Factors Limiting the Translatability of Rodent Model–Based Intranasal Vaccine Research to Humans

Abstract

The intranasal route of vaccination presents an attractive alternative to parenteral routes and offers numerous advantages, such as the induction of both mucosal and systemic immunity, needle-free delivery, and increased patient compliance. Despite demonstrating promising results in preclinical studies, however, few intranasal vaccine candidates progress beyond early clinical trials. This discrepancy likely stems in part from the limited predictive value of rodent models, which are used frequently in intranasal vaccine research. In this review, we explored the factors that limit the translatability of rodent-based intranasal vaccine research to humans, focusing on the differences in anatomy, immunology, and disease pathology between rodents and humans. We also discussed approaches that minimize these differences and examined alternative animal models that would produce more clinically relevant research.

Feasibility of intranasal delivery of thin-film freeze-dried, mucoadhesive AS01B-adjuvanted vaccine powders

“…However, as aforementioned, only a few nasal vaccines have received regulatory approval for human use around the world. Many nasal vaccine candidates that are safe and efficacious in preclinical studies often fail to move beyond phase 1 in clinical testing (Cai et al, 2022). For example, the ChAdOx1 nCoV-19 simian adenovirus-based COVID-19 vaccine that was effective in hamsters and non-human primates (NHP) when given intranasally failed to elicit consistent immune responses in humans (Madhavan et al, 2022).…”

“…Similarly, a dry powder delivery system that can deliver the vaccine powder to the desired region(s) of the human nasal cavity is also required because there has not been an approved nasal dry powder vaccine for human use yet. Since many intranasal vaccines failed to move beyond phase 1 clinical trials (Cai et al, 2022; Xu et al, 2021b), the formulation of a vaccine intended for intranasal administration must be optimized, and only a device that can efficiently target the vaccine formulation to the desired region(s) in the nasal cavity should be chosen. As aforementioned, in children and adults, the Waldeyer’s ring in the naso-oropharynx region is the key lymphoid tissue in the nasal cavity.…”

“…However, as aforementioned, only a few nasal vaccines have received regulatory approval for human use around the world. Many nasal vaccine candidates that are safe and efficacious in preclinical studies often fail to move beyond phase 1 in clinical testing (Cai et al, 2022).…”

“…Therefore, for an intranasal vaccine to induce specific immune responses, the vaccine needs to be delivered either directly to the nasopharynx region or to the posterior nasal cavity and then move by means of ciliary clearance to the naso-oropharynx region following the mucous blanket posterior movement. Within the posterior nasal cavity, delivery of the vaccine to the upper turbinate region, where the olfactory bulb resides, should be avoided or minimized to reduce the access of the vaccine to the brain via the olfactory nerves (Cai et al, 2022; Xu et al, 2021b).…”

Mucosal immunity: The missing link in comprehending SARS-CoV-2 infection and transmission

“…The WHO website shows that of 156 COVID vaccines in clinical development, 8 are intranasal, a further 3 are administered as aerosol or by inhalation, and 4 are orally delivered ( ; accessed May 18, 2022). Many efforts at intranasal vaccine development have been abandoned because of failure to repeat preclinical success in phase I trials, a common finding, often the result of inadequate understanding of differences in the human mucosal immune system from those of small animal models ( 94 ). It has already been noted above that nasopharyngeal immune anatomy differs between mice (which have NALT in the naso-pharyngeal duct) and humans (which have Waldeyer’s ring of tonsils and adenoids in the pharynx).…”