COVID-19 is still a global pandemic. Around the world, as of 5:40pm CEST, 20 June 2022, there have been 536,590,224 cumulative confirmed cases of COVID-19, including 6,316,655 deaths, reported to the World Health Organization. As of 16 June 2022, a total of 11,902,271,619 vaccine doses have been administered. The adoption of vaccines worldwide continues to increase, yet periodic spikes and surges in infection rates continue to occur with new SARS-CoV-2 variants, such as that observed in Australia over the past few months. Vaccine booster doses provide effective protection against developing severe disease and hospitalization, but vaccine adoption and distribution face ongoing challenges in low- and middle-income (LMIC) countries (1). Therapeutic interventions for those already infected are in development, with one (Paxlovid) currently available under emergency use authorization (EUA) in the US.
Cumulative COVID-19 statistics by country: WHO COVID-19 Dashboard. Geneva: World Health Organization, 2020. Available online: https://covid19.who.int/ (last cited: June 20, 2022).
Current COVID-19 vaccines, although diverse in composition (mRNA, adenoviral vector-based and protein subunits) have one feature in common: the route of administration. They are all administered by intramuscular injection. Intramuscular vaccines generate a systemic immune response, producing antibodies against the virus that circulate through the blood to other parts of the body. While these intramuscular vaccines have proven effective against developing severe symptoms of COVID-19, they do not necessarily stop viral infection at the source—the mucous membranes of the upper respiratory tract—as discussed previously. A systemic immune response is mediated primarily by immunoglobulin G (IgG), while mucosal immunity is mediated primarily by IgA, and protection of the nasal passages happens only at high titers of IgG (2).
It seems logical to develop vaccine strategies that treat the infection at the source, repelling invaders at the gates before they have a chance to run amok within a city. Although early COVID-19 vaccine development efforts did include intranasal vaccines, they were in the minority, and relatively little attention has been paid to intranasal vaccine strategies in the mainstream media—until recently.
Last month witnessed a surge of interest in COVID-19 intranasal therapies, with media coverage by Scientific American, PBS News Hour and the New York Times, among others. These articles focused on results from preclinical (animal model) trials of several intranasal vaccine candidates. An overview of some recently published results for intranasal COVID-19 vaccines follows.
Vaxart Inc. released a preprint of data from their preclinical studies of three COVID-19 candidate vaccines (3). These vaccines were based on a replication-deficient recombinant adenoviral vector, developed previously, that showed effectiveness against other respiratory viruses. The vaccine platform used was originally developed for oral administration in tablet form. However, due to the difficulty of administering an oral formulation in animals, a liquid formulation was delivered intranasally in this study. The researchers tested viral constructs expressing the SARS-CoV-2 Spike (S) protein alone or together with the nucleocapsid (N) protein, from the original SARS-CoV-2 strain as well as the beta variant, in cynomolgus macaques. The original strain S protein elicited strong cross-reactive responses against the original SARS-CoV-2 strain, as well as against beta, gamma and delta SARS-CoV-2 variants. The same vaccine candidate induced 1,000-fold increases in IgA against all variants of concern tested, based on nasal sampling, and showed neutralizing activity against the original and delta variants of SARS-CoV-2.
Two studies in mice used protein subunit vaccines containing the receptor-binding domain (RBD) of the SARS-CoV-2 S protein. In the first study, the RBD (either the original strain or omicron) was fused to a subdomain of the N protein and administered intranasally to mice as a booster after two doses of a standard mRNA intramuscular vaccine (4). The single-dose omicron booster induced systemic and mucosal antibody responses, and it potently enhanced neutralizing activity against SARS-CoV-2 omicron infection. In the second study, three-dose immunization in mice with an adjuvanted intranasal RBD vaccine induced and maintained high levels of serum neutralizing IgG antibodies for at least 1 year (5). The vaccine also produced strong mucosal immunity, based on secretory IgA levels.
Results of another study in mice, published as a preprint, examined a vaccination strategy using an intranasal booster vaccine containing unadjuvanted S protein, after intramuscular immunization with an mRNA-based vaccine (6). This strategy produced high IgA levels at the respiratory mucosa, boosted systemic immunity, and completely protected mice with partial immunity from lethal SARS-CoV-2 infection.
