Harnessing Adjuvants for Robust SARS-CoV-2 Vaccine Immunity
Aluminum Salts (Alum)
Mechanism: Alum adjuvants, such as aluminum hydroxide and aluminum phosphate, are among the oldest and most widely used adjuvants. They work by creating a depot effect that allows for the slow release of the antigen, enhancing the immune response. Alum can also stimulate the NLRP3 inflammasome, leading to the production of pro-inflammatory cytokines like IL-1β, which activates innate immune cells.
Vaccines: Examples include some of the inactivated virus vaccines and protein subunit vaccines.
MF59 (Oil-in-Water Emulsion)
Mechanism: MF59 is an oil-in-water emulsion that enhances the uptake of antigens by antigen-presenting cells (APCs) and stimulates the production of cytokines and chemokines, recruiting more immune cells to the site of injection.
Vaccines: Used in some protein subunit and inactivated virus vaccines.
AS03 (Oil-in-Water Emulsion)
Mechanism: Similar to MF59, AS03 contains squalene and vitamin E, which enhance the immune response by stimulating APCs and promoting a strong Th1 and Th2 immune response.
Vaccines: Used in some influenza vaccines and being evaluated in COVID-19 vaccines.
CpG 1018 (TLR9 Agonist)
Mechanism: CpG 1018 contains synthetic DNA sequences that mimic bacterial DNA, stimulating Toll-like receptor 9 (TLR9). This activation leads to the production of type I interferons and other cytokines, enhancing the immune response.
Vaccines: Used in some recombinant protein vaccines for SARS-CoV-2.
Matrix-M (Saponin-Based)
Mechanism: Matrix-M is a saponin-based adjuvant that enhances the immune response by stimulating APCs and promoting the production of cytokines and chemokines. It forms nanoparticles that facilitate the delivery of the antigen to immune cells.
Vaccines: Used in the Novavax COVID-19 vaccine.
Specific Examples in SARS-CoV-2 Vaccines
Novavax COVID-19 Vaccine (NVX-CoV2373)
Adjuvant: Matrix-M
Mechanism: Enhances antigen presentation and stimulates the production of cytokines, leading to a robust immune response.
Covaxin (Bharat Biotech)
Adjuvant: Algel-IMDG (a combination of alum and a TLR7/8 agonist)
Mechanism: The alum component enhances the depot effect and stimulates the NLRP3 inflammasome, while the TLR7/8 agonist further activates innate immune cells.
Sinovac-CoronaVac
Adjuvant: Aluminum hydroxide (Alum)
Mechanism: Creates a depot effect and stimulates the NLRP3 inflammasome, leading to the production of pro-inflammatory cytokines.
Engineered Nanoparticles as Vaccine Adjuvants
Scientists are exploring engineered nanoparticles as next-generation vaccine adjuvants to boost COVID-19 immunity. For example, MIT researchers encapsulated SARS-CoV-2 spike protein in a zinc-based metal–organic framework (ZIF-8) nanoparticle, which acts both as an antigen carrier and as an immune stimulant.
Immune Activation in Preclinical Models
In mice, this MOF vaccine triggered robust Toll-like receptor signalling: RNA sequencing of draining lymph nodes revealed pronounced activation of a TLR7-associated pathway and increased expression of inflammatory cytokines.
Enhanced Antibody Responses
Importantly, animals that received the MOF-encapsulated antigen generated much higher antibody responses than those given the protein alone. This approach even achieved an apparent dose-sparing effect, eliciting particular immune responses at lower antigen doses. Together, these findings suggest that nanoparticle-based adjuvants, such as ZIF-8, can enhance immune responses by mimicking pathogen-like signals that activate innate immune sensors.
Mechanism of Action of Matrix-M Saponin Adjuvant
Recent preclinical work has also elucidated how Novavax’s Matrix-M® saponin adjuvant works at the cellular level. Zarnegar et al. showed that Matrix-M’s Quillaja saponin nanoparticles (Matrix-A and Matrix-C) co-localise with the antigen inside dendritic cell lysosomes, where they induce lysosomal membrane permeabilisation (LMP).
Promoting CD8+ T-cell Responses
This LMP triggers the release of the inflammasome cytokines IL-1β and IL-18, allowing the antigen to be cross-presented on MHC-I and thereby promoting robust CD8+ T-cell responses. Remarkably, these effects occur even in the absence of NLRP3 inflammasome signalling, indicating a direct mechanism by which Matrix-M ruptures lysosomes to enhance adaptive immunity.
In short, this new research confirms that the ability of Matrix-M–adjuvanted vaccines to induce potent cellular immunity stems from their saponin particles’ capacity to open lysosomes and activate innate immune pathways.
Conclusion
Adjuvants in SARS-CoV-2 vaccines play a vital role in enhancing the immune response by activating the innate immune system. They work through various mechanisms, such as stimulating pattern recognition receptors (PRRs) like TLRs, creating depot effects, and promoting the recruitment and activation of antigen-presenting cells. These actions help to produce a robust and long-lasting adaptive immune response, improving the efficacy of the vaccines.
