I M M U N O L O G I C

A D J U V A N T SFreddy ChoyJoyce Lau

Agenda What are Adjuvants History of Adjuvants Reason for

Adjuvants Factors Affecting

Adjuvant Efficacy “Ideal Adjuvant”

Common Issues of Adjuvants

Types of Adjuvants Adjuvant in

Research Vaxjo Regulatory Hurdles Future Outlook

What are Adjuvants?

Adjuvare [Latin] - to help, to enhance Any product (or association of

components) that increases or modulates the humoral or cellular immune response against an antigen

“Universal adjuvant” non existent

History of Adjuvants 1925: Observed that the highest

antibody titers when local inflammation was induced by concomitant injection of other substances – tapioca, aluminum salts, lanolin etc.

1926: Introduced use of aluminum hydroxide as adjuvant in diphtheria toxoid

Reasons for Adjuvants1. To enhance the immunogenicity and potency of

highly purified or recombinant antigens

2. Reduce the amount of antigen required; and subsequent immunizations

3. To improve the efficacy of vaccines in newborns, the elderly or immuno-compromised persons

4. As antigen delivery systems for the uptake of antigens by the mucosa

Factors Affecting Adjuvant Efficacy Limited knowledge

of disease pathogenesis

Knowledge of MOA Target population

Genetic variation

Host immune status

Formulation of the vaccine + adjuvantDose,

combination, etc.

“Ideal Adjuvant” Safe and free from immediate + long-term side effects Biodegradable / easily excreted after adjuvant has

elicited its effects Exhibit protective / therapeutic immune response

when combined with antigen Chemically and biologically defined Efficacy of vaccine achieved with fewer doses / lower

concentration of antigen Shelf stable Affordable

Common Issues of Adjuvants

Little known about MOA Frequently induce toxicity Strong local stimulation Carcinogenesis Complicated preparations

Types of Adjuvants Mineral Salts: Aluminum salts

Standard adjuvant approved for human usePoor at inducing cellular immune responsePotential for aluminium intoxication

Emulsions: two immiscible liquids stabilized with surfactants/emulsifiersAllows slow release of antigenHighly toxic

Types of Adjuvants Microorganism-derived: Bacterial or fungal

substancesi.e. bacterial cell wall peptidoglycan or LPSStimulates humoral & cellular responses

Particulates: microscopic particlesVirosomes – induce potent immune responseLiposomes – potency depends on # of lipid layers,

electric charge, composition & preparation methodNano-beads – induce substantial cell mediated response

& moderate humoral response

Adjuvant in Research Phytol: natural, dietary diterpene alcohol

PHIS-01: hydrogenated derivative 2 recent studies in mice; similar findings

Low pro-inflammatory effectsSmall amounts of phytol + PHIS-01 required to stimulate

immune responses

PHIS-01 appears to be more useful than phytol

Vaxjo Central web-based vaccine adjuvant database and

analysis resourceCompliments VIOLIN

Published in the Journal of Biomedicine and Biotechnology in 2011

Comprehensive to include a large variety of infectious diseases, and diseases including cancer and allergies

Challenges and obstacles http://www.violinet.org/vaxjo/

Preclinical studies on adjuvantSame route of administrationDose & frequency similar to proposed

Toxicology studies on antigen-adjuvant formulation

Large population size required for testing

Regulatory Hurdles

Future Outlook Approval for additional human adjuvants Safer alternatives Longer lasting and stronger immunogenicity Define reliable animal models for adjuvant studies Define study protocols for safe and pivotal

observations Determine standards to test lots of adjuvants

Thank you!

Works Cited Petrovsky N., Aguilar J.C. Vaccine adjuvants: current state and future trends. Immunol Cell Biol 2004;82(5):488–96. Vogel F.R. Adjuvants in perspective. In: Brown F, Haaheim LR, editors. Modulation of the immune response to vaccine antigens. Dev.

Biol. Stand. vol 92. Basel: Karger; 1998. p. 241–8. Lima K.M., Aparecida dos Santos S., Rodrigues J.M. Jr., Silva C.L. Vaccine adjuvant: it makes the difference. Vaccine 2004; 22:2374–

2379. Ramon G. Sur l’augmentation anormale de l’antitoxine chez les chevaux producteurs de serum antidiphterique. Bull Soc Centr Med Vet

1925;101:227–34. Ramon G. Procedes pour accro¨ıtre la production des antitoxins. Ann Inst Pasteur 1926;40:1–10. Allison A.C., Byars N.E. Immunological adjuvants: desirable properties and side-effects. Mol Immunol 1991;28:279–84. Aguilar J.C., Rodriguez E.G. Vaccine adjuvants revisited. Vaccine 2007; 25:3752–3762 Freund J. The mode of action immunological adjuvants. Adv Tuberc Res 1956;7:50–5. Cox J. C., Coulter A. R. Adjuvants – a classification and review of their modes of action. Vaccine 1997;15:248-256. Lim, S-Y., Meyer, M., Kjonaas, R.A., Ghosh, S.K. Phytol-based novel adjuvants in vaccine formulation: 1. Assessment of safety and

efficacy during stimulation of humoral and cell-mediated immune responses. Journal of Immune Based Therapies and Vaccines 2006; 4:6.

Aachoui, Y., Ghosh, S.K., Immune enchancement by novel vaccine adjuvants in autoimmune-prone NZB/W F1 mice: relative efficacy and safety. BMC Imunology 2011; 12:61.

Walker, J.M. (2000). Vaccine Adjuvants: Preparation Methods and Research Protocols. D. T. O’Hagan (Ed.). Emeryville, CA: Humana Press.

Lima, K.M., dos Santos, S.A., Rodrigues, Jr., J.M., Silva, C.L., Vaccine adjuvant: it makes the difference. Vaccine 2004; 22:2374-2379. Bagherwal, P., Dwivedi, S.K. A Review: Adjuvants Designed for Vaccine. International Journal of Pharmaceutical & Research Sciences

2012; 1(2):113-126. Brennan F. R., Dougan G. Non-clinical safety evaluation of novel vaccines and adjuvants: new products, new strategies. Vaccines

2005;23:3210-3222. The European Agency for the Evaluation of Medicinal Products. Guideline on Adjuvants in Vaccines v5 Consultation (25 March 2004). Couch RB. Nasal vaccination, Escherichia coli enterotoxin, and Bell’s palsy. N Engl J Med 2004;350:860–1. Murphy TV, Gargiullo PM, Massoudi MS, Nelson DB, Jumaan AO, Okoro CA, et al. Intussusception among infants given an oral

rotavirus vaccine. N Engl J Med 2001;344:564–72.