Protein-Based Adjuvants for Vaccines as Immunomodulators of the Innate and Adaptive Immune Response: Current Knowledge, Challenges, and Future Opportunities

Abstract

New-generation vaccines, formulated with subunits or nucleic acids, are less immunogenic than classical vaccines formulated with live-attenuated or inactivated pathogens. This difference has led to an intensified search for additional potent vaccine adjuvants that meet safety and efficacy criteria and confer long-term protection. This review provides an overview of protein-based adjuvants (PBAs) obtained from different organisms, including bacteria, mollusks, plants, and humans. Notably, despite structural differences, all PBAs show significant immunostimulatory properties, eliciting B-cell- and T-cell-mediated immune responses to administered antigens, providing advantages over many currently adopted adjuvant approaches. Furthermore, PBAs are natural biocompatible and biodegradable substances that induce minimal reactogenicity and toxicity and interact with innate immune receptors, enhancing their endocytosis and modulating subsequent adaptive immune responses. We propose that PBAs can contribute to the development of vaccines against complex pathogens, including intracellular pathogens such as Mycobacterium tuberculosis, those with complex life cycles such as Plasmodium falciparum, those that induce host immune dysfunction such as HIV, those that target immunocompromised individuals such as fungi, those with a latent disease phase such as Herpes, those that are antigenically variable such as SARS-CoV-2 and those that undergo continuous evolution, to reduce the likelihood of outbreaks.

Humoral immunity against SARS-CoV-2 evoked by heterologous vaccination groups using the CoronaVac (Sinovac) and BNT162b2 (Pfizer/BioNTech) vaccines in Chile

“…It has been observed that anti-N antibody levels were higher in severe COVID-19 patients compared to those with mild symptoms (40). Although anti-N antibodies were associated with prolonged symptoms after COVID-19 infection, higher levels of IgG anti-N in the first week of SARS-CoV-2 infection were linked to a shorter time to sustained symptom resolution (41). These findings suggest that using inactivated viruses in designing vaccines against SARS-CoV-2 may not be adequate when a durable response against the N protein of SARS-CoV-2 is required (37,42).…”

VaccineDesigner: A Web-based Tool for Streamlined Multi-epitope Vaccine Design

“…Users are prompted to define the number of epitopes for Bcell, CTL, and HTL, while also specifying user-defined linker sequences (18) between the epitopes and the N-terminus sequence. A variety of different options of protein adjuvants are provided for the user to select and include in the multi-epitope vaccine sequences (22)(23)(24)(25).…”

Recent development of oral vaccines (Review)

“…The immunogenicity of antigenic proteins administered via oral mucosal inoculation alone is weak and is typically enhanced by the addition of specific adjuvants or vectors to achieve the desired effect. Different adjuvants, and even the same adjuvant with modified subunits, elicit different immune responses ( 11 ). Numerous adjuvants and vectors possess molecular structures that are recognized and targeted by innate immunity, such as lipopolysaccharides, the acidic components of membranes, basic peptidoglycan structures and non-methylated CpG structures ( 12 ).…”

“…The key to a successful oral vaccine lies in enhancing oral antigen presentation in the gastrointestinal mucosa and inducing effective mucosal and systemic immune responses. A well-designed adjuvant and antigen carrier system can reduce the antigen dose required for inducing an optimal immune response and immune tolerance ( 11 ). It is also important to note that, in the development of oral vaccines, it is crucial to consider their ability to withstand the various pH levels encountered throughout the gastrointestinal tract and the presence of proteolytic enzymes that can degrade antigen proteins ( 2 ).…”