Table 2 Main characteristics of the representative of bacterial original immunostimulants
Immunosimulants | Additional information | Immune responses | The merits | The drawbacks | (Potential) applications |
|---|---|---|---|---|---|
MPL | Detoxified TLR4 ligand | TLR4-TRIF signaling; TNF-α, IL-6, IFN-γ production; Th1 response | induce high and persistent-specific antibody responses | Contains several different MPL species that vary in length and degree/type of fatty acid acylation; MPL manufacturing process from LPS is complexity; hydrophobic nature; local adverse events (pain, erythema and swelling) | A component of AS04 in HBV vaccine Fendrix, and HPV vaccine Cervarix, a component of AS01 in varicella zoster vaccine Shingrix; vaccines targeting infectious diseases; vaccines targeting allergens; vaccines targeting cancers |
Bacterial lipoproteins/lipopeptides | Lipidated N-terminus of bacterial lipoproteins behave as potent adjuvant; Representative synthetic lipopeptide: PamnCys analogues Macrophage-activating Lipopeptide-2 (MALP-2) from Mycoplasma fermentans was synthesized as Pam2Cys; Pam3Cys ligand is derived from the N-terminal motif of Braun’s lipoprotein, a murein lipoprotein found in the cell walls of Gram-negative bacteria | PamnCys analogues activate TLR2/TLR1 or TLR2/TLR6 signaling; IFN-γ and TNF-α production; Th1, Th17 response | Potential to be a self-adjuvating vaccine; ease of design and synthesis small molecule lipopeptide | Potential adverse side effect due to the antigenic domain of a bacterial lipoprotein; structures of full-length bacterial lipoproteins are few and far between | self-or auto-adjuvating vaccine candidates |
Flagellin | Co-mixed with antigens; Chimeric expression or co-display of flagellin and foreign antigens in live bacterial strains; Recombinant proteins consisting of heterologous antigens fused to flagellin | TLR5 signaling with TNF-α, IL-10, IL-8, IFN-γ production; NLRC4/NAIP5 signaling with IL-1β production; Th1 and Th2 response | Excellent adjuvant activity (low dose); modifiable; flexible and efficient for antigen delivery | Anti-flagellin antibody could interfere with its adjuvant activity; potential low immune response to antigens fused to flagellin | Mucosal vaccines; antigen delivery vehicle; immunotherapy |
Bacterial CpG oligonucleotides | synthetic oligodeoxynucleotides containing a CpG ODN mimicking bacterial DNA | TLR9 and B-cell receptor or Src kinase family signaling; TNF-α, IL-1β, IL-1α, IL-6 production; Th1 response | Mucosal immune responses; boost immunity in groups with reduced immune function; directly activate human B cells | upregulation of indoleamine 2,3-dioxigenase expression in DCs, a well-described mediator of immunological tolerance; frequency and severity of local adverse events (injection site reactions such as pain, swelling, induration, pruritus, and erythema) and systemic symptoms (including flu-like symptoms) were elevated; increased host susceptibility to autoimmune disease or a predisposition to toxic shock | CpG1018 in hepatitis B vaccine (approved by FDA in 2017); Vaccines targeting allergens; Vaccines targeting cancer; Adjuvant for DNA vaccine; Applications in enhancing the immune responses of vaccines in immunocompromised populations |
Cholera toxin subunite | CTB forms a ring-like structure composed of five CTB monomers; Recombinant proteins consisting of heterologous antigens fused to CTB; Co-mixed with antigens | GM1 receptor mediating uptake; IL-4, IL-10, IFN-γ, IL-1β production; Th2 and Th1 response | mucosal immune responses; stability; ease to express CTB; modifiable; recognition receptor GM1 expressed in B cells | Potential low expression level with fusion antigen to CTB | Mucosal adjuvant; antigen delivery vehicle; Adjuvant for DNA vaccine; Vaccines targeting allergens and autoimmune disorders |
Bacterial OMVs | OMVs display a complex array of PAMPs, such as LPS, flagellin, and peptidoglycan, in their native conformation; Engineered to express antigenic proteins of interest or modulate toxicity and adjuvating effect, or target delivery | OMV-associated PAMPs contributing to innate immune response in various cell types; Th1 and Th2 response | Modifiable; nanoparticles | Toxicity of LPS and other OMPs; high cost for manufacture | OMV-based vaccine against meningococcus MenB (4CMenB, Bexsero; GSK); Antigen-delivering platform; immunotherapy; mucosal adjuvant |
Corynebacterium parvum | unique aspecific antiviral properties | interferon family, IL-8, IL-1b, TNF-α, IL-12, IL-15, GM-CSF induction; TLR2, TLR9, and MyD88 signaling; Th1 response | Strong macrophage activator; increase lymphocyte count (helper and killer lymphocytes) | Non-specific activation; Side effect like fever, malaise, and local reactions at the site of injection; potential for causing disease; enhance the toxicity of LPS endotoxin | antiviral activity during a pandemic emergency; cancer treatment; applications in enhancing the immune responses of certain vaccines |
BCG-CWS | a basic structure composed of mycolic acid, arabinogalactan, and peptidoglycan | TLR2 and TLR4, C-type lectin receptors signaling; TNF-α, IL-6, and IL-12 p40 production; Th1 response | long-lasting adaptive immune response | Insoluble in both aqueous and organic solvents; limited routes of administration and strong local inflammation | cancer treatment |
OK-432 | A streptococcal preparation | Activating various aspects of the immune response; IL-6, IL-8, IFN-γ, TNF-α, IL-12 p70 production; Th1 response | Potent and multifaced immune activation; a potent maturation factor for Mo-DCs | Side effect like fever, chill, and other flu-like symptoms; not tumor-specific | A cancer immunotherapy drug in Japan; Cancer treatment including lymphangiomas, pleural effusion due to lung cancer; otolaryngological cystic diseases therapy |