Nasal Approach to COVID Vaccination Gains Traction

Akiko Iwasaki, Ph.D.
February 14, 2022

As the coronavirus that causes COVID-19 continues to mutate, it presents new roadblocks to efforts to contain its spread. A Yale research team led by Akiko Iwasaki, PhD, Waldemar von Zedtwitz Professor of Immunobiology and professor of molecular, cellular, and developmental biology and of epidemiology (microbial diseases), has found success in a new approach to vaccination—systemic vaccines that train the entire body’s immune response followed by boosters administered directly to the nasal cavity, to deliver special protection in the part of the body most affected by SARS-CoV-2 infection.

In a research paper posted on the preprint site bioRxiv, Iwasaki and co-first authors Tianyang Mao, BS, and Benjamin Israelow, MD, PhD, note that the mRNA-based vaccines that have been such a powerful tool against COVID have shown diminished effectiveness over time. They especially appear to lack strength in the nasal cavity mucosa and respiratory tract—the region of the body where the virus is most likely to cause illness and from which it is most likely to be transmitted to other people. The Omicron variant’s higher transmissibility than that of previous variants has caused particular concern, and the approach suggested by Iwasaki’s team, called Prime and Spike, is meant to address that. The Prime portion is what millions of people have already received—injections of the mRNA vaccine into a muscle. Spike is following up those vaccinations with familiar spike proteins that are derived from the coronavirus and are sprayed directly into the nose. The work follows recent research that evaluated use of another nasal vaccine technique for influenza virus.

A Potent Vaccine Combination

The researchers found that the Prime and Spike together were a potent combination in mice. They induced robust tissue-resident memory T cells, resident memory B cells, and immunoglobulin A in the respiratory mucosa—including the lungs—while also boosting immunity throughout the body, which also is called systemic immunity. And a second version of the Spike, where mRNA vaccine coated by a polymer that was both non-inflammatory and biodegradable was delivered to the nasal cavity, performed similarly when the Prime preceded it. The laboratory of W. Mark Saltzman, PhD, Goizueta Foundation Professor of Biomedical Engineering and professor of cellular and molecular physiology and of chemical engineering, developed the polymer. In both cases, neither the Prime nor the Spike alone came close to the results from combining the two methods, which “completely protect[ed] mice with partial immunity from lethal SARS-CoV-2 infection.” 

Iwasaki says she is already optimistic about the benefit of her approach for humans. “Our data demonstrated that Prime and Spike significantly reduced the viral load in the nasal cavity and the lung compared to injected vaccine alone, indicating the promise of Prime and Spike in reducing infection and transmission,” she says. “Improving upon current vaccine platforms to provide mucosal immunity is important to prevent infection and transmission and to curb this current pandemic, and certainly will be important to combat the next.”

Improving upon current vaccine platforms to provide mucosal immunity is important to prevent infection and transmission and to curb this current pandemic, and certainly will be important to combat the next.

Akiko Iwasaki, PhD Iwasaki and co-author Saltzman are cofounders of Xanadu Bio, a company through which they hope to take their vaccination techniques, licensed by Yale University, to completion. Submitted by Robert Forman on February 14, 2022

External link: 

Research Interests

Drug Delivery
Gene Therapy
Tissue Engineering


Department of Biomedical Engineering  |  Yale University
Malone Engineering Center (map)
55 Prospect St.  |  New Haven, CT 06511

Vascular Biology & Therapeutics Program | Yale School of Medicine
Amistad Research Building (map)
10 Amistad St.  |  New Haven, CT 06520

For Undergraduate Research Opportunities

Thank you for your interest in a research position in our lab! We have an application process to help match interested students with mentors and current research projects. Submission of applications are rolling, but we will review all applications on September 14th (fall term) and January 18th (spring and summer term). If you have any questions about the application, please contact We look forward to receiving your application.