "we're going to have an amazing toolbox to use to combat infectious disease for a long time to come," she says.

Booster shots are part of the plan to protect against COVID-19, but so are entirely new approaches to vaccines, including delivery routes that eliminate the need for injections, and easier storage to help ease vaccine supply shortages.

Supply-chain problems are the first major obstacles that teams like Fuller's are tackling. Anything that can break vaccines free of the so-called cold chain — the need for deep freezing or refrigeration — is a priority, she explains. The ability to store vaccines at room temperature would increase accessibility in parts of the world where cold storage is hard to come by.

We're going to have an amazing toolbox to use to combat infectious disease for a long time to come.

The messenger (m)RNA vaccines, like the Pfizer and Moderna ones currently being used in the United States, are the most temperature-sensitive. "You can just look at a global map of where they're distributed and see which countries can accommodate the cold chain," says Fuller. Companies that produce the mRNA vaccines are working on different formulations to make the molecules stable at room temperature, she explains.

The vaccines that rely on viral vectors, such as those produced by Johnson & Johnson and AstraZeneca, "are stored at much nicer temperatures," says Anna Blakney, PhD, a vaccine developer and assistant professor in the Michael Smith Laboratories and the School of Biomedical Engineering, University of British Columbia, in Vancouver, Canada. Improvements in storage requirements across the board "will be here before we know it."

People who have received either of the two-shot mRNA vaccines might already be familiar with the common adverse effects of fatigue, arm pain, fever, aches, and chills, which are directly related to the mRNA in the vaccine, explains Blakney. "Being able to optimize the dose will cut down on side effects and presumably have the same efficacy."

Reducing Adverse Effects

The self-amplifying mRNA vaccines currently in development contain a lot of antigens to stimulate a strong immune response but have fewer infected cells. With less mRNA but an added replication protein, the molecule can make more copies of itself once it is inside the cell, with fewer adverse effects, says Blakney.

And with a strong immune response, a booster might not even be needed, Fuller adds.

As vaccination becomes more common and the threat of COVID-related death diminishes, one of the next priorities will be to minimize adverse effects. With an endemic virus circulating at low levels, "you're probably not willing to lose a day or two of work to suffer side effects," says Gregory Poland, MD, director of the Mayo Vaccine Research Group in Rochester, Minnesota.

And people might be able to avoid the needle entirely if some next-generation candidates get off the ground. At least seven non-injectable vaccines are in development, including a version of AstraZeneca's ChAdOx1 nCoV-19 (AZD1222).

Vaccines that could be delivered directly to the nose, for example, might confer mucosal protection, according to Fuller. Nasal vaccines don't have to be administered by a trained clinician and have the added advantage of inducing antibodies in the respiratory system to stop the virus before it gets a cellular foothold, she explains.

No Needles

Other groups are developing "swish-and-swallow" and pill-based vaccines, Poland reports.

"The beauty of this touches on the self-administered option," says Fuller. Imagine if people could have picked up self-administered vaccines in pharmacies early on in the pandemic. "We would have shut this thing down by now."

But despite the fast pace of COVID vaccine development, ongoing struggles in vaccine research programs remain and will likely create obstacles in coronavirus vaccine research.

A pan-virus vaccine — a "brass ring" in vaccine development — has been elusive for many infectious diseases, including influenza and HIV.

Some vaccinologists are trying to develop a meta-pan-virus vaccine that covers both influenza and coronaviruses, which would enable a single immunization to protect against both viruses, says Poland, who is working on vaccines for COVID-19.

Universal Vaccines

The high rates of morbidity, death, and long-term symptoms related to COVID-19 have pushed the search for a pan-coronavirus vaccine into high gear.

At the onset of the pandemic, "the house was on fire" so developers focused on the most expedient way to get vaccines out, says Poland. A focus on spike sequences from already circulating strains of COVID-19 was the fastest, most efficient approach.

Now researchers have time to look at pan-coronavirus candidates, and will rely on these narrow-target vaccines that can be updated to take on emerging variants.

The tricky part about pan-coronavirus vaccines, Fuller explains, is that they are "not something we're looking at next year, but probably a good 5 years down the line."

Even more difficult, she adds, is the identification of a part of the virus that won't mutate much but will still trigger an immune response. "The parts that are really vulnerable are poorly immunogenic, and the immune system can't 'see' them," so getting around this problem is "not trivial."

But the pace of vaccine development has accelerated during the pandemic and a first workable pan-virus vaccine is in sight.

A peptide-based version of a vaccine that targets several coronavirus antigens is being developed by Poland's team. And researchers are already testing a multivalent two-dose candidate at the Walter Reed Army Institute of Research. Their platform will allow add-ons of antigens from other coronaviruses to protect broadly and proactively against multiple coronavirus species and strains.

Researchers are also investigating the use of different combinations of vaccines to bolster an immune response with a cocktail of antigens. A trial of sequential immunization with Pfizer's mRNA-based vaccine and AstraZeneca's adenovirus-vectored version is underway in the United Kingdom. For mRNA vaccines, a cocktail could be built with multiple mRNA sequences that encode different bits of the virus, Blakney explains.

But how much protection is needed? "We don't know if there are certain thresholds of antibodies" that would be a marker of sufficient protection, she says. This is a strategy used for polio vaccines, and some clinical trial data already suggest that a target antibody level could be identified, she points out.

This threshold could also guide decision-making about boosters. "We don't know what level we need to meet, and the second dose increases your immunity so much," says Blakney. "There is a possibility that you'd only need one if you got to that antibody level" determined to be protective. "That would open up a lot of doors."

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