Skip to main content
SpringerLink
Log in

Formulation Approaches and Strategies for Vaccines and Adjuvants

  • Chapter
  • First Online:
Sterile Product Development

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 6))

  • 4266 Accesses

Abstract

In order to create safe and efficacious vaccines, formulations that confer stability must generally be developed. In this chapter, formulation considerations consisting of solution conditions, particles, delivery route, endotoxin level, and preservatives will be covered along with the addition of adjuvants currently approved for use in vaccines and adjuvants currently being researched. Methods to increase vaccine stability and analytical techniques used to monitor vaccines will be discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 229.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 299.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 299.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Adams MM et al (2010) Design and synthesis of potent Quillaja saponin vaccine adjuvants. J Am Chem Soc 132(6):1939–1945

    Article  PubMed  CAS  Google Scholar 

  • Akers MJ, Vasudevan V, Stickelmeyer M (2002) Formulation development of protein dosage forms. In: Nail SL, Akers MJ (eds) Development and manufacture of protein pharmaceuticals. Kluwer Academic/Plenum Publishers, New York, pp 47–127

    Chapter  Google Scholar 

  • Amorij JP et al (2008) Development of stable influenza vaccine powder formulations: challenges and possibilities. Pharm Res 25(6):1256–1273

    Article  PubMed  CAS  Google Scholar 

  • Aucouturier J et al (2002) Montanide ISA 720 and 51: a new generation of water in oil emulsions as adjuvants for human vaccines. Expert Rev Vaccines 1(1):111–118

    Article  PubMed  CAS  Google Scholar 

  • Aucouturier J, Ascarateil S, Dupuis L (2006) The use of oil adjuvants in therapeutic vaccines. Vaccine 24:S44–S45

    Article  Google Scholar 

  • Bachmann MF, Jennings GT (2010) Vaccine delivery: a matter of size, geometry, kinetics and molecular patterns. Nat Rev Immunol 10(11):787–796

    Article  PubMed  CAS  Google Scholar 

  • Bal SM et al (2010) Advances in transcutaneous vaccine delivery: do all ways lead to Rome? J Control Release 148(3):266–282

    Article  PubMed  CAS  Google Scholar 

  • Baldridge JR et al (2004) Taking a toll on human disease: toll-like receptor 4 agonists as vaccine adjuvants and monotherapeutic agents. Expert Opin Biol Ther 4(7):1129–1138

    Article  PubMed  CAS  Google Scholar 

  • Bee JS et al (2009) Monoclonal antibody interactions with micro- and nanoparticles: adsorption, aggregation, and accelerated stress studies. J Pharm Sci 98(9):3218–3238

    Article  PubMed  CAS  Google Scholar 

  • Berthold I et al (2005) Immunogenicity in mice of anthrax recombinant protective antigen in the presence of aluminum adjuvants. Vaccine 23(16):1993–1999

    Article  PubMed  CAS  Google Scholar 

  • Boland G et al (2004) Safety and immunogenicity profile of an experimental hepatitis B vaccine adjuvanted with AS04. Vaccine 23(3):316–320

    Article  PubMed  CAS  Google Scholar 

  • Bowey K, Neufeld RJ (2010) Systemic and mucosal delivery of drugs within polymeric microparticles produced by spray drying. BioDrugs 24(6):359–377

    Article  PubMed  CAS  Google Scholar 

  • Brandau DT et al (2003) Thermal stability of vaccines. J Pharm Sci 92(2):218–231

    Article  PubMed  CAS  Google Scholar 

  • Braun LJ et al (2009) Development of a freeze-stable formulation for vaccines containing aluminum salt adjuvants. Vaccine 27(1):72–79

    Article  PubMed  CAS  Google Scholar 

  • Brazeau GA et al (1998) Current perspectives on pain upon injection of drugs. J Pharm Sci 87(6):667–677

    Article  PubMed  CAS  Google Scholar 

  • Brito LA, Singh M (2011) Acceptable levels of endotoxin in vaccine formulations during preclinical research. J Pharm Sci 100(1):34–37

    Article  PubMed  CAS  Google Scholar 

  • Burger JL et al (2008) Stabilizing formulations for inhalable powders of live-attenuated measles virus vaccine. J Aerosol Med Pulm Drug Deliv 21(1):25–34

    Article  PubMed  CAS  Google Scholar 

  • Carpenter JF et al (1997) Rational design of stable lyophilized protein formulations: some practical advice. Pharm Res 14(8):969–975

    Article  PubMed  CAS  Google Scholar 

  • Casella CR, Mitchell TC (2008) Putting endotoxin to work for us: monophosphoryl lipid A as a safe and effective vaccine adjuvant. Cell Mol Life Sci 65(20):3231–3240

