Explained: Intranasal Vaccines, Their Effectiveness and Challenges in Making

This nasal vaccine will be used as a booster shot for those who have been inoculated against COVID-19 with two doses of the intramuscular vaccines such as Covishield and Covaxin. It will be administered as a spray or nose drop to 1 billion individuals making it non-invasive, needle free and easy to administer.

Bharat Biotech announced a licensing agreement with American vaccine company Precision Virologics and Washington University School of Medicine to advance intranasal vaccine technology in September 2020. Bharat Biotech owns the rights to distribute the vaccine in all markets except the USA, Japan and Europe.

Nasal spray vaccines have been only used for flu-related illnesses in the past as there have been several setbacks in the development stages of such vaccines.

How Effective are Nasal Vaccines?

Since the entry route for SARS-CoV-2 is generally via the nose, nasal vaccines aim to target the virus present in the mucous in the nose instead of injecting it into the vein. All existing COVID-19 vaccines are intramuscular injections which trigger body-wide immune responses whereas nasal vaccines trigger primary local response because it targets the site of infection.

Mucosal vaccines can, in principle, trigger mucosal Immunoglobulin A (IgA) antibodies, found in the linings of the respiratory tract (antibodies that act as the first line of defence in the resistance against infections). And, intramuscular vaccines primarily produce a lot of Immunoglobulin G (IgG) which is less effective at mucosal surfaces, said experts.

"If potent, nasal vaccines can provide transmission blocking immunity, whereas intramuscular vaccines provide disease severity-reducing immunity," said Dr Vineeta Bal, immunologist and visiting professor at Indian Institute of Science Education and Research in Pune.

When local IgA antibodies triggered by mucosal vaccines are present in sufficient amounts, chances of virus infecting ACE2 expressing cells in the nasal and pharyngeal epithelial cells goes down significantly. Antibodies will bind the virus and hence are likely to block entry into and further replication in the cells. Hence, the infection can be locally nipped in the bud, before the local virus replication takes place, she explained.

Intranasal vaccines can thwart transmission by reducing virus load at mucosal surfaces. "Vaccines inoculated on mucosal surfaces like mouth (open to stomach and intestines) and nose (open to throat, windpipes and lungs) have their attractions because it mimics natural route of entry of the microbe and induce mucosal immunity that should protect against infection itself," said Dr TJ John, virologist and former professor at the Christian Medical College, Vellore. Administering nasal vaccines would also require less trained personnel, he added.

Further, a December 2021 study led by scientists from the Yale School of Medicine found that local vaccines administered with a nasal spray were more effective in protecting mice against influenza than standard flu shots administered via needles.

According to lead scientist Akiko Iwasaki, the study found that nasal vaccines provided cross-protective long-lasting immunity within the respiratory mucosa. On the frequency of delivery of such vaccines compared to an injected vaccine, Iwasaki, in a discussion, said, "The beauty of the local mucosal vaccine is that not only does it provide protection acutely, but also it's a long-lasting immunity. What happens is that these T-cells and B-cells come into that mucosal surface and they remain there and they become what's known as tissue-resident memory cells."

Challenges in Developing Intranasal Vaccine

Developing intranasal vaccines has been a challenging task in the past. For instance, FluMist, a nasal vaccine first approved in 2003 was briefly removed due to efficacy issues. Another intranasal influenza vaccine developed in Switzerland reported 46 cases of Bell's Palsy or facial paralysis. In 2021, biopharmaceutical company Altimmune stopped testing a nasal COVID-19 vaccine candidate due to trial setbacks.

According to Dr Bal, making of the nasal vaccine comes with various hurdles such as:

1. Ability to manufacture the live attenuated virus at a very high concentration or ability to concentrate it after production without changing properties.

2. Immunogenicity of the vaccine in different animal models and in humans.

3. Optimising volume to be used for spraying and if that can accommodate the dose.

4. How well the nose absorbs the dose.

The virologists also highlighted technical issues that should be carefully considered. "Mucosal surfaces of nose and mouth and their extensions are the open doors for innumerable microbes for entry and also for innumerable things we breathe in and swallow. Since nature's norm is to mute immune responses in general, the path of development and use has to be very carefully carved," he said.

Bharat Biotech requires 5,000 healthy individuals to participate in their Phase 3 clinical trials. This is a challenging task because more than 4.28 crore people in India have been diagnosed with COVID-19 and over 96% of the population in the country have been vaccinated with the first COVID-19 vaccine. This means they have antibodies against the virus. When it comes to efficacy, Bal stressed on the fact that in most tropical countries, mucosal vaccines trigger poorer immune response as compared to developed countries.