The next wave of COVID-19 vaccines: In through the nose

Seventy years ago, polio had parents around the world trembling in fear. The highly infectious poliovirus paralyzed thousands of children before two vaccines emerged – one injected through the arm and the other taken orally. 

Like many other children, Ulrich von Andrian was given the oral vaccine – a few drops of weakened poliovirus on a sugar cube. This vaccine built up defenses in his intestines, where the virus first infects the body and replicates, protecting against initial infection in the gut lining.

“It is important that your immune vaccine effect is particularly strong at the site of entry,” because it can prevent the virus from spreading to others, says von Andrian, who is now a professor of immunobiology at Harvard University and scientific advisor to Moderna.

While the intramuscular polio vaccine defends against paralysis, it is less effective at stopping virus replication in the gut and protecting unvaccinated individuals from infection. The oral vaccine was critical in bringing the polio pandemic under control because it reduced transmission.

The nose is the first line of defence for the coronavirus, much like the gut is for the poliovirus. Currently, COVID-19 vaccines are injected into the muscles but many immunologists think a nasal vaccine may also be needed to end the pandemic. Like the oral polio vaccine, it could offer local protection – right at the source.

Both the inner nose and gut are covered in mucosa – a moist tissue lining that protects exposed areas from outside invaders. It produces special mucosal antibodies designed to neutralize viruses before they can spread to the rest of the body. These mucosal antibodies are extra effective against the coronavirus – 7.5 times more effective than normal antibodies according to some estimates.

Intramuscular vaccines typically do not stimulate powerful mucosal immune system responses. But the immune response to mRNA vaccines is a new field of study. A recent preprint analysis of the Pfizer and Moderna vaccines suggests that they may stimulate the production of mucosal antibodies, and preliminary data from Israel suggest the Pfizer vaccine reduces viral load fourfold.

While the risk of transmission is still being investigated in humans, animal models – including experiments with non-human primates – show that the coronavirus still replicates in the nose after vaccination, though likely at a reduced rate, says Michael Diamond, an immunologist at Washington University.

So while vaccinated individuals are less likely to harbour and transmit the virus, they still may be able to spread it to others. This is partly why health officials recommend vaccinated individuals continue wearing masks even after getting the jab. Furthermore, any continued replication presents the risk of not only more COVID-19 cases, but also new mutations.

Immunologists at the University of Buffalo argue that mucosal immunity should be central to future vaccine efforts. As the largest part of the immune system, the mucosa needs to be directly stimulated and recruited to defend against the coronavirus, they say.

Michael Diamond has recently used a single-dose nasal vaccine to successfully cut off the virus at the point of entry in mice. His team found that nasal delivery stimulated a strong immune response throughout the body, particularly in the upper respiratory system. “We have to wait and see what its efficacy is on humans,” he says.

Unlike the influenza vaccine administered through the nose, this intranasal vaccine doesn’t use a live virus to stimulate immunity. Instead, it uses a modified adenovirus to carry the coronavirus spike protein into the nose, which should be safer.

Many biopharmaceutical companies have just started human trials on nasal COVID-19 vaccines. While these will take time, Bharat Biotech says they may provide better mucosal immunity and increase vaccination willingness among both kids and adults. Nasal sprays could also be easier to store at room temperature, administer without medical training, and dispose of without needle pollution.

In the effort to create global immunity, the intranasal vaccine may be particularly important in low-resource settings. Anything that is more stable than current mRNA vaccines could target a wider audience, says Jennifer Dan, an infectious disease specialist at the University of California, San Diego. “It’s a good idea to try any method to get a good immune response to prevent infections,” she adds.

Both types of vaccines were ultimately needed to stop the poliovirus. The intramuscular polio vaccine is better than the oral vaccine at protecting vaccinated individuals, so it remains the most popular polio vaccine. But the oral polio vaccine is still used by the World Health Organization eradication program to reduce spread in countries with wild polio.

While the first wave of intramuscular vaccines curbs severe COVID-19 disease, a second wave of nasal vaccines may be able to help slow transmission, Diamond suggests. As human trials commence on nasal vaccines, many hope this new delivery method will be the next addition to the world’s coronavirus-fighting toolbox.

The comments section is closed.

  • Edwin L. Weinstein says:

    An article published in Canada should certainly mention McMaster University work on a mucosal vaccine. As I understand it, they are doing clinical trials now.

  • Dean says:

    Early on in the pandemic I wrote the following published paper for treatment and vaccination using the respiratory route, and was unsuccessful at obtaining any funding for further research. I believe that “We” need to through everything we have at this virus to help unlock better treatment and cheaper vaccines.
    Also I written the following paper on a missed opportunity with the drug called Miglustat.


Robin Blades


Robin Blades is a Fulbright Scholar and clinical research coordinator in psychiatry at a California University. She is currently a fellow in the Dalla Lana Global Journalism program.

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