    Article  PubMed  CAS  Google Scholar 

  • Chang BS, Hershenson S (2002) Practical approaches to protein formulation development. Pharm Biotechnol 13:1–25

    Article  PubMed  CAS  Google Scholar 

  • Chang M et al (2001) Degree of antigen adsorption in the vaccine or interstitial fluid and its effect on the antibody response in rabbits. Vaccine 19(20–22):2884–2889

    Article  PubMed  CAS  Google Scholar 

  • Clapp T et al (2011) Vaccines with aluminum-containing adjuvants: optimizing vaccine efficacy and thermal stability. J Pharm Sci 100(2):388–401

    Article  PubMed  CAS  Google Scholar 

  • Clausi A et al (2008a) Influence of particle size and antigen binding on effectiveness of aluminum salt adjuvants in a model lysozyme vaccine. J Pharm Sci 97(12):5252–5262

    Article  PubMed  CAS  Google Scholar 

  • Clausi AL et al (2008b) Inhibition of aggregation of aluminum hydroxide adjuvant during freezing and drying. J Pharm Sci 97(6):2049–2061

    Article  PubMed  CAS  Google Scholar 

  • Clausi AL et al (2009) Influence of protein conformation and adjuvant aggregation on the effectiveness of aluminum hydroxide adjuvant in a model alkaline phosphatase vaccine. J Pharm Sci 98(1):114–121

    Article  PubMed  CAS  Google Scholar 

  • Cleland JL et al (1996) Isomerization and formulation stability of the vaccine adjuvant QS-21. J Pharm Sci 85(1):22–28

    Article  PubMed  CAS  Google Scholar 

  • Cooper CL et al (2005) CPG 7909 adjuvant improves hepatitis B virus vaccine seroprotection in antiretroviral-treated HIV-infected adults. AIDS 19(14):1473–1479

    Article  PubMed  CAS  Google Scholar 

  • Corradin G, Giudice Giuseppe D (2005) Novel adjuvants for vaccines. Curr Med Chem Anti Inflamm Anti Allergy Agents 4(2):185–191

    Article  CAS  Google Scholar 

  • Davis SS (2001) Nasal vaccines. Adv Drug Deliv Rev 51(1–3):21–42

    Article  PubMed  CAS  Google Scholar 

  • Descamps D et al (2009) Safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine for cervical cancer prevention: a pooled analysis of 11 clinical trials. Hum Vaccin 5(5):332–340

    Article  PubMed  Google Scholar 

  • Devriendt B et al (2012) Crossing the barrier: targeting epithelial receptors for enhanced oral vaccine delivery. J Control Release 160(3):431–439

    Article  PubMed  CAS  Google Scholar 

  • Diminsky D et al (1999) Physical, chemical and immunological stability of CHO-derived hepatitis B surface antigen (HBsAg) particles. Vaccine 18(1–2):3–17

    Article  PubMed  CAS  Google Scholar 

  • Dong A et al (2006) Secondary structures of proteins adsorbed onto aluminum hydroxide: infrared spectroscopic analysis of proteins from low solution concentrations. Anal Biochem 351(2):282–289

    Article  PubMed  CAS  Google Scholar 

  • Egan PM et al (2009) Relationship between tightness of binding and immunogenicity in an aluminum-containing adjuvant-adsorbed hepatitis B vaccine. Vaccine 27(24):3175–3180

    Article  PubMed  CAS  Google Scholar 

  • Evans TG et al (2001) QS-21 promotes an adjuvant effect allowing for reduced antigen dose during HIV-1 envelope subunit immunization in humans. Vaccine 19(15–16):2080–2091

    Article  PubMed  CAS  Google Scholar 

  • FDA (2012a) Vaccines licensed for immunization and distribution in the US with supporting documents. Available from http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm093830.htm

  • FDA (2012b) Thimerosal in vaccines. [Online]. Available from http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/VaccineSafety/UCM096209

  • Fradkin AH, Carpenter JF, Randolph TW (2011) Glass particles as an adjuvant: a model for adverse immunogenicity of therapeutic proteins. J Pharm Sci 100(11):4953–4964

    Article  PubMed  CAS  Google Scholar 

  • Frokjaer S, Otzen DE (2005) Protein drug stability: a formulation challenge. Nat Rev Drug Discov 4(4):298–306

    Article  PubMed  CAS  Google Scholar 

  • Garcon N, Chomez P, Van Mechelen M (2007) GlaxoSmithKline adjuvant systems in vaccines: concepts, achievements and perspectives. Expert Rev Vaccines 6(5):723–739

