Is the future of vaccines intranasal?

24 Jan 2024 10min read

In recent years there has been considerable interest in developing intranasal COVID vaccines, with several in clinical development globally and a small number approved in countries such as India and Russia. New data has shown the potential for better efficacy with an intranasally-administered COVID vaccine, compared with the standard delivery route of an intra-muscular injected vaccine. This is perhaps not surprising, considering that COVID is a respiratory tract infection, and intranasal vaccines provide a targeted local delivery to the upper respiratory airway mucosa. Building immunity directly in the nasal mucosa also has better potential to prevent disease transmission, since the nasopharynx is the body’s first encounter with infectious aerosols. Early clinical data for intranasal vaccines suggest they avoid side-effects such as “flu symptoms” associated with existing COVID vaccines. 

This growth in interest for intranasal vaccine delivery follows a trend of steady development of intranasal flu vaccines. One of those, FluMist/Fluenz Tetra, has been available to patients in US and EU markets for several years now. If a COVID intranasal vaccine is successful in reducing transmission rates, where the current intramuscular vaccines cannot, then this may increasingly become the delivery route of choice for vaccine developers, particularly for respiratory tract infections. 

Intranasal delivery is also a growing route of interest for systemic drug delivery to the bloodstream for several medicines. Drugs such as analgesics and treatments for migraine, osteoporosis and sexual dysfunction, are all now established as intranasal therapies. Most recently, anti-anxiety/depression medication and opiate overdose reversal have also joined them. Currently, intranasal delivery is an important area of research for delivery of biological large molecules such as peptides or mRNA, because it bypasses the gastrointestinal route and the potential for digestive destruction of these sensitive compounds. 


  1. What are the benefits of intranasal delivery?
  2. What challenges are associated with intranasal delivery?
  3. Key intranasal device design considerations
  4. Intranasal product performance testing
  5. What are the potential opportunities in intranasal delivery?

What are the benefits of intranasal delivery?

Intranasal offers pain-free delivery that can be administered at home, without exposing patients to the risks of sharing a closed space with other potentially infected people, among other downsides associated with attending health clinics, such as the inconvenience or accessibility-barriers of travel. Furthermore, individuals with needle phobia (or other anxieties about the perceived invasiveness of an injection) may be more likely to accept an intranasal vaccine.  

Intranasal delivery of dry powder formulations is a particularly interesting option. Although it is in its infancy, this approach offers the possibility of avoiding cold chain transport and storage. Doing so would not only improve product shelf life and reduce product wastage, it would also avoiding the considerable energy and carbon costs of low temperature supply chains. Adopting this dry powder technology could also be key to improving vaccine access within remote, deprived communities. 

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What challenges are associated with intranasal delivery?

Despite its obvious advantages, intranasal delivery does bring some challenges compared to injection. This includes a comparatively high dose variability, resulting from factors such as product shaking before use, plume velocity and length of actuation stroke, angle and depth of insertion to nasal cavity, as well as nasal cavity geometry and mucociliary clearance rates. It is therefore necessary to ensure adequate provision of user information on dose-critical steps like shaking or angle of insertion.  

There are also compliance and adherence challenges around the use of an intranasal vaccine during a pandemic. If users are given a vaccine to take at home, how can public health authorities have confidence that the vaccine was taken and that the efficacious dose was delivered? In addition, there is a need to develop intranasal immune biomarkers to measure vaccine efficacy. This is because systemic immune responses are typically low for intranasal vaccines and are not the most relevant or important efficacy measure for an intranasal vaccine. Rather, the level of intranasal immunity is more important with regards to preventing disease infection or transmission. 

In addition to these challenges, there are also a number of key device design considerations that intranasal device manufacturers should be aware of. 

Key intranasal device design considerations

Various device options exist for intranasal delivery that could feasibly be used to deliver vaccines, with aerosolised liquid spray pumps currently dominating the market. Most relevant to vaccine delivery are unit-dose, bi-dose (one for each nostril) formats, but multidose devices also exist. Other options include dropper, pressurised gas canister and dry powder devices. Side actuated devices are also available, which can provide a more comfortable user-experience compared with vertically actuated nasal pumps where the patient’s hand may be at an awkward angle and fingers can obstruct placement of the nozzle within the nostril. 

