Pairing COVID-19 mRNA vaccines with an immune system enhancer, known as an adjuvant, could make the vaccines more effective and longer-lasting, according to new research led by Harvard Medical School researchers at Boston Children’s Hospital.
The findings, published May 22 in Nature Immunology, show that combining a COVID-19 mRNA vaccine with a custom-made adjuvant extended the duration of the vaccine’s protection in mice from a few months up to two years. The combination also showed a more pronounced response against components of the omicron variant of the virus than the vaccine alone.
The work still needs to be tested and validated in humans, but introducing adjuvants like this one to mRNA vaccines may alleviate the need for frequent boosters due to waning antibodies against a virus or new variants of a virus, the researchers said. Rather than chasing each new variant with an updated booster, adjuvants could train the immune system to respond more broadly and stay effective as viruses evolve.
Broader, longer-lasting protection
While the majority of FDA-approved vaccines already use adjuvants to improve their efficacy, mRNA vaccines typically do not.
“Even though the mRNA technology is the biggest breakthrough for vaccine technology in the last two decades, we thought that there was still room for us to improve this platform,” said Ivan Zanoni, HMS professor of pediatrics at Boston Children’s and senior author on the study.
The research team developed the new adjuvant from a branched sugar molecule, known as mannan, found on the outer cell wall of the yeast Candida. They combined mannan with aluminum hydroxide, a long-used vaccine adjuvant, to create what they call a “mannadjuvant.”
“Our strategy takes advantage of the immune system’s innate ability to ramp up broadly in response to a variety of components found in and on pathogens,” Zanoni said.
An mRNA COVID vaccine contains genetic material, which encodes the instructions for building a piece of the SARS-CoV-2 virus’ outer spike protein, encased in a fatty, protective shell that shuttles the vaccine inside immune cells. Zanoni’s team ensured that the vaccine — in this case, the one developed by Pfizer-BioNTech and marketed as Comirnaty — remained stable when combined with the adjuvant.
Next, the researchers tested the vaccine and adjuvant in mice. Compared to a few months of protection that the typical vaccine provided, mice given the vaccine with the mannadjuvant still had antibodies to the virus’ spike protein up to two years later.
One of the challenges with SARS-CoV-2 is that the virus keeps evolving, Zanoni said. “The virus mutates so quickly that the antibodies your body creates from the original vaccine don’t recognize the newer versions of the virus in circulation.”
In addition to extending the duration of protection, the mannadjuvant helped broaden that protection to cover more viral variants.
In their experiments, the researchers used the original Comirnaty vaccine, not one of the updated versions formulated to protect against later variants such as delta or omicron. But with the mannadjuvant added to the vaccine, vaccinated mice mounted markedly stronger immune responses to the omicron variants. Non-human primates vaccinated with the combination showed a similar response.
Next steps
The work builds on an earlier study from Zanoni’s team, which used the mannadjuvant to enhance the effectiveness of a protein-based influenza vaccine.
For future studies, the team plans to continue dissecting the molecular mechanism for how their adjuvant works to stimulate the immune system. This is especially important since the immune system’s response to fungi isn’t well understood.
The team has filed patents on the mannadjuvant and formed a spinoff biotech company to further develop the technology for eventual use in human trials.
Adapted from a Boston Children’s Hospital news release.
Authorship, funding, disclosures
Additional authors include Kautilya K. Jena, Pengxiang Qu, Lauren Baracco, Shahab Saghaei, Keerti, Zahra Allahyari, Daniel Boehmer, Moriah Mitchell, Carly A. Dillen, Hai-Yun Li, Enqi Liu, Valentina Poli, Océane Dufies, David P. Hoytema van Konijnenburg, Roberto Spreafico, Caihong Bi, Rebecca Hall, Michael D. Kruppa, Zuchao Ma, Amy Gravitte, Douglas W. Lowman, Harry E. Ensley, Pierre Marty, Laurent Boyer, Rémy Collomp, David L. Williams, Victor Pui-Yan Ma, Pui Y. Lee, Peter A. Nigrovic, Jeffrey M. Karp, Stephen J. Elledge, Duane R. Wesemann, Yi Wu, and Matthew Frieman.
This work was supported by the National Institutes of Health (grants R01AI165505, 5R01AI121066, 5R21AI159877, R01GM119197, R01GM83016, R21AI173607, 5K12HD052896, R01AR065538, R01AR073201, P30AR070253, AI170715, AI165072, and OT2CA297288, the Lloyd J. Old STAR Program (grant CRI3888), the Investigators in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund, the Carroll H. Long Endowment, the Crohn’s & Colitis Foundation (award 1282696), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, project number 515356385), the Office of Faculty Development at Boston Children’s, the Fundamental Research Funds for the Central Universities (grant xtr052025019), the National Natural Science Foundation of China (grant 32371305), the Howard Hughes Medical Institute and the MATCHMAKERS team, the Cancer Grand Challenges partnership funded by Cancer Research UK (CGATF-2023/100005 and CGCATF-2023/100008), and the Mark Foundation for Cancer Research.
Jeffrey M. Karp has been a paid consultant and/or equity holder for multiple companies, including Edge Immune Inc., a company that has licensed intellectual property generated by Karp that may benefit financially if the intellectual property is further validated. Other companies for which Karp has been a paid consultant and/or equity holder are listed here.
Stephen J. Elledge is a founder of TSCAN Therapeutics, MAZE Therapeutics, and Mirimus and serves on the scientific advisory board of Homology Medicines, TSCAN Therapeutics, and MAZE Therapeutics, none of which impacts this work.
David P. Hoytema van Konijnenburg has been a paid consultant for Herspiegel, Guidepoint Global, and AlphaSense.
Karp, Kautilya K. Jena, and Ivan Zanoni are named inventors on invention disclosures and patents involving vaccine adjuvants. Karp and Zanoni are founders of a company involving vaccine adjuvants.
The remaining authors declare no competing interests.
