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AAs the world accumulates more experience with Covid-19 vaccines, something we should have known all along is becoming obvious.
Vaccines injected into the arm muscles are unlikely to be able to protect our nasal passages from marauding SARS-CoV-2 viruses for very long, even though they do a tremendous job protecting the lungs from the virus. If we want vaccines that protect our upper respiratory tract, we may need products that are given through the nose – intranasal vaccines.
Can they be manufactured? Probably. Will they do what we want them to do, if they are done? Perhaps. Is there still room for this type of new generation product, given the record number of Covid vaccines already in service? Potentially. Will it be difficult to get them to go through development? Likely.
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A few basics in immunology would be helpful in understanding the issues here.
SARS-2 attacks us through the respiratory tract, the resulting infections cause no symptoms in some people, mild to moderate cold and flu symptoms in others, and severe and potentially fatal illness in the lungs. ‘others.
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The vaccines injected into the arm have done a spectacular job in preventing serious illness and death. But they don’t generate the kind of protection in the nasal passages that would be needed to block any infection. This is called “sterilizing immunity”.
There’s no reason to believe intranasal vaccines would block all infections either, but experts say they might do a better job than existing vaccines, protecting the lining of the nose and throat better.
Florian Krammer, a vaccinologist at the Icahn School of Medicine at Mount Sinai Hospital in Manhattan, believes existing vaccines likely induce sufficiently high levels of circulating antibodies soon after vaccination that some of them end up in the mucous membranes. nose and throat. But as antibody levels begin to drop in the months following vaccination, that early nasal protection seems to wear off with it – especially in the face of the onslaught of the Delta variant, he suggested.
For Disclosure: Krammer’s colleague, senior virologist Peter Palese, is developing an intranasal vaccine that recently completed a Phase 1 trial in Mexico. Krammer is involved in the project. But he sees potential in the larger effort to develop intranasal vaccines against Covid.
“There are some approaches that… seem correct and I think they can be put forward – if there is funding,” he said. That’s a big “if,” he admits, explaining that funding for next-generation Covid vaccines – innovations over the initial options – has dried up.
Other experts are uncertain whether intranasal vaccines are a high priority at this point in the pandemic.
“I think right now we’re still at the stage where we need to prevent just the basic disease. But I could imagine in the future using this approach, ”said Stanley Perlman, coronavirus expert at the University of Iowa.
“I think mucosal immunity will help. I’m just concerned that these are really cold viruses, even if they cause pneumonia, and you will never have sterilizing immunity, ”he said.
The fact that vaccines don’t block all infections and prevent people vaccinated from spreading themselves is no big surprise, said Kathryn Edwards, a vaccine expert at the Vanderbilt School of Medicine. Years of experience with influenza vaccines – almost all of which are given by intramuscular injection – have shown that the route of administration protects the lungs, but not always the upper respiratory tract.
“We know it works, but it’s definitely not perfect,” Edwards said.
Kanta Subbarao, an influenza expert who heads the WHO Collaborating Center on Influenza in Melbourne, Australia, agrees. “None of the currents [Covid] vaccines are likely to provide robust protection in the upper respiratory tract. I think we would need something different for that, ”she said.
Intranasal vaccines have multiple advantages. They do not need syringes, which reduces immunization expenses and the amount of medical waste generated by an immunization program. A vaccine that can be inflated through the nostril probably does not require administration by a healthcare professional; oral polio vaccine used in many developing countries is poured into children’s mouths by trained volunteers.
And intranasal vaccines are – in theory, anyway – easier to administer to children and people with needle phobia. That said, O’Brien says that in his experience as a pediatrician, children aren’t necessarily much more willing to take the nasal influenza vaccine, FluMist, than a vaccine. “It doesn’t solve the delivery issues,” she said.
The manufacture of vaccines administered in this manner poses challenges. Research on intranasal vaccines that do not use live viruses to trigger immune responses – inactivated vaccines – has produced disappointing results over the years, Edwards said.
And it’s not yet clear whether the mRNA vaccines that have been so important in the pandemic could be reformulated to be given intranasally.
“It might be possible, but it would take a lot of work and may require new innovations,” said Barney Graham, who led the team at the National Institute of Allergy and Infectious Diseases that designed the vaccine. Moderna, in an email. “Childbirth in the respiratory tract is complicated by the mucociliary covering that covers the [upper] respiratory tracts. There are other groups working there.
An intranasally administered mRNA vaccine is not likely to emerge soon, Krammer said, suggesting it could be a “next, next, next generation vaccine.”
Several intranasal vaccines are in development, in the United States and elsewhere. But a project was recently scrapped after Altimmune, a Gaithersburg, Md., Biotech company, had disappointing results for its vaccine candidate.
One of the challenges of intranasal administration, at least for vaccines that use live modified viruses to trigger an immune response in the nasal passages, is that they must strike a delicate balance. Vaccines must provide enough antigen – the trigger for the immune response – to effectively trigger an infection in the nose. This awakens the immune system to the existence of an invader against which it must protect itself. Vaccines are designed so that infection does not turn into disease. But too much dose, and the vaccine could trigger illness or nasty side effects, Subbarao said.
FluMist, which is marketed by AstraZeneca, had to be reformulated several years ago because US data suggested it no longer protected children. And the vaccine has never been approved for use in the elderly, whose years of exposure to influenza viruses interfere with the vaccine’s ability to trigger this infection in the nose. At the other end of the spectrum, an intranasal influenza vaccine developed by Berna Biotech and licensed in Switzerland was withdrawn from the market in 1997 after causing Bell’s palsy, a temporary facial palsy, in some recipients.
AstraZeneca is working on an intranasal version of the vaccine it developed with the University of Oxford. A recently published animal study of the experimental vaccine at NIAID’s Rocky Mountain Laboratories in Hamilton, Mont., Showed that hamsters vaccinated with the intranasal vaccine and then experimentally infected with SARS-2 had less virus in their nasal passages than hamsters exposed who had not been vaccinated. Importantly, vaccines always protected the lungs of animals.
Vincent Munster, who led this work, said that if the goal of the Covid vaccination becomes to try to block the transmission of the virus, intranasal vaccination could help. “The idea, of course, is that it works best where it matters,” he said.
Would vaccines administered in this way produce as long lasting protection – enduring in the vaccine world lexicon – as that of the Covid vaccines we currently have? Munster said answering this question would require human trials. “I think it would also be sustainable. But you really need to have data side by side.
Some vaccine researchers are not sure that when it comes to developing intranasal vaccines, the juice is worth it. Many virologists believe that over time, as people’s immune systems develop an experience with SARS-2 – whether through vaccination or infection – the virus and humans will reach relaxation with SARS. -2, becoming like the four human coronaviruses, one of the causes of the Common Cold. “If it’s really a cold virus, more than a flu-like virus, we might not care,” Perlman said.
Krammer, however, believes vaccines now have a role to play. The one Mount Sinai is developing is produced from eggs – a low-tech, low-cost production approach that could easily be adopted in low- and middle-income countries that lack the capacity to produce mRNA vaccines. the most sophisticated.
For his part, WHO’s O’Brien appears to be reserving judgment on whether intranasal Covid vaccines will gain us much ground in the battle against SARS-2.
“Are they more durable? Do they really have a different course of action? Are there ways to use them to make them better vaccines? I’m very supportive of that, but I don’t think it’s obvious that if we only had nasal vaccines, you know, something would be resolved, ”she said.
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