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Why are scientists developing intranasal therapies to treat COVID-19 infections?

The nasal and respiratory tracts are the primary sites of SARS-CoV-2 infections. Since these regions highly express the ACE-2 receptors, the virus can easily enter and cause severe respiratory disorders and pneumonia. Many of the treatments and vaccines are administered through the intramuscular (IM) route. By the time the therapeutic components of these reach the lungs through the bloodstream, the effectiveness would reduce and is not enough to completely clear out the viral population. 

Many scientists are coming up with intranasal therapies to efficiently ward off infection and protect the respiratory tracts. Since they are administered via the intranasal route, the antibody response will be more robust in clearing out the infection from the nasal and pulmonary regions. These therapies also have the potential of not allowing the virus to reach the lungs. The nasal vaccine candidates can reduce the expression of pulmonary ACE-2 receptors and prevent the COVID-19 infection. These nasal options also have the added advantage of increased patient compliance as it gets rid of the fear and hesitation of injections. 

A team at The University of Texas Health Science Center wanted to improve on the available antibody therapy. The protective antibodies bind to the receptor-binding domain of the SARS-CoV-2 virus. They developed an IgM antibody from convalescent IgG antibodies which was administered through the intranasal route. These engineered IgM antibodies also protected against the various SARS-CoV-2 variants. The results of the study were published in Nature as a preview paper. 

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Antibodies are of five types: IgG, IgM, IgA, IgE and IgD. The first antibody formed against an infection is the IgM type whereas the IgG type being more effective gets generated a little later and completely clears out the infection. The IgA antibodies are released along with the mucosal immune response. The current monoclonal antibody treatment involves taking IgG antibodies from convalescent plasma and injecting them into the patients via the IM route. For the IgG antibodies to be effective, they should be administered at extremely high doses at around 8g/ml and even then, the antiviral effect is not enough.

Each singular antibody has two antigen recognising sites or antigenic determinants (valency). The IgM antibody is a pentamer and is hence decavalent, indicating its high neutralising ability as compared to the monomeric IgG antibody. The scientists combined five IgG antibodies with an engineered CR3022 anti-covid antibody resulting in the formation of a pentameric IgM-14 antibody.  

IgM-14 was capable of inducing an immune response at a concentration as low as 0.4mg/kg when administered into mice. A single dose was enough to neutralise and lower the viral load in the nasal regions and lungs, thus providing prophylactic and therapeutic efficacy. These antibodies remained active upto 168 hours in the lungs. The IgM-14 antibodies were also found to protect the mice against the SARS-CoV-2 variants of concern such as the B.1.1.7, P.1 and B1.351 strains. 

On 7th June, 2021, Prime Minister Narendra Modi had announced that the research for the new nasal vaccine is underway. The CDSCO had approved conducting the Phase II trials of the new nasal COVID-19 vaccine in January, 2021. The BBV154 vaccine formulated by Bharat Biotech is an inactivated Chimpanzee Adenovirus having stabilised spike protein was seen to prevent SARS-CoV-2 lung infection and pneumonia in mice. The Phase I trial results were published in Cell. This vaccine is capable of inducing the formation of neutralising IgG antibodies, mucosal IgA antibodies and potent T-cell responses. This vaccine is unique since it is a non-invasive approach and works similar to the flu shot. 

Scientists at the Pittsburgh School of Medicine have developed inhalable nanobodies which when delivered in the aerosol form, treated SARS-CoV-2 infections in Syrian hamsters. Another study even explained how people who took inhaled corticosteroids for Asthma and other Chronic Obstructive Pulmonary Disorders, were protected from the SARS-CoV-2 infections. 

The intranasal options are still in the early phase trials and further studies need to be conducted especially for the BBV154 vaccine and the engineered IgM-14 anti-SARS-CoV-2 antibodies to determine its efficacy. Having these non-invasive options can make prophylactic treatments more available to everyone and can accelerate the vaccination drive and completely eradicate the deadly SARS-CoV-2 infections.

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