Are Intranasal Vaccines A Better Approach To Combat SARS-CoV-2?

By Ashley Lai 

The UK government has announced a month-long lockdown regarding the worsening situation of SARS-CoV-2 starting on the 5th of November.  The novel coronavirus has now infected over 46 million and caused the death of over 1 million people worldwide (Centre for Systems Science and Engineering, 2020). To combat the disease and avoid further lockdowns, pharmaceutical companies with various vaccine candidates are competing against time to win the race for an effective SARS-CoV-2 vaccine. Herd immunity with the aid of vaccines is no doubt one of the trending topics in the life science community.

SARS-CoV-2 is an airborne disease that can be transmitted through respiratory droplets. The coronavirus S1 subunit of a spike glycoprotein binds to the cell surface membrane receptor, carboxypeptidase angiotensin-converting enzyme 2 (ACE-2). TMPRSS2, a transmembrane serine protease in the host cell cleaves the ACE-2 receptor and activates the fusion by changing the conformation of the S2 subunit of the virus to form an endosome. The endosome is then acidified, and the virus is released by cathepsin, a cysteine protease inside the host cell (Heurich et al., 2014). Cells that line the airways, the lungs and intestine are found to be the main target of the virus. Single-cell RNA sequencing showed it is mainly the goblet secretory cells and type II pneumocytes expressing RNAs of proteins that are required for SARS-CoV-2 invasion. Goblet secretory cells produce mucus in the nasal passage where type II pneumocytes help to keep the alveoli of the lungs open (Trafton, 2020).

The mucosal immune system has been specialised to prevent the invasion of airborne viruses. Goblet cells and mucus sub glands produce different types of mucins, (MUC1, MUC4, MUC5A, MUC5B and MUC16) to cover the nasal cavity surface, trapping any small pathogens. The mucosal surface is lined by immune cells known as Mucosa-Associated Lymphoid Tissues (MALT), producing a local immune response against pathogens. A sub-compartment of MALT is called the Nasopharynx-Associated Lymphoid Tissue (NALT), located in the nasal mucosal immune system. Foreign antigens are recognised by antigen-presenting cells and taken to the NALT by memory cells in the epithelial cell layers. The immune response is activated when the antigens are presented to T cells. Immunoglobulin A (IgA) is produced by the MALT, where it exists as a dimer of a secretory component polypeptide chain and a joining J-chain polypeptide. Polymeric Ig receptor is cleaved by proteases to release the nasal IgA into the mucus and it sterically blocks the foreign antigen from binding to the surface of the epithelium (Yusuf and Kett, 2017).

SARS-CoV-2 usually invades humans initially through the upper respiratory tract and results in symptoms such as coughing and sore throat. Therefore, intranasal vaccines with the same entry route can possibly be used as an alternative way for more effective vaccination compared to traditional intramuscular injections. With the enhanced humoral and cell-mediated immune responses in both local sites and the whole system, intranasal vaccines involving the stimulation of cells of NALT offers more comprehensive protection against the 70% of pathogens that use the mucosal surfaces for invasion. Besides, this method of vaccination is non-invasive so it can lower the risk of blood-borne diseases’ transmission as well as the costs (Xu et al., 2014).

A study by the School of Medicine at Washington University has compared both methods of vaccination in stimulating the immune response of mice against SARS-CoV-2. Results show intranasal vaccination induced a higher level of anti-SARS-CoV-2 IgA antibodies in the lungs and serum. Other than lowering the symptoms severity, the induced IgA can also prevent infections of different virus strains. A large number of memory T cells, CD103+, CD69+ were found in the lungs with a low number of viral RNA detected in the upper respiratory tract, implying infection and inflammation in upper and lower respiratory tracts are less likely. However, this sterilizing effect is not present for intramuscular injection. Also, B cells that synthesize IgA antibodies were not detected in the spleen of mice. With the additional mucosal immune response shown, intranasal delivery offers better protection against both the normal and D614 variant SARS-CoV-2 with a stronger induced local immune response in the initial location of the infection (O. Hassan et al., 2020). However, the effectiveness of the intranasal vaccine in generating human immune response is still questionable as many intranasal vaccine candidates for SARS-CoV2 are still in the pre-clinical trial phase.

Safety concerns have been raised when a severe side effect, facial nerve paralysis (Bell’s palsy), was developed after the usage of a dose of intranasal influenza vaccine, named NasalFlu. The project was withdrawn after 2 cases of Bell’s palsy were reported. Accumulation of the mutant LT adjuvant in the vaccine was later proved to be the cause as it interferes with the peripheral nerve function (Lewis et al., 2009). Enterotoxin adjuvant may enter the central nervous system (CNS), bypassing the blood-brain barrier to cause serious damages. Hence, developers of intranasal vaccines must consider the inflammation effect of the adjuvants carefully to lower any risks to the CNS. Another challenge faced by the developers is the physical barrier of the nasal passage. The effectiveness of intranasal vaccines may be greatly reduced if it is trapped and diluted by the mucosal fluids, leading to the degradation by enzymes in the mucus. The ciliated epithelium may remove mucus with the vaccine contents from the nasal passage to the nasopharynx before it initiates a strong immune response (Xu et al., 2014).

In conclusion, intranasal vaccines provide a more comprehensive solution compared to the traditional intramuscular vaccines. Developed by the University of Hong Kong in collaboration with Xiamen University and Wantai Biopharmaceutical, the first SARS-CoV-2 intranasal vaccine candidate has been approved for the clinical trial last month, which holds great potential in combatting and possibly eliminating the virus with further studies.


Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU). (2020) ‘COVID-19 Map – Johns Hopkins Coronavirus Resource Center’. Available from: [Accessed 31/10/2020]. 

Heurich, A., Hofmann-Winkler, H., Gierer, S., Liepold, T., Jahn, O. & Pohlmann, S. (2014) TMPRSS2 and ADAM17 Cleave ACE2 Differentially and Only Proteolysis by TMPRSS2 Augments Entry Driven by the Severe Acute Respiratory Syndrome Coronavirus Spike Protein.   J Virol. 88 (2), 10/31/2020. Available from: [Accessed 10/31/2020]. 

Lewis, D. J. M., Huo, Z., Barnett, S., Kromann, I., Giemza, Rafaela, Galiza, Eva & Rappuoli, R. (2009) Transient Facial Nerve Paralysis (Bell’s Palsy) following Intranasal Delivery of a Genetically Detoxified Mutant of Escherichia coli Heat Labile Toxin. PLoS One. 4 (9). Available from: [Accessed 10/31/2020]. 

O. Hassan, A., M. Kafailgor, N., P. Dmitriev, I., M.Fox, J., K. Smithlan, B. & B. Harvey, I. (2020) A Single-Dose Intranasal ChAd Vaccine Protects Upper and Lower Respiratory Tracts against SARS-CoV-2. Cell. 183 (1). Available from: [Accessed 10/31/2020]. 

Trafton, A. (2020) Researchers identify cells likely targeted by Covid-19 virus. MIT News. 04/22/2020. Available from: [Accessed 10/31/2020].

Xu, Y., Yuen, P. & Lam, J. K. (2014) Intranasal DNA Vaccine for Protection against Respiratory Infectious Diseases: The Delivery Perspectives. Pharmaceutics. 6 (3). Available from: [Accessed 10/31/2020]. 

Yusufa, H. & Kettb, V. (2017) Current prospects and future challenges for nasal vaccine delivery. Hum Vaccin Immunother. 13 (1). Available from: [Accessed 10/31/2020]. 

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