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Recent advances in the discovery and delivery of vaccine adjuvants

Nature Reviews Drug Discovery volume 2, pages 727–735 (2003) Cite this article

Key Points

  • Adjuvant is a term used to describe a variety of components co-administered with a vaccine that enhance the immunogenicity of vaccine antigens. These components can be broadly divided into two subsets on the basis of their dominant mechanism of action: delivery systems and immune potentiators.

  • The cells, receptors and signalling pathways of the innate immune system are important targets for improved delivery systems and immune potentiators. The integrated model of host defence indicates that optimal generation of antigen-specific memory (the goal of vaccination) requires innate immune activation.

  • Recent advances in elucidating the mechanisms of innate immune activation and the links between innate and adaptive responses have shown that numerous natural and synthetic compounds possess specific immune-potentiating activities. These compounds have promise as next generation vaccine adjuvants.

  • The identification of the imidizaquinoline class of SMIPs (small-molecule immune potentiators) as Toll-like receptor-dependent indicate that the small-molecule platform could be exploited for immune potentiator design and discovery.

  • Vaccine delivery systems are used to ensure that the antigens and immune potentiators included in a vaccine are able to interact with the appropriate tissues or cells to promote the induction of a potent immune response. Biodegradable microparticles are proving to be attractive delivery systems for both vaccine antigens and adjuvants.

  • Mucosal vaccine delivery systems are specifically designed to allow vaccines to be successfully applied to mucosal surfaces, mostly involving oral or intranasal administration. Important elements of mucosal delivery systems include components designed to protect antigens from degradation and to promote their interaction with mucosal-associated lymphoid tissue.

Abstract

Adjuvant design has historically had a touch of alchemy at its heart due to its reliance on the complex biology of innate immune activation. However, a new mechanistic understanding of innate immunity, combined with new adjuvant and delivery platforms for exploiting this knowledge, has led to significant advances recently. Although many challenges remain, the field is moving rapidly and the proper tools and methodologies are in place for the use of traditional drug discovery engines in guiding the development of vaccine adjuvants. In this review, we outline the current trends in immune potentiator, delivery system and adjuvant design that will shape the vaccines of the future.

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Figure 1: The three components of optimal subunit vaccines.
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Figure 2: The integrated model of vaccine efficacy.
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Figure 3: Antigen-presenting cells serve as the bridge between innate and antigen-specific responses.
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Figure 4: Representation of a cationic poly(lactide co-glycolide) (PLG) microparticle (1 μm mean size) with adsorbed DNA on the surface.
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Figure 5: A schematic representation of LT.
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Figure 6: In vitro and in vivo toxicity of various mutants of heat-labile enterotoxin from Escherichia coli.
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Acknowledgements

We would like to acknowledge the contributions of our colleagues in Chiron for their research efforts and ideas. In particular, we thank M. Giulianni, M. Grazia Pizza, R. Rappuoli and G. Del Giudice for the toxicity data on the LT mutants. In addition, we acknowledge the contributions of our colleagues in the Vaccine Delivery Group at Chiron, Emeryville, USA. Finally, we thank N. Cronen for manuscript formatting.

Author information

Authors and Affiliations

  1. Chiron Corporation, Vaccines Research, 4560 Horton Street, Emeryville, 94608, California, USA

    Derek T. O'Hagan & Nicholas M. Valiante

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  1. Derek T. O'Hagan
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  2. Nicholas M. Valiante
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Corresponding author

Correspondence to Derek T. O'Hagan.

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DATABASES

LocusLink

CD14

CD80

CD86

CD91

Dectin1

TLR1

TLR2

TLR3

TLR4

TLR5

TLR6

TLR7

TLR8

TLR9

TLR10

TREM1

TREM2

FURTHER INFORMATION

Encyclopedia of Life Sciences

vaccination

vaccines: presentation

vaccines: subunit

Glossary

ADJUVANT

The functional definition of diverse components co-administered with vaccine antigens that enhance antigen-specific immune responses in vivo.

INNATE IMMUNITY

The system of rapid host defence that has evolved to respond to broad and highly conserved pathogen-associated molecular patterns (PAMPs).

IMMUNE POTENTIATOR

A natural or synthetic compound which directly activates immune cells through specific receptors and/or pathways.

DELIVERY SYSTEM

A vaccine formulation that localizes vaccine antigens and/or immune potentiators, and targets them to key immune cell types.

IMMUNOLOGICAL MEMORY

The long-lived protective immunity elicited by vaccines and many naturally occurring infections, which is mediated by expanded populations of previously activated B and T cells selected for their expression of specific receptors for the antigens of a given pathogen.

TOLL-LIKE RECEPTORS

(TLRs). An evolutionarily conserved family of pattern-recognition receptors that detect unique microbial products and allow rapid activation of innate immunity.

MICROPARTICLES

Particulate carrier systems in the micron size range, normally prepared with synthetic polymers, which can be used as delivery systems for drugs or vaccines that are usually trapped within the particles.

MF59

An oil-in-water microemulsion adjuvant which has been approved in Europe for use in combination with influenza vaccine in the elderly (Fluad).

POLY(LACTIDE CO-GLYCOLIDE)

(PLG). A biodegradable and biocompatible synthetic polymer that has been used to prepare a number of successfully marketed drug delivery systems.

HEAT-LABILE ENTEROTOXIN

(LT). A bacterial toxin secreted from Escherichia coli which is potently immuno-stimulatory when applied to mucosal surfaces and can also act as an adjuvant for co-administered antigens. However, the molecule is also the causative agent of traveller's diarrhoea.

TRANSCUTANEOUS IMMUNIZATION

Involves the topical application of vaccines, usually in a specially designed patch, and mediates effective immunization without penetrating the protective layer of the skin with a device or needle.

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O'Hagan, D., Valiante, N. Recent advances in the discovery and delivery of vaccine adjuvants. Nat Rev Drug Discov 2, 727–735 (2003). https://doi.org/10.1038/nrd1176

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