From:  Flagellin fusion proteins as self-adjuvanting vaccines for viral infections and cancer

 Advantages and limitations of flagellin fusion proteins in comparison with other vaccine platforms.

PlatformExamplesCommonly used adjuvants *ProsCons
Live attenuatedMMR, BCG, yellow fever

  • Typically none

  • Strong, long-lasting cellular and humoral immunity

  • Mimics natural infection

  • A single dose can sometimes be sufficient

  • Good induction of CD8+ T-cell responses

  • Risk of reversion to virulent form

  • Risk of disease in immunocompromised patients

  • Requires an effective cold-chain

  • Difficult manufacturing

Inactivated (killed)Hepatitis A, Polio (IPV), Rabies

  • Alum

  • MF59

  • CpG 1018

  • Stable and safe

  • No risk of reversion or disease

  • Often requires multiple doses and boosters

  • Weaker immune response than live vaccines

Viral vector (non-replicating)AstraZeneca COVID-19, J&J

  • Typically none

  • Strong cellular and humoral immunity

  • Good induction of CD8+ T-cell responses

  • Pre-existing vector immunity may reduce efficacy

  • Risk of vector-related side effects

  • Requires an effective cold-chain

Subunit/Recombinant proteinHepatitis B, HPV, Shingrix

  • Alum

  • MF59

  • CpG 1018

  • Matrix-M

  • Very safe

  • Well-characterized antigens

  • Scalable production

  • Weak immunogenicity

  • Requires careful choice of the most relevant epitopes

  • Needs strong adjuvants

  • Poor induction of CD8+ T-cell responses

ToxoidDiphtheria, tetanus

  • Alum

  • Highly safe

  • Shorter immunity

  • Requires boosters

  • Limited to toxin diseases

  • Poor induction of CD8+ T-cell responses

mRNAPfizer-BioNTech, Moderna COVID-19

  • mRNA itself

  • Rapid design and development

  • Strong immunogenicity

  • No risk of infection

  • Good induction of CD8+ T-cell responses

  • Stability relatively low

  • Requires ultra-cold distribution and storage (some versions)

DNAZyCoV-D (India), Inovio (trials)

  • DNA itself

  • Stable for distribution and storage

  • No risk of infection

  • Induces both arms of immunity

  • Good induction of CD8+ T-cell responses

  • Low immunogenicity in humans so far

  • Needs to enter the nucleus

  • Requires electroporation or complex transfection formulation

Virus-like particles (VLPs)HPV (Gardasil), Hepatitis B (some forms)

  • Alum

  • AS04

  • Highly immunogenic

  • Safe (non-infectious)

  • Complex manufacturing

  • Costlier than simple subunits

  • Poor induction of CD8+ T-cell responses

FlagellinExperimental

  • None

  • Highly immunogenic

  • Can induce mucosal immunity

  • Can be given intranasally

  • Does not require a separate adjuvant

  • Simple formulation

  • Stable for distribution and storage

  • Can polymerise to enable repeating epitope display

  • Induction of CD8+ T-cell responses

  • Requires careful choice of the most relevant epitopes for fusion

  • Requires endotoxin removal unless expressed in yeast or mammalian systems

  • Not all protein partners will fold correctly within the preferred D3 domain location

  • Off-patent platform limits interest from investors

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*: Live attenuated and viral vector vaccines typically do not require an adjuvant as the vector oranisms contain a range of naturally occuring PAMPs, alum (usually aluminium hydroxide or aluminim phosphate) promotes immunogenicity via inflammasome activation, MF59 (a squalene oil-in-water emulsion) and Matrix M (a saponin-based nanoparticle) appear to work by promoting inflammation via localised cellular damage, CpG 1018 (a synthetic DNA) and the DNA present in DNA vaccines function as TLR9 agonists via their CpG motifs, modified mRNA in RNA vaccines is an agonist of TLR7/8, AS04 (a mixture of alum and monophosphoryl lipid A) is a weak activator of TLR4. BCG: Bacillus Calmette-Guérin; MMR: measles, mumps, and rubella; PAMPs: Pathogen-Associated Molecular Patterns; TLR: Toll-like receptor.