Ongoing Clinical Trials
At the time of writing, there are seven intranasal vaccines in clinical trials (summarized in a table here and reviewed in 7). The types of vaccines being tested include viral vectors, live-attenuated viruses and a protein subunit. No preliminary data have been published as yet.
|Vaccine Platform||Type||Doses||Developers||Current Phase||Phase 1||Phase 1/2||Phase 2||Phase 3|
|VVnr||ChAdOx1-S – (AZD1222)|
|1-2||AstraZeneca, University of Oxford||Phase 1||NCT04816019|
|VVr||DelNS1-2019-nCoV-RBD-OPT1 (Intranasal flu-based-RBD )||2||University of Hong Kong, Xiamen Universit and Beijing Wantai Biological Pharmacy||Phase 3||ChiCTR2000037782 NCT04809389||ChiCTR2000039715 NCT05200741||ChiCTR2100051391 PACTR202110872285345|
|LAV||COVI-VAC||1-2||Codagenix, Serum Institute of India||Phase 3||NCT04619628 NCT05233826||ISRCTN15779782|
|PS||CIGB-669 (RBD+AgnHB)||3||Center for Genetic Engineering and Biotechnology (CIGB)||Phase 1/2||RPCEC00000345|
|VVnr||BBV154, Adenoviral vector COVID-19 vaccine||1||Altimmune,* Bharat Biotech International Limited||Phase 3||NCT04751682||CTRI/2022/02/040065|
|LAV||MV-014-212, a live attenuated vaccine that expresses the spike (S) protein of SARS-CoV-2||1||Meissa Vaccines, Inc.||Phase 1||NCT04798001|
|VVnr||PIV5 vector that encodes the SARS-CoV-2 spike protein||1||CyanVac LLC||Phase 1||NCT04954287|
*Altimmune has discontinued further development of AdCOVID; therefore, the candidate vaccine has been removed from the landscape summary analysis. Vaccine platforms: LAV, live attenuated virus; PS, protein subunit; VVnr, viral vector (nonreplicating); VVr, viral vector (replicating). Data from the WHO Vaccine Tracker; last updated June 17, 2022.
Challenges and Opportunities
Intranasal vaccines, while showing significant promise, also face some challenges. While the route of administration is easier than intramuscular injections, making them particularly attractive for young children (like the FluMist influenza vaccine), ensuring the correct dose is administered can be difficult (Mouro, 2022). For example, the recipient could sneeze out part of the vaccine, resulting in a lower effective dose than administered. Further, the thick mucus layer in the upper respiratory tract may hinder the absorption of vaccine components. The IgA response in the mucosa is typically short-lived, so repeated doses of the intranasal vaccine may be required to provide effective protection. Interestingly, a novel approach to overcoming some of these problems may lie in the use of nanomaterials as delivery vehicles (reviewed in 8, 9).
Despite these challenges, the advantages of intranasal vaccines—lower production, storage and distribution costs—coupled with their noninvasive route of administration make them an attractive option to prevent COVID-19 infection at the source. A combination of current intramuscular vaccines followed by intranasal boosters may prove to be the best defense against SARS-CoV-2 infection.
Learn about tools to study SARS-CoV-2 with our SARS-CoV-2 Drug Discovery and Vaccine Development page.
- Mobarak, A.M. et al. (2022) End COVID-19 in low- and middle-income countries. Science 375(6585), 1105.
- Lund, F.E. and Randall, T.D. (2021) Scent of a vaccine: Intranasal vaccination should block SARS-CoV-2 transmission at the source. Science 373(6553), 397–399.
- Flitter, B.A. et al. (2022) [preprint] Mucosal immunization of cynomolgus macaques with adenoviral vector vaccine elicits neutralizing nasal and serum antibody to several SARS-CoV-2 variants. bioRxiv doi: https://doi.org/10.1101/2022.02.21.481345
- Lam, J.-Y. et al (2022) A nasal omicron vaccine booster elicits potent neutralizing antibody response against emerging SARS-CoV-2 variants. Emerg. Microbes & Infect. 11(1), 964–967.
- Lei, H. et al. (2022) Intranasal administration of a recombinant RBD vaccine induces long-term immunity against Omicron-included SARS-CoV-2 variants. Signal Transduct. Target Ther. 7, 159.
- Mao, T. et al. (2022) [preprint] Unadjuvanted intranasal spike vaccine booster elicits robust protective mucosal immunity against sarbecoviruses. bioRxiv doi: https://doi.org/10.1101/2022.01.24.477597
- Mouro, V. and Fischer, A. (2022) Dealing with a mucosal viral pandemic: lessons from COVID-19 vaccines. Mucosal Immunol. doi: https://doi.org/10.1038/s41385-022-00517-8
- Wilson, B. and Geetha, K.M. (2022) Nanomedicine to deliver biological macromolecules for treating COVID-19. Vaccine doi: https://doi.org/10.1016/j.vaccine.2022.05.068
- Tang, J. et al. (2022) Nanotechnologies in delivery of DNA and mRNA vaccines to the nasal and pulmonary mucosa. Nanomaterials 12, 226.
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