Can The Mucosal Immunity Protect Against COVID-19?

by Liana Relina Contributor , Illia Petrov    

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Topics: Novel Therapeutics   

Common vaccines are synonymous with injections and grant you systemic immunity. But the injection isn’t the only way to develop immunity. And considering how most pathogens, including coronaviruses, get into our bodies, injections might not even be the best way.

SARS-CoV-2 often enters through the nose, where it encounters a specific protein, ACE2, which is found in abundance in the nasal passage. ACE2 is the virus’s doorway into our cells. In fact, the mucosal membrane that lines your airways is often the frontier of your body to face SARS-CoV-2. Immune cells reside underneath your mucosal membranes, creating a front line of defense against invaders and preventing infection from taking root. Your mucosal immune cells produce a special class of antibodies, immunoglobulin A (IgA), that are constantly secreted from the mucosae to protect the nose, gut, and other vulnerable sites from pathogens we’ve seen in the past. This is the mucosal immune system and it is hard to study. Secreted IgA is tricky to measure. “It is a lot easier to measure things from the blood than it is to measure from mucosa,” says Michael Barry, who has developed an experimental intranasal vaccine for COVID-19 at the Mayo Clinic. To determine how much IgA an animal has produced after vaccination typically requires killing the animal to wash IgA off its lungs. In humans, IgA can be measured by collecting nasal fluid or saliva, but the IgA levels will vary depending on how the sample is collected. 

In addition to the complexity of IgA tests, intranasal vaccines have another drawback. “It is actually quite difficult to get the nasal spray to stay in the nasal tract,” says Victoria Kett, a drug delivery scientist at Queen’s University Belfast who has worked on intranasal vaccines. “If you use a nasal spray, it often doesn’t take long before you can taste it. And if you can taste it, it has left your nose,” Herman Ford Staats, immunologist, Duke University School of Medicine, says. Another risk of intranasal vaccines is sneezing. You take only a deep breath and sneeze the dose right out. All this means that researchers aren’t sure of the exact dose a person receives. 

These considerations explain why up to the present, pharmaceutical companies have been reluctant to invest in the needle-free approach. 

Nevertheless, some immunologists think the mucosal immune system has been seriously underestimated. Recently, it has been demonstrated that in the absence of local (mucosal) immunity, the nasal cavity may become a reservoir for the coronavirus, putting the patient at risk for reinfection or disease transmission to others. Mucosal immunity can stop both infections and the spread of the virus. However, mucosal immunity needs triggering. “…if you don’t stimulate the immune system in the mucosae, you don’t obtain mucosal immune responses,” says Pierre Charneau, head of the Molecular Virology and Vaccinology Unit at the Pasteur Institute. It is very important that mucosal immunity can only be achieved by administering a vaccine intranasally, not intramuscularly.

Now mucosal immunologists are hoping that the pandemic will contribute to the high noon for intranasal vaccines. “…critically, while injected vaccines induce only systemic immunity, vaccines delivered to mucosal sites can induce both systemic and mucosal immunity”, says J. Robert Coleman, CEO, and co-founder of Codagenix, which is developing an intranasal COVID-19 vaccine that’s being manufactured by the Serum Institute of India. “This climate is a game-changer,” says Hiroshi Kiyono, co-director of the University of California San Diego Center for Mucosal Immunology, Allergy, and Vaccines. “This is a great opportunity to advance nasal vaccines, not just for COVID-19…” 

More than a dozen (according to C&EN’s count; source) intranasal COVID-19 vaccines are being developed.  Over the past year, preclinical studies of intranasal vaccines have reinforced the notion that mucosal immunity matters. Several research groups developing intranasal COVID-19 vaccines have tested them in animals. Later, when scientists infected those animals with SARS-CoV-2, they found almost no virus replicating in the animals’ nasal cavities. It is noteworthy that animals that got injected versions of the same vaccines, in contrast, still had easily detectable viruses replicating in their noses. Intranasal COVID-19 vaccine AdCOVID was designed by Altimmune, a company specializing in therapies for anthrax, influenza, and COVID-19, to stimulate a broad immune response including both systemic immunity (neutralizing antibodies, IgG) and local immunity (mucosal IgA, T cells) in the nasal cavity and respiratory tract. AdCOVID elicited highly potent responses in an animal model, as all the three critical pathways of the immune system were strongly activated after a single AdCOVID: serum neutralizing activity, T cell immunity, and mucosal immunity. Assessment of the serum neutralizing activity revealed that a serum neutralization titer was 1:580 by Day 28, which was several-fold higher than the minimum titer recommended by the FDA.  T cell immunity was manifested as a potent stimulation of antigen-specific CD8+ killer T cells in the lungs of mice as early as 10 days after vaccination. Assessment of the mucosal immunity showed a 29-fold increase in mucosal IgA, well above the level associated with protection in clinical studies of other vaccines. It should be noted that Altimmune is developing its intranasal COVID-19 vaccine based on the major viral variants that have emerged as the virus mutates around the world. All these aspects make AdCOVID unique. 

AdCOVID boasts three more advantages. First of all, it is its superior stability. The stability, or shelf-life, of a vaccine, is also a critical consideration. Unlike other COVID-19 vaccines that must be stored and shipped at ultra-low freezing temperatures and have a several-day shelf-life in a refrigerator, many intranasal vaccines are stable for years when refrigerated and can be stored for months at room temperature. The possibility to distribute a vaccine without cold-chain requirements will allow for more cost-efficient logistics. On-site availability of vaccines will be a critical issue for hospitals and pharmacies, as ultra-low freezers are not available in most institutions. 

Another advantage is the easiness of administration. AdCOVID is administered as a simple nasal spray, being less invasive than an injection. It can be self-administered. 

The last, but not the least, advantage of intranasal vaccines is scalable manufacturing, i.e. the ability to meet national and international demand. For example, a representative of Codagenix says that the Serum Institute of India has pledged to manufacture 100 million doses of its intranasal vaccine by the end of 2021.

This makes AdCOVID and other intranasal vaccines more appealing than other vaccines both to patients and to physicians. 

The table below illustrates that Altimmune’s AdCOVID offers important differentiations from other vaccine candidates currently in clinical development for COVID-19 (Source:

Some experts think that none of the intranasal COVID-19 vaccines in development will play a role in ending the pandemic. But intranasal vaccine developers are not going to give up. For example, TheraVectys, a spin-off from the Pasteur Institute, plans on testing an intranasal vaccine developed in Charneau’s lab as a booster for people already vaccinated with existing COVID-19 vaccines (when people have to get revaccinated because of waning immunity or because of a variant). Anyway, there is a fairly high chance that intranasal vaccines will rank high in the further control of COVID-19. 

Topics: Novel Therapeutics   

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