    Article  PubMed  CAS  Google Scholar 

  • Geier DA, Jordan SK, Geier MR (2010) The relative toxicity of compounds used as preservatives in vaccines and biologics. Med Sci Monit 16(5):SR21–SR27

    PubMed  CAS  Google Scholar 

  • Gnjatic S, Sawhney NB, Bhardwaj N (2010) Toll-like receptor agonists—are they good adjuvants? Cancer J 16(4):382–391

    Article  PubMed  CAS  Google Scholar 

  • Gorbet MB, Sefton MV (2005) Endotoxin: the uninvited guest. Biomaterials 26(34):6811–6817

    Article  PubMed  CAS  Google Scholar 

  • Hansen B et al (2011) Effect of the strength of adsorption of HIV 1 SF162dV2gp140 to aluminum-containing adjuvants on the immune response. J Pharm Sci 100(8):3245–3250

    Article  PubMed  CAS  Google Scholar 

  • Helling F et al (1995) GM2-KLH conjugate vaccine: increased immunogenicity in melanoma patients after administration with immunological adjuvant QS-21. Cancer Res 55(13):2783–2788

    PubMed  CAS  Google Scholar 

  • Hem SL et al (2010) Preformulation studies—the next advance in aluminum adjuvant-containing vaccines. Vaccine 28(31):4868–4870

    Article  PubMed  CAS  Google Scholar 

  • Holmgren J, Czerkinsky C (2005) Mucosal immunity and vaccines. Nat Med 11(4 suppl):S45–S53

    Article  PubMed  CAS  Google Scholar 

  • Kamerzell TJ et al (2011) Protein-excipient interactions: mechanisms and biophysical characterization applied to protein formulation development. Adv Drug Deliv Rev 63(13):1118–1159

    Article  PubMed  CAS  Google Scholar 

  • Kamstrup S et al (2000) Preparation and characterisation of quillaja saponin with less heterogeneity than Quil-A. Vaccine 18(21):2244–2249

    Article  PubMed  CAS  Google Scholar 

  • Kanchan V, Panda AK (2007) Interactions of antigen-loaded polylactide particles with macrophages and their correlation with the immune response. Biomaterials 28(35):5344–5357

    Article  PubMed  CAS  Google Scholar 

  • Kensil CR, Kammer R (1998) QS-21: a water-soluble triterpene glycoside adjuvant. Expert Opin Investig Drugs 7(9):1475–1482

    Article  PubMed  CAS  Google Scholar 

  • Kensil CR et al (1991) Separation and characterization of saponins with adjuvant activity from Quillaja saponaria Molina cortex. J Immunol 146(2):431–437

    PubMed  CAS  Google Scholar 

  • LiCalsi C et al (2001) A powder formulation of measles vaccine for aerosol delivery. Vaccine 19(17–19):2629–2636

    Article  PubMed  CAS  Google Scholar 

  • Lopez JA et al (2001) A synthetic malaria vaccine elicits a potent CD8(+) and CD4(+) T lymphocyte immune response in humans: implications for vaccination strategies. Eur J Immunol 31(7):1989–1998

    Article  PubMed  CAS  Google Scholar 

  • Lycke N (2004) From toxin to adjuvant: the rational design of a vaccine adjuvant vector, CTA1-DD/ISCOM. Cell Microbiol 6(1):23–32

    Article  PubMed  CAS  Google Scholar 

  • Maddux NR et al (2011) Multidimensional methods for the formulation of biopharmaceuticals and vaccines. J Pharm Sci 100(10):4171–4197

    Article  CAS  Google Scholar 

  • Magalhaes PO et al (2007) Methods of endotoxin removal from biological preparations: a review. J Pharm Sci 10(3):388–404

    Google Scholar 

  • Malyala P, Singh M (2008) Endotoxin limits in formulations for preclinical research. J Pharm Sci 97(6):2041–2044

    Article  PubMed  CAS  Google Scholar 

  • Manning MC, Patel K, Borchardt RT (1989) Stability of protein pharmaceuticals. Pharm Res 6(11):903–918

    Article  PubMed  CAS  Google Scholar 

  • Mbawuike I, Zang Y, Couch RB (2007) Humoral and cell-mediated immune responses of humans to inactivated influenza vaccine with or without QS21 adjuvant. Vaccine 25(17):3263–3269

    Article  PubMed  CAS  Google Scholar 

  • Mbow ML et al (2010) New adjuvants for human vaccines. Curr Opin Immunol 22(3):411–416