Liquid spray pump devices typically deliver a pre-metered dose of a solution such as a vaccine. Historical products have also included viscous suspensions. They may also be preservative free, requiring robust sealing against the external environment. The spray is typically formed via either a standard orifice or swirl atomisation. For swirl atomisation, a tiny vortex is created within a swirl chamber and as this vortex moves out of the nozzle, centrifugal forces cause it to spread outwards and form a hollow cone. As the hollow cone spreads, the fluid continues to thin until eventually it breaks up, initially into liquid-filaments and then into droplets which deposit in the nasal passages. The nozzle orifice and swirl chamber geometry all play an important role in controlling spray formation and its characteristics. These in turn affect what proportion of the dose penetrates the nasal cavity or is deposited on the external nares, and the vaccine dose delivered to the immune active cells in the mucosa. 

The form of the stem is also critically important, since this influences how well the spray orifice is aligned with the nasal valve in the nostril. The stem must be sufficiently long and narrow to fully enter the nostrils, but not so long and narrow that there is a risk of it being placed in the nasal valve itself. Stem orientation at the point of spraying has been shown to be critical to dose delivery, therefore ergonomic device features that can aid this are often beneficial. 

Intranasal product performance testing

Critical parameters for drug delivery include shot weight and single actuation drug content, alongside the spray characteristics of spray pattern, plume geometry and droplet size distribution. Spray characteristics can impact where and over how large an area in the nasal cavity the dose is delivered, or indeed if it is delivered there at all. In many cases the aim is to deliver to the highly vascularised nasal turbinates, which means directing the spray through the narrow nasal valve.  

Vaccines delivered to the turbinates typically pass via mucociliary clearance to the Nasal-Associated Lymphoid Tissue (NALT), where a strong immune response can be generated. Any portion of the dose impacting the nares will drain out and will be lost. Droplets smaller than 10 µm may pass through the nasal passages to the lungs, where they may contribute to local side-effects. The optimal droplet size is therefore one which is sufficiently small to generate a soft spray on impact with sensitive nasal tissues that is comfortable to users, but with the vast majority of droplets being larger than 10 µm. 

Regulators such as the EMA and FDA stipulate how critical performance parameters should be measured for intranasal products. Shot weight may be obtained gravimetrically, whilst single actuation content (dose) is measured via a suitable quantitative analytical method to determine the local drug concentration. Spray pattern and plume geometry measurements can be obtained using laser imaging of the spray in axial and transverse planes. Droplet size distribution is measured using laser diffraction, a light scattering particle measurement technique. Automated actuation is preferrable, to ensure consistency, however, actuation profiles should be guided by user data on actuation speeds, accelerations and hold times. From a user perspective, the forces required to be applied to receive the medication must be demonstrated to be achievable by the target population.

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What are the potential opportunities in intranasal delivery?

The challenges of intranasal delivery open up a number of opportunities. For example, ergonomic device features could help to reliably control angle and depth of insertion into the nostril. Design innovations could also support patients in actuating to full stroke and delivering a full dose, while ensuring consistency of delivery velocity. As is the case for injection and pulmonary drug delivery devices, onboard digital sensors may also open up valuable opportunities to track patient compliance and confirm if a dose has been delivered correctly. 

There are considerable benefits from developing a COVID vaccine if it can be shown to reduce disease transmission in a way which intra-muscular alternatives cannot. It goes without saying that this breakthrough would bring high potential payback for investments in these endeavours. This is an exciting time for intranasal delivery and it will be interesting to see if some of its potential can be fulfilled and it can give rise to an effective COVID vaccine. Regardless of the outcome for COVID, the possibilities of intranasal delivery are many and are clearly now at the forefront of the minds of product vaccine developers and device manufacturers. It will be fascinating to see what this intranasal drug delivery technology brings next. 

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