Researchers at Boston Children’s Hospital have found that combining an adjuvant with the mRNA COVID-19 vaccine prolonged immune protection and broadened responses against viral variants in animal models, a discovery that could reduce the need for repeated booster vaccinations. The study, published in Nature Immunology, examined the effects of pairing the original SARS-CoV-2 mRNA vaccine with a fungal-derived immune enhancer called “mannadjuvant,” a formulation made from fungal mannan and aluminum hydroxide.
“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,” says Ivan Zanoni, PhD chair in immunology at Boston Children’s. “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.”
The research focused on whether tuning inflammation through activation of pattern recognition receptors, or PRRs, could improve the effectiveness and durability of mRNA vaccines. The researchers tested whether stimulation of these receptors using fungal mannan could enhance immune responses generated by an mRNA vaccine targeting the ancestral SARS-CoV-2 spike protein.
The current research builds on earlier findings from Zanoni’s lab studying the same adjuvant in protein-based influenza vaccines. In the current study, investigators evaluated whether the mannadjuvant could improve performance of the original monovalent BNT162b2 Comirnaty vaccine encoding the spike protein from the ancestral WA1 strain of SARS-CoV-2.
To conduct the study, the team first confirmed that the mRNA vaccine remained stable after being mixed with the adjuvant. Researchers then vaccinated mouse models with either the mRNA vaccine alone or the vaccine combined with mannadjuvant. Additional testing was later conducted in non-human primates and human immune cells.
The research evaluated durability of antibody responses, T-cell activity, inflammatory signaling, and immune recognition of SARS-CoV-2 variants. Vaccinated mice were also exposed to mutated spike proteins from omicron variants of the virus to find out if the immune response generated by the adjuvant-enhanced vaccine could also recognize strains that emerged after the original vaccine design.
The data showed that mice that received the vaccine with the mannadjuvant retained antibodies to the viral spike protein for up to two years, compared with only a few months for animals given the vaccine alone. The adjuvant combined with the original vaccine was also shown to create a strong immune responses against omicron variant spike proteins.
“In mice and non-human primates, mannadjuvant increased the magnitude and durability of the response elicited by the mRNA-based vaccine, and it also led to the induction of neutralizing antibodies directed against variants of concern with a high escape capacity, overcoming antigenic imprinting,” the researchers wrote adding that their findings suggested antifungal PRRs could be used to create more potent and durable mRNA-based vaccines.
The researchers also evaluated the safety of the combination in mice and non-human primates and found that the adjuvant improved immune response “without increasing reactogenicity or breaking self-tolerance in mice and NHPs.”
The clinical implications of this finding shows that adjuvants targeting innate immune pathways could make mRNA vaccines more durable and less dependent on repeated reformulation or booster administration. Rather than updating vaccines to match each new variant, the researchers believe that the broader immune training elicited by combining the vaccine with an adjuvant may allow vaccines to remain effective as viruses evolve.
Future studies will focus on clarifying the molecular mechanisms by which the adjuvant stimulates immunity, particularly because immune responses to fungi are not fully understood. The team also plans to further investigate how mannadjuvant regulates interferon and interleukin-1 signaling and controls inflammasome activation.
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