The potential efficacy of nasal nanoparticle COVID-19 vaccines

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the ongoing outbreak of coronavirus disease 2019 (COVID-19) that has taken over 6 million lives so far. With the emergence of new variants, the virus evades immunity elicited by natural infection or vaccination with the ancestral strain. A new paper discusses the potential efficacy of nasal vaccines to counter this threat and provide sterilizing immunity.

Study: Nasal Nanovaccines for SARS-CoV-2 to Address COVID-19. Image Credit: Pazargic Liviu/Shutterstock
Study: Nasal Nanovaccines for SARS-CoV-2 to Address COVID-19. Image Credit: Pazargic Liviu/Shutterstock


The search for effective measures to counteract the morbidity and mortality caused by SARS-CoV-2 infection led to the repurposing of drugs like remdesivir, hydroxychloroquine, azithromycin, and tocilizumab. However, these have not shown adequate efficacy or have severe adverse effects.

This spurred the development of effective vaccines based on the viral spike antigen or using the whole virus in an inactivated form. Over 200 vaccines have passed initial development, and billions of doses of vaccines have been distributed worldwide. However, there are significant hindrances to controlling the pandemic through vaccination.

These include vaccine hesitancy and unwillingness, fears of vaccine-associated risks, and a lack of confidence in vaccine efficacy and safety. There is still a need to develop a vaccine that is undoubtedly safe and efficacious. The current paper, published in the journal Vaccines, reviews progress in this field regarding nasal nanoparticle vaccines for COVID-19.

As of now, nanoparticles (NPs) are gaining much attention as the delivery platform for vaccines to deliver the antigen to the living organism while enhancing the immune response and producing greater cross-reactivity. NPs in SARS-CoV-2 vaccines may play different roles, including promoting the vaccine uptake, mimicking the virus, or protecting the antigen from degradation. NPs may be polysaccharides, lipids or proteins, polymers, or biomimetics.

Liposomes are membrane-bound vesicles that can enter the cell via endocytosis, with strong adjuvant properties. Newer lipid NPs are being developed, including solid LNPs, virosomes, and lipid nanocapsules.

Self-assembled proteins fused with inactivated viruses or viral antigens can form safe molecules that easily enter the host cell to produce an immune response. Indeed, ferritin self-assembled NP nasal vaccines are undergoing clinical trials.

Virus-like particles (VLPs) of the same size and form as viruses but sans the genetic material promise to be very effective as vaccines while being devoid of any infectious risk. Several candidate VLP vaccines are being developed. Other promising molecules include capsid-like molecules and a nucleic acid vaccine encoding SARS-CoV-2 VLPs.

Poly(D,L-lactic-co-glycolic acid), or PLGA, is the most common synthetic polymer NP used in vaccine development. It is highly biocompatible and biodegradable, with sustained release characteristics as well as the ability to prevent antigen degradation.

Antigens are studded on the surface of the NP to form a virus-size particle or encapsulated in a nanovesicle. The use of liposomes or cationic polysaccharide NPs can enhance antigen entry into the cell.

The advantages of nasal vaccines

A nasal vaccine avoids the use of a syringe and is thus non-invasive, bolstering its public acceptance while averting the need for technically skilled staff to administer it. Nasal vaccines are part of mucosal vaccines, including oral and aerosol vaccines.

These target the mucosal-associated lymphatic tissues (MALT) of the nose, gut, lungs, and other body orifices. Oral vaccines may be digested by gastric enzymes or acid, rendering them ineffective. Aerosol vaccines elicit both mucosal and systemic immunity via the bronchus-associated lymphatic tissue (BALT).

In the current situation, faced with a respiratory virus, nasal vaccines appear to be ideal and the easiest to administer. Not only is the nose the entry site of the virus, it first encounters this pathogen. Its mucosa is thus the most important and first-line defense of the body against SARS-CoV-2.

Antigen-presenting dendritic cells present the viral antigens to the nasopharynx-associated lymphatic tissue (NALT) throughout the oropharynx and nasopharynx, stimulating both mucosal and systemic immunity. Anti-spike and anti-envelope SARS-CoV-2 antibodies can neutralize the corresponding antigens and the virus within the dendritic cells.

After NPs enter the nasal cavity, they linger briefly in the nasal mucosa before entering the epithelial cells of the airway. The time spent in the mucus is dependent on the size of the NPs, the charge, and chemical composition. The best response has been observed with nanovaccines of 20-80 nm size.

Both passive entry as well as endocytosis have been noted to occur in the nasal mucosa. They may be directly captured by dendritic cells or by M cells. Once this occurs, mucosal immunity is elicited, preventing future viral entry more effectively than the humoral immunity produced by injectable vaccines.

This is because nasal vaccines produce high levels of neutralizing antibodies as well as immunoglobulin A (IgA) and T cell responses in the mucosa that clear the virus from the upper and lower respiratory tract. Antigen-specific IgA prevents viral adherence to and infection of the epithelium, thus safeguarding the mucosal barrier. IgA antibodies are not typically produced by intramuscular vaccines. 

In contrast to the use of live attenuated viruses, inactivated vaccines, and vector-based vaccines, NPs are safer and better controlled while being less likely to be neutralized by antibodies and capable of being taken up by the cell more efficiently. In addition, NP vaccine development may be nimbler in the face of the repeated emergence of new escape variants of SARS-CoV-2, threatening herd immunity.


With much higher acceptability, multiple advantages in the mechanism and scope of immunity, higher safety margins, and an increasingly broad array of structures that offer specific benefits for vaccine delivery, nasal nanovaccines appear to be an attractive option for the achievement of global immunization against COVID-19.  

Journal reference:
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.


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