Needle-free mRNA vaccines protect mice against COVID-19 and flu

A needle-free vaccination method protected mice against the viruses that cause COVID-19 and flu, offering a possible new way to deliver mRNA vaccines while limiting unwanted inflammation.

The Journal of Clinical Investigation study from researchers at Rutgers and the Japanese institutions tests experimental improvements to mRNA vaccine delivery. The approach combines a high-pressure liquid jet that delivers mRNA into the skin with two substances that strengthen the immune response.

"Showing that a carrier-free, needle-free vaccine can be made protective opens a different design space than the one the field has been working in," said coauthor Renata Pasqualini of Rutgers New Jersey Medical School and Rutgers Cancer Institute, New Jersey's only National Cancer Institute-designated Comprehensive Cancer Center, together with RWJBarnabas Health.

mRNA vaccines give cells temporary instructions to make a protein that trains the immune system to recognize a threat. In existing vaccines, tiny fat-based particles form capsules around the fragile mRNA, helping it enter cells and stimulate immunity.

The researchers explored another approach: delivering unencapsulated, or "naked," mRNA into the skin, which is rich in immune cells. Earlier work showed that jet injection could effectively deliver mRNA, but the resulting immune response was weak.

Researchers tried to bolster the effect by adding adjuvants, substances that enhance conventional vaccines. Unfortunately, these adjuvants offered little benefit when used individually with the mRNA. Some actually weakened parts of the response.

However, combining two different adjuvants--aluminum phosphate and short DNA molecules called CpG--boosted both antibody and cellular responses.

The researchers traced part of the benefit to immune signals activated in the skin and nearby lymph nodes. Their findings suggest that selecting the right immune stimulation and delivering mRNA into cells are essential to making this method work.

One of the most exciting discoveries in developing our carrier-free mRNA vaccines was that a combination of adjuvants could markedly improve vaccine efficacy while maintaining a favorable safety profile in our animal studies."

Satoshi Uchida, senior author, Institute of Science Tokyo

After three doses, infectious virus was below detection limits in lung samples from mice given the boosted vaccines and later exposed to SARS-CoV-2 or influenza A. In the COVID-19 experiment, lung viral RNA was about 24 times lower than after vaccination without the adjuvants. Both flu vaccine groups survived, so no additional survival benefit from the boosters was established.

Separate experiments found less local and systemic inflammation than with laboratory lipid-particle formulations of mRNA vaccine.

Despite its success in mice, the new approach still needs testing in larger animals before human trials, including establishing suitable doses. 

"What encourages us is that we achieved protective immunity in mice with a delivery device and adjuvant components that have each already been clinically used in human patients," said coauthor Wadih Arap of Rutgers New Jersey Medical School and Rutgers Cancer Institute.