    Article  PubMed  CAS  Google Scholar 

  • McKenzie A, Watt M, Gittleson C (2010) ISCOMATRIX vaccines—safety in human clinical studies. Hum Vaccin 6(3):237–246

    Article  CAS  Google Scholar 

  • Morel S et al (2011) Adjuvant system AS03 containing alpha-tocopherol modulates innate immune response and leads to improved adaptive immunity. Vaccine 29(13):2461–2473

    Article  PubMed  CAS  Google Scholar 

  • Moser C, Amacker M, Zurbriggen R (2011) Influenza virosomes as a vaccine adjuvant and carrier system. Expert Rev Vaccines 10(4):437–446

    Article  PubMed  CAS  Google Scholar 

  • Naylor PH et al (2010) IRX-2 increases the T cell-specific immune response to protein/peptide vaccines. Vaccine 28(43):7054–7062

    Article  PubMed  CAS  Google Scholar 

  • Nechansky A, Kircheis R (2010) Immunogenicity of therapeutics: a matter of efficacy and safety. Expert Opin Drug Discov 5(11):1067–1079

    Article  PubMed  CAS  Google Scholar 

  • Noe SM et al (2010) Mechanism of immunopotentiation by aluminum-containing adjuvants elucidated by the relationship between antigen retention at the inoculation site and the immune response. Vaccine 28(20):3588–3594

    Article  PubMed  CAS  Google Scholar 

  • O’Hagan DT, De Gregorio E (2009) The path to a successful vaccine adjuvant—‘The long and winding road’. Drug Discov Today 14(11–12):541–551

    Article  PubMed  Google Scholar 

  • O’Hagan DT, Ott GS, Van Nest G (1997) Recent advances in vaccine adjuvants: the development of MF59 emulsion and polymeric microparticles. Mol Med Today 3(2):69–75

    Article  PubMed  Google Scholar 

  • O’Hagan DT et al (2011) MF59 adjuvant: the best insurance against influenza strain diversity. Expert Rev Vaccines 10(4):447–462

    Article  PubMed  Google Scholar 

  • Oyewumi MO, Kumar A, Cui Z (2010) Nano-microparticles as immune adjuvants: correlating particle sizes and the resultant immune responses. Expert Rev Vaccines 9(9):1095–1107

    Article  PubMed  CAS  Google Scholar 

  • Pearse MJ, Drane D (2005) ISCOMATRIX(R) adjuvant for antigen delivery. Adv Drug Deliv Rev 57:465–474

    Article  PubMed  CAS  Google Scholar 

  • Peek LJ et al (2007) Effects of stabilizers on the destabilization of proteins upon adsorption to aluminum salt adjuvants. J Pharm Sci 96(3):547–557

    Article  PubMed  CAS  Google Scholar 

  • Pulendran B, Ahmed R (2011) Immunological mechanisms of vaccination. Nat Immunol 12(6):509–517

    Article  PubMed  CAS  Google Scholar 

  • Rappuoli R et al (2011) Vaccines for the twenty-first century society. Nat Rev Immunol 11(12):865–872

    PubMed  CAS  Google Scholar 

  • Reed SG et al (2009) New horizons in adjuvants for vaccine development. Trends Immunol 30(1):23–32

    Article  PubMed  CAS  Google Scholar 

  • Roestenberg M et al (2008) Safety and immunogenicity of a recombinant Plasmodium falciparum AMA1 malaria vaccine adjuvanted with Alhydrogel, Montanide ISA 720 or AS02. PLoS One 3(12):e3960

    Article  PubMed  Google Scholar 

  • Romero Mendez IZ et al (2007) Potentiation of the immune response to non-adsorbed antigens by aluminum-containing adjuvants. Vaccine 25(5):825–833

    Article  PubMed  CAS  Google Scholar 

  • Rowe RC, Sheskey PJ, Quinn ME (2009) Handbook of pharmaceutical excipients. Pharmaceutical Press, London

    Google Scholar 

  • Russell-Jones GJ (2000) Oral vaccine delivery. J Control Release 65(1–2):49–54

    Article  PubMed  CAS  Google Scholar 

  • Schultze V et al (2008) Safety of MF59 adjuvant. Vaccine 26(26):3209–3222

    Article  PubMed  CAS  Google Scholar 

  • Seeber SJ, White JL, Hem SL (1991) Predicting the adsorption of proteins by aluminium-containing adjuvants. Vaccine 9(3):201–203

    Article  PubMed  CAS  Google Scholar 

  • Shire SJ, Shahrokh Z, Liu J (2004) Challenges in the development of high protein concentration formulations. J Pharm Sci 93(6):1390–1402

