A drop under the tongue and you're done: Researchers test sublingual COVID vaccine in primates

What if the COVID-19 vaccine could be a simple drop under the tongue instead of a shot in the arm?

That's the result researchers from Japan’s Intelligence & Technology Lab Inc. and the Biomedical Institute of NPO Primate Agora are hoping for. Results of a study published Sept. 13 in Biology Methods and Protocols described how they developed a protein-based COVID vaccine for delivery under the tongue, or sublingually. When they tested it in primates, the animals produced antibodies against COVID without side effects.

The researchers’ vaccine is a combination of an antibody against the receptor-binding domain of the spike protein on the SARS-CoV-2 virus and an adjuvant called poly(I:C), a synthetic double-stranded RNA that binds to genes associated with viral infection. It activates a subset of immune cells called antigen-presenting cells that initiate the adaptive immune response by displaying captured antigens to B and T cells, which then target the invader.

Despite being a “potent” adjuvant, the researchers wrote, poly(I:C) hasn’t been approved yet for use in vaccines but is used in oncology as a complement to immunotherapy. Some studies in mice have shown that the compound increases levels of proinflammatory cytokines when administered via the nose, which raises the risk of side effects like pain, fever and swelling.

Perhaps a different route of administration would temper the potential for adverse effects, the scientists reasoned.

The primates received three vaccinations to start, administered four weeks apart. A booster dose was given 15 weeks after the final round in the primary series. The scientists also included a control group of three primates.

After the booster dose, the team analyzed the amount and type of antibodies found in fluids from the monkeys’ mouths. They observed a desirable dose-dependent increase in IgA antibodies, “guardians of the oral and nasopharyngeal galaxy” that prevent the virus from attaching to cells in the mucosa. What’s more, they didn’t detect any obvious side effects nor did they see an increase in IgE antibodies, which are associated with an allergic response.

It’s not yet clear how efficacious the vaccine is against COVID-19 nor how long protection might endure. The researchers are currently conducting additional studies to address these questions, looking at changes in markers of gene expression to better quantify how well it works.

Results from other research groups might offer a preview. ImmunityBio and NantKwest launched a phase 1b trial of sublingual, subcutaneous and oral versions of their COVID-19 vaccine in March 2021. The primary completion date was set for January 2023, though there haven’t been any updates since. Meanwhile, in March, researchers at the University of California, Los Angeles reported that their universal oral COVID-19 vaccine prevented severe illness in hamsters, one of the most vulnerable models to the disease.

More progress is being made on intranasal vaccines. The furthest along is a live attenuated vaccine from Codagenix, which is currently being tested in Africa in a phase 3 trial backed by the World Health Organization. Startup Blue Lake Biotechnology reported phase 1 results in February showing that its intranasal vaccine reduced the risk of contracting COVID by 83% in people who received it as a booster dose. It’s now undergoing a phase 2 trial.