Understanding Mechanisms of Actions for Vaccine Adjuvants Critical for Designing Effective Vaccines: A narrative review
Vaccine adjuvants enhance immunogenicity of antigens through one or a combination of mechanisms that include; improved antigen delivery to the innate immune system or by providing signals that activate the innate immune system. Activation may lead to induction of cytokines and chemokines, recruitment of immune cells to the site of vaccine inoculation or trafficking of innate immune cells to draining lymph nodes. These events culminate in activation of adaptive immunity.
Objective : To identify the Current status of knowledge on action modes for vaccine adjuvants, modes under investigation and future directions in this important area of biomedical research. influence on molecular and physical interactions between vaccine components and innate immune cells that affect the degree of immune responses given first priority.
Methodology: Published studies in English language on vaccines and adjuvants were identified by key words from Comprehensive searches with no formal assessments for risk of biases. The type of publications included basic research using experimental animals and clinical research in human. A recent study using recombinant hemmaglutinin (rH5) protein of highly pathogenic avian influenza (HPAI) virus as antigen demonstrated a quicker antibody production. IL -17 and IFN-γ when adjuvant combinations of CpG and nanoemulsion were used in comparison to nanoemulsion alone . Equally, potential vaccine adjuvants including pathogen associated molecular patterns (PAMPs) derived from microbes with their synthetic analogs like cytosine and guanine (CpG) oligodeoxynucleotide that targeted toll-like receptors (TLRs) and mast cell activating compound such as compound 48/80 (C48/80) [23, 24]. Combination of cationic peptide HH2 with CpG induced IgG1 (Th2) and IgG2a (Th1) type antibodies in experimental animals  Other vaccine adjuvants developed for human use included Monophosphoryl lipid A (MPLA) and MF59 (oil in water emulsion). MPLA is a detoxified form of bacterial cell wall lipid A from Salmonella Minnesota R595 combined with alum to augment immunogenicity of subunit vaccines. When mediated through activation of TLR4 induced Th1 type immune responses . Combined with alum for hepatitis B virus (FENDrix) Human Papilloma Virus (Cervarix)  and then combined with a water-soluble triterpene glucoside as adjuvants for malaria vaccine trials in human . Combination of a mucopolysaccharide chitosan as a mucosal vaccine with Norwalk norovirus demonstrated induction of antigen-specific antibody.
Cytomegalovirus Glycoprotein B antigen when adjuvanted with MF59 induced a higher antibody titer using a lower antigen dose compared to antibody titer induced by a higher dose of the same antigen  Inactivated hepatitis A antigen induced a significantly higher seroconversion rate at two weeks after the first injection with 100 U of antigen compared to 50 or 25 U of the antigen . Intranasal meningococcal subtype B vaccine induced highly bactericidal immunity with day 0, 7, 28 and 56 schedules than same vaccine given on days 0, 28 and 56 . Induction of dsDNA released when bound by adjuvants formed a complex and trans-located into the endosome to activate TLR9 cascading to MyD88 adaptor molecule [29, 51] immunity .
Results (Data Synthesis) : This literature review has shown that, several strategies exist that can be applied in order to maximize immune activation and improve vaccine efficacy. Such strategies include combination of adjuvants that activate different pathways of the innate immunity. Combination of adjuvants produced synergistic effect in immune responses and pathogen clearance, but individual adjuvants more often provided a response that was narrow in its effect, being either Th1 or Th2 biased.
Conclusion : Selection of the right adjuvant for a vaccine antigen requires knowledge on the mode of action of the adjuvant. Different adjuvants and different routes of vaccine administration could generate various types of immune responses. The route of vaccine administration might influence the type of cells in the innate immunity activated by an adjuvant. Antibodies with high avidity strongly bound to antigenic determinants on the pathogen inducing destructive processes against the pathogen. Intranasal adjuvants can be suitable for mass vaccination against respiratory infections such as influenza and CORONA viruses ( SARS Cov-2 (COVID-19)). The ratio between the antigen and adjuvant in a vaccine would influence the structure of the final complex formed and its biological activities.
Recommendations: To effectively design an adjuvant within a vaccine formulation, first understand its mechanisms of activity in order to develop a potent, effective and safe vaccine. Induce sufficiently mature (high avidity) antibodies by a vaccine to avoid lack of protection.
Key words: Vaccine adjuvants, mechanisms of actions of vaccines, mechanisms of actions of adjuvants, vaccines design and development.