Key Points
- Nasal vaccines trigger mucosal immune responses, in addition to systemic responses elicited by traditional vaccines, providing more comprehensive protection against respiratory pathogens.
- There is 1 nasal vaccine approved in the U.S. (FluMist), with others targeting various respiratory pathogens under preclinical and clinical development.
- Generating effective nasal vaccines requires overcoming barriers imposed by the nasal cavity, like mucus and immunological tolerance, while prioritizing safety.
- Although nasal vaccine technology is advancing, its success depends on the stability of the scientific institutions and systems that support vaccine development.
Vaccines are usually administered with a needle poke into the arm. But what if instead of a poke, you could get vaccinated with a huff and a puff?
Behold: Nasal Vaccines
Administered through the nose, nasal vaccines are particularly appealing for their lack of needles. But they come with other attributes, too, including their ability to trigger immune responses against respiratory pathogens at the site of infection, in addition to the systemic responses elicited by traditional vaccines. The immunological potential of nasal vaccines has prompted scientists to design innovative candidates targeting a swath of pathogens. However, getting those vaccines out of the lab and into people's schnozzes depends on overcoming barriers-both in the nose and outside of it.
Why Nasal Vaccines?
When we inhale a pathogen like SARS-CoV-2 or influenza, the virus infects cells lining the tissue (mucosa) extending from the nose and into the lungs. Despite being the first to confront the invader, immune cells that live in the nasal/respiratory mucosa are outside the educational purview of traditional vaccines, which "train" immune cells to recognize and respond to a given pathogen.
When a vaccine is injected into the arm muscle, as a majority are, specialized innate immune cells shuttle the vaccine antigen to a lymph node. There, the antigen is presented to and activates adaptive immune cells (B and T cells), priming them to combat the real pathogen. During infection, cells and antibodies travel from the lymph node to the infection site to destroy the invader. This response is excellent at limiting disease severity, though it depends on the movement of cells along the circulatory highways of the body. In other words, it takes a while to develop.
Intranasal vaccines stimulate cellular and antibody responses on-site at the source of infection. If a virus enters the nasal mucosa, immune cells don't need to travel to the threat-they already live there. These resident warriors quickly mobilize to combat the invader. Such mucosal protection extends along the respiratory mucosa into the lungs.
Notably, nasal vaccines still induce systemic immunity via the lymph node route, but with the bonus of rallying localized mucosal responses, too. This double-whammy of immunity helps limit disease severity and can potentially halt an infection in its tracks. In doing so, it may also prevent viral transmission-something traditional vaccines don't do well, but which has important implications for controlling the spread of respiratory infections.
Are There Nasal Vaccines Available?
Though they have potential, nasal vaccines are still few and far between. In the U.S., there is 1 nasal vaccine approved by the Food and Drug Administration (FDA)-FluMist, a live-attenuated influenza vaccine. On the market since 2003, FluMist was approved for at-home administration for eligible individuals during the 2025-2026 flu season, highlighting the potential of nasal vaccines to overcome logistical barriers posed by their needled counterparts.
In addition to seasonal flu, vaccines targeting various pathogens, including respiratory syncytial virus (RSV) and H5N1, are in the works around the world. In the shadow of the COVID-19 pandemic, vaccines conferring protection against SARS-CoV-2 have been a particular focus. Nasal COVID-19 vaccines have been approved in India, Russia, China and Iran under emergency licenses; various candidates are also in preclinical development or are moseying through the clinical trial pipeline with encouraging results.
For example, a study in hamsters showed that immunization with a nasal vaccine with a chimpanzee adenovirus vector (a chimpanzee-infecting virus engineered to carry genetic material from SARS-CoV-2 without causing illness in people) prevented sequential viral transmission to unvaccinated hamsters. Another vaccine uses parainfluenza virus type 5 (PIV5)-which infects various animal species, though is not associated with disease in humans-to deliver SARS-CoV-2 Spike protein to the nasal mucosa. In a phase 1 trial, the vaccine (CVXGA1) was elicited both mucosal and systemic responses in individuals 12-53 years of age. Researchers are recruiting for a phase 2b trial to further assess the vaccine's safety and relative efficacy.
