Review: Current trends, challenges, and success stories in adjuvant research

Abstract

Vaccine adjuvant research is being fueled and driven by progress in the field of innate immunity that has significantly advanced in the past two decades with the discovery of countless innate immune receptors and innate immune pathways. Receptors for pathogen-associated molecules (PAMPs) or host-derived, danger-associated molecules (DAMPs), as well as molecules in the signaling pathways used by such receptors, are a rich source of potential targets for agonists that enable the tuning of innate immune responses in an unprecedented manner. Targeted modulation of immune responses is achieved not only through the choice of immunostimulator – or select combinations of adjuvants – but also through formulation and systematic modifications of the chemical structure of immunostimulatory molecules. The use of medium and high-throughput screening methods for finding immunostimulators has further accelerated the identification of promising novel adjuvants. However, despite the progress that has been made in finding new adjuvants through systematic screening campaigns, the process is far from perfect. A major bottleneck that significantly slows the process of turning confirmed or putative innate immune receptor agonists into vaccine adjuvants continues to be the lack of defined in vitro correlates of in vivo adjuvanticity. This brief review discusses recent developments, exciting trends, and notable successes in the adjuvant research field, albeit acknowledging challenges and areas for improvement.

Adjuvants for COVID-19 Vaccines

“…Each adjuvant has a limited stimulation system, which only allows for the “touching” of some parts of the complex immune response. Therefore, one of the possible solutions could be the use of combined adjuvants, which can stimulate different parts of the immune response at the same time, and also boost the response jointly [ 102 ]. However, these combinations should be made by searching for the best optimal ratio and the best associated adjuvants, thus looking for the combination that provides an additive and truly synergistic effect.…”

Multifunctional Lipidated Protein Carrier with a Built-In Adjuvant as a Universal Vaccine Platform Potently Elevates Immunogenicity of Weak Antigens

“…Additionally, adjuvants also play a crucial role in vaccines for enhancing the immunogenicity of antigens and boosting immune responses. − In vaccine designs, adjuvants are typically physically mixed with antigens and bolster antigen-specific immune responses by activating innate immunity, such as aluminum-containing adjuvants (Alum adjuvant), invariant natural killer T (iNKT) cell agonists, toll-like receptors (TLR) agonists, − and stimulator of interferon genes (STING) agonists. , However, the direct administration of adjuvants may result in the dispersion of adjuvants from the injection site, which may reduce the effective concentration of adjuvants and trigger inflammation or systemic toxicity . In recent years, the adjuvant-antigen conjugation strategy has been demonstrated to be an effective vaccine design approach. − Built-in adjuvant molecules may confer various advantages to vaccines, including reproducibility, controllability, and uniform chemical composition .…”

Call for Papers: Medicinal Chemistry of Next Generation Vaccine Adjuvants

“…Several aspects such as disease mechanisms and correlates of protection, immune biasing capabilities, route of administration, antigen compatibility, vaccine technology platform, as well as age- and species-specific effects are to be considered for appropriate vaccine adjuvant design . The next generation adjuvants termed “immune potentiators” (albeit associated with possible side effects such as tendency of inducing a cytokine storm and reactogenicity), with a detailed medicinal chemistry explorations, may lead to success stories …”

“…Until recently, only a small number of adjuvants have been licensed for human use. Significant regulatory hurdles account for the status quo . Aluminum salts have been used in human vaccines since the 1920s and remained as the only adjuvant for over seven decades until the introduction of virosome in the 1990s, followed by the approval of MF59, an oil-in-water emulsion.…”

“…A sudden boost in vaccine development during the COVID-19 pandemic has benefited the adjuvant research field. Recent approvals of vaccines containing new adjuvants targeting TLR4 (AS04 and RC-529 with MPL and its derivative), TLR9 (CpG1018 and Advax/CpG55.2, wherein the carrier and co-adjuvant is crystalline carbohydrate rather than Alum), as well as TLR7/8 (Alhydroxiquim-II, an imidazoquinoline molecule chemisorbed on Alhydrogel) indicate the strong potential of targeting PRRs for the development of new adjuvants for improved vaccines . Many emerging concepts in new vaccine adjuvant design and development for use in vaccines against COVID-19 are being showcased by researchers, with great success.…”