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COVID-19 vaccines are working incredibly well at preventing severe disease, but future boosters will likely need to be tailored to target new and existing variants, strengthen immunity and ultimately help regain control over the pandemic.
The vaccines currently used were made to target the original strain of the virus, which is dramatically different from the highly transmissible Omicron variant that has become dominant globally in the weeks since it was identified.
Protection against infection has dropped significantly with Omicron, largely due to the dozens of mutations on the virus’s spike protein, making it much easier to spread through both vaccinated and unvaccinated populations than with previous variants.
But while defence against hospitalization has held up remarkably well in the face of this new challenger, immunologists and virologists agree that updating vaccines to be more similar to circulating variants will provide better long-term protection.
“Omicron is different enough where I think we need to update it,” said Deepta Bhattacharya, an immunologist and professor at the University of Arizona.
“In some ways, I guess I’m a little surprised that third doses do as well as they do.”
Vaccines holding up well against Omicron
New research is showing just how well boosters are holding up in the Omicron wave — still protecting against infection, symptoms and especially hospitalization. But how long that protection lasts is still an open question.
A new report from the U.S. Centers for Disease Control and Prevention found that while vaccine effectiveness against Omicron hospitalization fell to just 57 per cent in people who were more than six months out from a second shot — it grew to 90 per cent with a booster.
A second CDC report looked at 25 U.S. states between April and December and similarly found that while defence against infection waned, those with boosters had much higher protection against symptoms both when Delta was dominant and when Omicron overtook it.
And a third study from CDC researchers published in the the Journal of the American Medical Association this week found three shots of mRNA vaccines were close to 67 per cent effective against symptomatic disease from Omicron compared to the unvaccinated.
Additional CDC data released this week also found unvaccinated Americans over the age of 50 were close to 45 times more likely to be hospitalized than the vaccinated.
“Three doses of the original recipe seem to give good resistance towards Omicron-induced severe COVID-19,” said University of Toronto immunologist and associate professor Jennifer Gommerman. “What we don’t know is how long that will last because Omicron is so different.”
Omicron has “drifted” away from the original strain of the virus, Gommerman said, but mRNA vaccines are “very versatile” and manufacturers are already pivoting their formulations against it.
“It makes sense that if we administer any future doses they would be tailored to prompt an immune response to Omicron,” she said.
“One of the reasons healthy vaccinated folks are getting Omicron infections, which is sometimes accompanied by mild illness, is because the immune response must shift towards recognizing this new variant.”
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Bhattacharya said that while additional doses of the original vaccine formulation will provide added protection against severe disease for those who need it — they won’t completely control spread.
“It might be able to get you through the Omicron wave and maybe that’s the goal,” Bhattacharya said. “But our expectations should be fairly low in what we can expect these unmatched boosters to do.”
4th doses may not be as effective
Israel has begun offering fourth doses to those over 60, immunocompromised people and health-care workers, but preliminary unpublished hospital data has found it was largely ineffective in preventing Omicron infections.
“Beyond third doses, it is unclear what extra doses of the original recipe will do beyond temporarily raising your antibody levels,” said Gommerman.
“I don’t think boosting everybody every few months to bump up our antibody levels is a practical solution, especially since we know three doses can generate sufficient immunity to prevent healthy people from developing severe COVID-19.”
Bhattacharya said if we did have access to Omicron-matched boosters in combination with the protection from the original vaccine strain, we’d be in a much better position to control the spread of the virus globally — even if a new variant were to emerge.
“I do think we’ll cover a lot more possibilities of what the virus might do next,” he said. “It won’t cover them all, but again, maybe it buys us a little more time until the next thing.”
More variants ‘fairly certain’
Tailoring vaccines to an evolving virus might sound complex, but it’s not unheard of. The annual flu vaccine, for example, is changed each year to match the influenza strains that are forecast to circulate in the coming season.
Alyson Kelvin, a virologist at the Canadian Center for Vaccinology and the University of Saskatchewan’s Vaccine and Infectious Disease Organization in Saskatoon, says vaccine manufacturers need to be thinking ahead to adapt to emerging variants long-term.
“This is the headspace we need to be in … figuring out a proper scientific method of determining when COVID-19 vaccines need to be updated and then how best to implement that and design these,” she said.
“This might be the last big surge that we have to deal with now. But I’m fairly certain we’ll see other variants come up and how those interact with humans, as well as our pre-existing immunity, there will be a lot of questions to answer.”
Ciriaco Piccirillo, an immunologist and senior scientist at the Research Institute of the McGill University Health Centre and the Coronavirus Variants Rapid Response Network (CoVaRR-Net), said it’s possible we’ll need variant–specific boosters regularly going forward.
“Although that’s a great idea and great news — it will be late. It’s a bit like running after a moving train,” he said. “The speed of the pandemic is much quicker than we are capable of doing that.”
Gommerman said moving toward developing, testing and deploying mucosal boosters — much like the nasal spray vaccines used for influenza — can build on existing immunity and actually deploy immune cells into the upper respiratory tract to better prevent infection.
Canadian researchers at McMaster University have already begun clinical trials for two inhaled vaccines, with plans to adapt their formulation to new and existing variants.
“The combination of respiratory immunization and intramuscular immunization [with a needle] is the most effective at creating a broadly protective response,” added Kelvin. “So intranasal primary, followed by an intramuscular boost.”
Piccirrillo said much like we need to be thinking ahead to variant-specific boosters, we have to start thinking about different delivery methods for the vaccine.
“I think you’re going to get far more rapid, far more efficient immune protection against both infection and hospitalization,” he said. “That will have a huge impact.”
What will post-Omicron immunity look like?
But as early signs point to the hope that Canada’s Omicron wave has peaked, what will our population-level immunity look like after it crashes? And will it be enough to stave off yet another variant-driven surge?
Piccirillo said Omicron will likely become the dominating endemic strain of the virus, meaning it could overtake future variants due to its high transmissibility and bring more immunity to the population through infection in addition to vaccines.
“There’s possibly a silver lining to this cloud,” he said. “I do think that this increased infection rate is likely going to contribute directly to our much-wanted herd immunity.”
But Kelvin cautioned that while Omicron may increase the level of immunity in the population among both the vaccinated and unvaccinated — creating so-called “hybrid immunity” — it does come at a cost.
“We have to weigh that benefit with the unfortunate consequences of being infected with COVID-19,” she said. “Which could be long COVID or other pathological diseases that might arise.”
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Bhattacharya said after this surge in COVID-19 levels drops off, there will likely be much more immunity in the population to both the original virus and Omicron, and that it appears the immunity gained from infection is “additive” to vaccines.
“On one hand, Omicron is evolutionarily coming out of left field. It’s not a derivative of Delta, which is what many of us had thought would be the next thing to come,” he said.
“But I do think that Omicron immunity plus immunity to the original variant does cover a lot of the possibilities of what the virus might do next.”
Could the virus still mutate into something even more transmissible or immune evasive than Omicron, jeopardizing the hard fought immunity we’ve gained in the population?
“Sure. But it’s not unreasonable to hope that this will buy us a little bit more time,” he said. “Because boy, we sure need it.”
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