What Are the Challenges in Nasal Vaccine Development?
Though administering a nasal vaccine may be easy, developing them is tricky.
Part of the problem is that the nose is rife with obstacles meant to keep foreign materials out. Mucosal epithelial cells are lined with mucus and protrusions (cilia) that sweep particles, including vaccine antigens, out of the nasal cavity. Nasal secretions also contain molecules that can dilute and degrade vaccine components.
These barriers are not airtight; particles can, and do, frequently pass through. The mucosal immune system can't react to every tidbit that crosses its path without risking significant damage to host tissues. As such, it largely exists in a tolerant state, springing into action only when it detects clear signs of danger, such as signals from invading microbes or damaged cells. The key is to formulate a vaccine that overcomes this threshold to induce a protective response. Adjuvants-immunity-boosting compounds added to some vaccines-can help do this. However, such additions must be carefully considered for nasal vaccines.
The nasal passages link up to the brain via the olfactory bulb. Consequently, it is possible vaccine antigens or adjuvants could be transported to the brain and impact neuronal function. The only confirmed example of this was a nasal influenza vaccine licensed in Switzerland in 2000 that used Escherichia coli heat-labile enterotoxin as the adjuvant. The vaccine was removed from market after it was associated with an increased risk of facial palsy. Ensuring nasal vaccine safety is a paramount priority in nasal vaccine development.
Sometimes, an immune response may put a damper on nasal vaccine efficacy. For instance, despite the advantages of nasal vaccines, the protection conferred by FluMist is generally comparable to flu shots. One reason for this may be that pre-existing immunity to the flu neutralizes the vaccine's weakened viruses in the nose before they can radically boost immunity. The effectiveness of both FluMist and flu shots also varies depending on age/risk groups, and whether viruses in the vaccine match circulating flu strains. Thus, how a vaccine works "in the real world" is a mixing pot of factors related to the virus, vaccine composition and host response; getting all of them to work together is a key challenge in vaccine design.
What Advancements Are Being Made?
Nevertheless, the difficulties in generating nasal vaccines are also powering innovative solutions. Researchers are exploring diverse vaccine vectors, types (e.g., mRNA), adjuvants and delivery systems that overcome barriers imposed by the nose to kickstart immunity. These include developments like antigen-loaded polymeric nanogels that stick to the nasal mucosa, where they then release their antigenic cargo. In a recent study, a nanogel-based vaccine containing an RSV surface protein prevented viral invasion of both the upper and lower respiratory tracts in rats.
Additional research is shining light on the ins and outs of the mucosal immune response, including tracking how cells respond post-vaccination, to better refine nasal vaccine technology. Relatedly, studies with COVID-19 vaccines suggest that primary immunization via a standard shot followed by a nasal vaccine boost (known as the "prime and spike" method) could be beneficial for bolstering mucosal defenses and providing durable protection against SARS-CoV-2. This is useful intel, given most people vaccinated against COVID-19 have been so via the intramuscular route; adding nasal vaccines to the picture could fill the gap in mucosal immunity standard vaccines miss. The same approach may elicit superior protection against other respiratory pathogens, too, like RSV or influenza.
What Does the Future Hold?
Whether new nasal vaccines reach the market depends on how well they navigate the complex regulatory processes that determine which candidates move forward-and which are left behind. The arduous process of vaccine testing and approval has become more tenuous in the U.S., where funding cuts to scientific agencies and shifting federal health priorities have shaded the future of vaccines in general. Indeed, stop-work orders and suspended or terminated grants have placed several candidates in clinical development on shaky ground. At the end of the day, while the science behind emerging nasal vaccines is strong-and so is the need-their fate may rest less on scientific ingenuity and more on the stability of the systems that support it.
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