Despite the hype surrounding nasal vaccines recently, they are not new really a new concept. These vaccines came back on the radar after Bharat Biotech’s Incovac was recently launched as a two-dose regimen for primary vaccinations and a booster dose in India on Jan. 26.

In fact, nasal vaccines against the flu have been in existence since 2003. Currently, FluMist Quadrivalent, a live attenuated influenza vaccine administered via the nose, offers protection against four flu viruses for the present flu season.

Still, it is more common to expect an injection when you think about vaccines. Intranasal vaccines also confer several advantages over intramuscular vaccines, so why are they not flooding the markets?

How do nasal vaccines even work?

There are different routes of administration such as oral and nasal pathways which confer mucosal immunity BUT the most common ones are intramuscular injections which usually generate systemic immunity.

Nasal vaccines stimulate an immune response in the tissues that line the nasal cavity. The nasopharyngeal-associated lymphoid tissue (NALT) is a source of memory B and T cells that migrate to effector sites to elicit immune responses. This in turn generates T cell responses which will secrete immunoglobulins into the blood whereby IgA diffuses into the lumen and IgG and IgM help to neutralize viruses in the blood.

Therefore, intranasal vaccines can produce IgG, IgA, and T cell responses which can protect the mucous membrane against colonization, prevent the uptake of undegraded antigens, and prevent the development of potentially harmful immune responses if antigens penetrate the epithelial barrier.

Mucosal immunity is important as it is the first barrier against respiratory infectious diseases, presenting the possibility of blocking even mild infections before they can cause more harm.

The nasal approach is intended to enhance mucosal immunity, or the immune system’s ability to fend off pathogens at the point of contact on mucosal membranes rather than with antibodies or immune cells circulating in the bloodstream. 

“We urgently need more research to develop vaccines which can block transmission of respiratory pandemic viruses using delivery routes which are safe and practical at large scale,” said Alexander Douglas who led the failed phase 1 clinical trial of AstraZeneca’s nasal vaccine.

Last year, three nasal Covid-19 vaccines were approved including Russia’s Salnavac from the Generium company, China’s Convidecia Air from CanSino Biologics, and India’s Incovac from Bharat Biotech on July 5,  Sept. 4, and Sept. 6 respectively. However, Iran’s Razi Cov Pars was the first Covid-19 nasal vaccine approved in October 2021 but did not receive as much media attention. Among the four approved nasal vaccines, all use adenovirus vectors and are only domestically approved against one of the domestic Covid-19 vaccine injections but have not yet been welcomed in bigger markets like the U.S. and the EU.

Why are nasal vaccines not more common?

Despite these successes, it appears that nasal vaccines have not yet attained the high expectations of researchers.

For starters, there seem to be few studies conducted on nasal vaccines thus far and the results published are also conflicting. One study indicates that the protective effect conferred by nasal mucosal IgA antibodies is maintained only for roughly seven months. Also, the study suggested that IgA antibodies wane faster than other antibodies, and thus booster shots would likely be required more frequently. Meanwhile, another study suggested that longer-term immunity can be achieved, for up to one year.

According to the CDC, the nasal spray vaccine was found to be effective against different flu viruses before the 2009 flu pandemic. After this period, however, several U.S. studies showed that it was as effective against influenza B viruses and influenza A(H3N2) viruses as inactivated influenza vaccines. However, it was less effective than inactivated flu vaccines against the 2009 pandemic H1N1 viruses leading the CDC to recommend against the use of the nasal spray vaccine for the 2016-17 and 2017-18 seasons.

Subsequently, nasal spray vaccines have been manufactured with new influenza A(H1N1) virus ingredients but due to limited use, it is still difficult to estimate effectiveness.

Although Covid-19 spurred the momentum for the development of nasal vaccines, they have not publicly published clinical data so it is also hard to compare. For example, AstraZeneca also used the same adenovirus platform but yielded dismal results in phase 1 studies for its nasal vaccine candidate.

“The reason why the nasal vaccine was not effective was that the vaccine sprayed in the nose was swallowed into the esophagus through the throat,” explained the U.K. researchers. They proposed increasing the concentration of the vaccine or increasing the amount of the vaccine to improve the amount that sticks to the inner wall of the respiratory tract.

Domestically too, researchers have been struggling. 

GeneOne Life Science was developing a Covid-19 infection prevention nasal spray treatment, GLS-1200. In a public filing, it also said that it expects to receive approval for phase 3 clinical trials in the first quarter of 2022 and product approval in the third quarter of 2022 for GLS-1200. Still, the company terminated the phase 2 study.

SK Bioscience is now the only domestic intranasal Covid-19 vaccine manufacturer but is still conducting early-phase research. Together with the International AIDS Vaccine Initiative (IAVI) and the Bill and Melinda Gates Foundation (BMGF), they are developing an antiviral nasal spray that is expected to offer both preventative and therapeutic functions. It works by using a small protein to create a protective layer inside the upper respiratory tract to prevent the virus from penetrating the body and may alleviate symptoms of an established infection by disrupting the virus’ ability to replicate.

An official from SK Bioscience explained that this mechanism can also be used to target other respiratory viruses other than Covid-19. For example, RSV and influenza are other respiratory viruses that can equally benefit.

Although nasal vaccines are promising, it appears that more research is needed before they can replace intramuscular vaccines. Additionally, real-world efficacy studies for the recently released Covid-19 nasal vaccines will be required to prove their worth against their intramuscular counterparts and clarify the conflicting study results that currently exist.