    Article  PubMed  CAS  Google Scholar 

  • Singh M et al (2006) A preliminary evaluation of alternative adjuvants to alum using a range of established and new generation vaccine antigens. Vaccine 24(10):1680–1686

    Article  PubMed  CAS  Google Scholar 

  • Sou T et al (2011) New developments in dry powder pulmonary vaccine delivery. Trends Biotechnol 29(4):191–198

    Article  PubMed  CAS  Google Scholar 

  • Steinhagen F et al (2011) TLR-based immune adjuvants. Vaccine 29(17):3341–3355

    Article  PubMed  CAS  Google Scholar 

  • Stolnik S, Shakesheff K (2009) Formulations for delivery of therapeutic proteins. Biotechnol Lett 31(1):1–11

    Article  PubMed  CAS  Google Scholar 

  • Stoute JA et al (1997) A preliminary evaluation of a recombinant circumsporozoite protein vaccine against Plasmodium falciparum malaria. N Engl J Med 336(2):86–91

    Article  PubMed  CAS  Google Scholar 

  • Sun H-X, Xie Y, Ye Y-P (2009) ISCOMs and ISCOMATRIX. Vaccine 27:4388–4401

    Article  PubMed  CAS  Google Scholar 

  • Titkov ES, Oganesian GA (1995) The chronic action of large doses of aluminum on nervous and cardiac activities in rats administered it intramuscularly. Zh Evol Biokhim Fiziol 31(1):52–58

    PubMed  CAS  Google Scholar 

  • Vajdy M et al (2004) Mucosal adjuvants and delivery systems for protein-, DNA- and RNA-based vaccines. Immunol Cell Biol 82(6):617–627

    Article  PubMed  CAS  Google Scholar 

  • Vecchi S et al (2012) Aluminum adjuvant dose guidelines in vaccine formulation for preclinical evaluations. J Pharm Sci 101(1):17–20

    Article  PubMed  CAS  Google Scholar 

  • Vessely C et al (2009) Stability of a trivalent recombinant protein vaccine formulation against botulinum neurotoxin during storage in aqueous solution. J Pharm Sci 98(9):2970–2993

    Article  PubMed  CAS  Google Scholar 

  • Vogel FR (2000) Improving vaccine performance with adjuvants. Clin Infect Dis 30(suppl 3):S266–S270

    Article  PubMed  CAS  Google Scholar 

  • Volkin DB et al (2002) Preformulation studies as an essential guide to formulation development and manufacture of protein pharmaceuticals. Pharm Biotechnol 14:1–46

    Article  PubMed  CAS  Google Scholar 

  • Wang W et al (2007) Antibody structure, instability, and formulation. J Pharm Sci 96(1):1–26

    Article  PubMed  CAS  Google Scholar 

  • WHO (1977) Manual for the production and control of vaccines—tetanus toxoid. BLG/UNDP/77.2 Rev. 1

    Google Scholar 

  • WHO, UNICEF, World Bank (2009) State of world’s vaccines and immunization, 3rd edn. World Health Organization, Geneva

    Google Scholar 

  • Wilson-Welder JH et al (2009) Vaccine adjuvants: current challenges and future approaches. J Pharm Sci 98(4):1278–1316

    Article  PubMed  CAS  Google Scholar 

  • Worrall EE et al (2001) Xerovac: an ultra rapid method for the dehydration and preservation of live attenuated Rinderpest and Peste des Petits ruminants vaccines. Vaccine 19(28–29):834–839

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Chemical and Biological Engineering, University of Colorado, Boulder, CO, USA

    Kimberly J. Hassett & Theodore W. Randolph

  2. Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, USA

    Pradyot Nandi

Authors
  1. Kimberly J. Hassett
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pradyot Nandi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Theodore W. Randolph
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Theodore W. Randolph .

Editor information

Editors and Affiliations

  1. Pharmaceutical R&D-BioTx Pharmaceutical, Chesterfield, Missouri, USA

    Parag Kolhe

  2. LifeCell Corporation, Bridgewater, New Jersey, USA

    Mrinal Shah

  3. Drug Product Engineering, Amgen, Thousand Oaks, California, USA

    Nitin Rathore

Rights and permissions

Reprints and permissions

Copyright information

© 2013 American Association of Pharmaceutical Scientists

About this chapter

Cite this chapter

Hassett, K.J., Nandi, P., Randolph, T.W. (2013). Formulation Approaches and Strategies for Vaccines and Adjuvants. In: Kolhe, P., Shah, M., Rathore, N. (eds) Sterile Product Development. AAPS Advances in the Pharmaceutical Sciences Series, vol 6. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7978-9_6

Download citation

Publish with us

Policies and ethics

Search

Navigation