Credit Intranasal COVID-19 vaccines: From bench to bed
While current COVID vaccines can greatly reduce the severity of COVID infection in most people, they don't do a very good job of stopping infection, usually acquired through the upper respiratory system.
Many scientists believe an intranasal spray (IN) COVID vaccine - as opposed to the typical IM (intramuscular) injection - would increase nasal/oral mucosal immunity, improving its effectiveness (see Mucosal immune response in BNT162b2 COVID-19 vaccine recipients).
There are reportedly a dozen or more IN vaccines in clinical trials around the world, with two - from China and India - recently approved for use in their countries. The Chinese vaccine notably uses a nebulizer delivery system, while the Indian vaccine uses drops.
Thus far, only limited data from phase II and phase III clinical trials of these vaccines have been published.
In theory, these IN vaccines should be more successful at preventing COVID infection, but how well they will work in the real world remains to be seen. Vaccine creation is difficult, and as we've seen in the past, not always successful.
Overnight Oxford University released a statement on their early clinical trials on the AstraZeneca intranasal ChAdOx1 nCoV-19 vaccine - published in eBioMedicine - where they disappointingly report a weak and inconsistent mucosal antibody and systemic response:
`This formulation of intranasal ChAdOx1 nCoV-19 showed an acceptable tolerability profile but induced neither a consistent mucosal antibody response nor a strong systemic response.'
The summary statement follows, after which I'll have a postscript.
Tolerability and immunogenicity of an intranasally-administered adenovirus-vectored COVID-19 vaccine: An open-label partially-randomised ascending dose phase I trial
Open Access Published:October 10, 2022
Summary
Background
Intranasal vaccination may induce protective local and systemic immune responses against respiratory pathogens. A number of intranasal SARS-CoV-2 vaccine candidates have achieved protection in pre-clinical challenge models, including ChAdOx1 nCoV-19 (AZD1222, University of Oxford / AstraZeneca).
Methods
We performed a single-centre open-label Phase I clinical trial of intranasal vaccination with ChAdOx1 nCoV-19 in healthy adults, using the existing formulation produced for intramuscular administration. Thirty SARS-CoV-2 vaccine-naïve participants were allocated to receive 5 × 109 viral particles (VP, n=6), 2 × 1010 VP (n=12), or 5 × 1010 VP (n=12). Fourteen received second intranasal doses 28 days later. A further 12 received non-study intramuscular mRNA SARS-CoV-2 vaccination between study days 22 and 46.
To investigate intranasal ChAdOx1 nCoV-19 as a booster, six participants who had previously received two intramuscular doses of ChAdOx1 nCoV-19 and six who had received two intramuscular doses of BNT162b2 (Pfizer / BioNTech) were given a single intranasal dose of 5 × 1010 VP of ChAdOx1 nCoV-19.Objectives were to assess safety (primary) and mucosal antibody responses (secondary).
Findings
Reactogenicity was mild or moderate. Antigen-specific mucosal antibody responses to intranasal vaccination were detectable in a minority of participants, rarely exceeding levels seen after SARS-CoV-2 infection. Systemic responses to intranasal vaccination were typically weaker than after intramuscular vaccination with ChAdOx1 nCoV-19. Antigen-specific mucosal antibody was detectable in participants who received an intramuscular mRNA vaccine after intranasal vaccination. Seven participants developed symptomatic SARS-CoV-2 infection.
InterpretationThis formulation of intranasal ChAdOx1 nCoV-19 showed an acceptable tolerability profile but induced neither a consistent mucosal antibody response nor a strong systemic response.Funding
AstraZeneca.
Within the body of the report (14-page PDF), the authors report these findings are disappointing enough to abandon the current approach, but that research on intranasal COVID vaccines should continue.
Added value of this study
We present a first-in-human study of intranasal COVID19 vaccination with an adenovirus-vectored vaccine. Reactogenicity was acceptable at all doses but immunogenicity was insufficient to warrant further development of the current formulation / device combination.
Implications of all the available evidence
There remains a need for clinical development of needle-free vaccines capable of inducing consistent protective mucosal immune responses. Although the vaccine and delivery device combination in this study did not warrant further exploration, optimisation of this vaccine and other candidates for mucosal delivery remains a key opportunity for transmission blocking vaccines.
While far from perfect, it is remarkable that multiple COVID vaccines were released less than a year after the SARS-CoV-2 virus was discovered. As we saw in 2019's Manufacturing Pandemic Flu Vaccines: Easier Said Than Done, successfully creating, producing, and deploying a pandemic vaccine is far from guaranteed.
Hopefully we'll see better results from some of the other IN vaccine candidates in the pipeline.
