Skip to main content
SpringerLink
Log in

Advances in Vaccine Adjuvants: Nanomaterials and Small Molecules

  • Chapter
  • First Online:
Drug Delivery and Targeting

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 284))

  • 146 Accesses

Abstract

Adjuvants have been extensively and essentially formulated in subunits and certain inactivated vaccines for enhancing and prolonging protective immunity against infections and diseases. According to the types of infectious diseases and the required immunity, adjuvants with various acting mechanisms have been designed and applied in human vaccines. In this chapter, we introduce the advances in vaccine adjuvants based on nanomaterials and small molecules. By reviewing the immune mechanisms induced by adjuvants with different characteristics, we aim to establish structure–activity relationships between the physicochemical properties of adjuvants and their immunostimulating capability for the development of adjuvants for more effective preventative and therapeutic vaccines.

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 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 179.99
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

Abbreviations

AAHPs:

Amorphous aluminum hydroxyphosphate nanoparticles

AAHS:

Amorphous aluminum hydroxyphosphate sulfate

AlOOH:

Aluminum oxyhydroxide

APC:

Antigen presenting cell

CD:

Cluster of differentiation

CpG:

Cytosine-phosphodiester-guanine

DC:

Dendritic cell

FDA:

Food and Drug Administration

HAP:

Hydroxyapatite

HBsAg:

Hepatitis B surface antigen

HIV:

Human immunodeficiency virus

HPV:

Human papillomavirus

IFN-γ:

Interferon-γ

IgG:

Immunoglobulin G

IL:

Interleukin

LNPs:

Lipid nanoparticles

LPS:

Lipopolysaccharide

mRNA:

Messenger ribonucleic acids

NLRP3:

NOD-like receptor thermal protein domain associated protein 3

NR:

Nanorice

ODNs:

Oligodeoxynucleotides

OVA:

Ovalbumin

Poly(I:C):

Polyriboinosinic acid-polyribocytidylic acid

RBD:

Receptor-binding domain

SARS-CoV-2:

Severe acute respiratory syndrome coronavirus 2

STING:

Stimulator of interferon genes

Th1:

Type 1 T helper

Th2:

Type 2 T helper

TLR:

Toll-like receptor

TNF-α:

Tumor necrosis factor-α

VLPs:

Virus-like particles

WHO:

World Health Organization

References

  • Al-Shakhshir R, Regnier F, White JL et al (1994) Effect of protein adsorption on the surface charge characteristics of aluminium-containing adjuvants. Vaccine 12:472–474

    Article  CAS  PubMed  Google Scholar 

  • Al-Shakhshir RH, Regnier FE, White JL et al (1995) Contribution of electrostatic and hydrophobic interactions to the adsorption of proteins by aluminium-containing adjuvants. Vaccine 13:41–44

    Article  CAS  PubMed  Google Scholar 

  • Becker GD, Moulin V, Pajak B et al (2000) The adjuvant monophosphoryl lipid A increases the function of antigen-presenting cells. Int Immunol 12:807–815

    Article  PubMed  Google Scholar 

  • Bi S, Li M, Liang Z et al (2022) Self-assembled aluminum oxyhydroxide nanorices with superior suspension stability for vaccine adjuvant. J Colloid Interface Sci 627:238–246

    Article  CAS  PubMed  Google Scholar 

  • Campbell JD (2017) Development of the CpG adjuvant 1018: a case study. Methods Mol Biol 1494:15–27

    Article  CAS  PubMed  Google Scholar 

  • Caulfield MJ, Shi L, Wang S et al (2007) Effect of alternative aluminum adjuvants on the absorption and immunogenicity of HPV16 L1 VLPs in mice. Hum Vaccin 3:139–145

    Article  PubMed  Google Scholar 

  • Cervarix (n.d.). https://www.fda.gov/vaccines-blood-biologics/vaccines/cervarix. Accessed 14 Oct 2022

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

    Article  CAS  PubMed  Google Scholar 

  • Cote-Cyr M, Zottig X, Gauthier L et al (2022) Self-assembly of flagellin into immunostimulatory ring-like nanostructures as an antigen delivery system. ACS Biomater Sci Eng 8:694–707

    Article  CAS  PubMed  Google Scholar 

  • Dai L, Gao GF (2021) Viral targets for vaccines against COVID-19. Nat Rev Immunol 21:73–82

    Article  CAS  PubMed  Google Scholar 

  • Fu D, Wang M, Yang T et al (2022) Self-assembled flagella protein nanofibers induce enhanced mucosal immunity. Biomaterials 288:121733

    Article  CAS  PubMed  Google Scholar 

  • Gale EC, Roth GA, Smith AAA et al (2019) A nanoparticle platform for improved potency, stability, and adjuvanticity of poly(I:C). Adv Ther 3

    Google Scholar 

  • Glenny AT (1930) Insoluble precipitates in diphtheria and tetanus immunization. Br Med J 2:244–245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gregorio ED, Tritto E, Rappuoli R (2008) Alum adjuvanticity: unraveling a century old mystery. Eur J Immunol 38:2068–2071

    Article  PubMed  Google Scholar 

  • Hafner AM, Corthesy B, Merkle HP (2013) Particulate formulations for the delivery of poly(I:C) as vaccine adjuvant. Adv Drug Deliv Rev 65:1386–1399

    Article  CAS  PubMed  Google Scholar 

  • Hansen B, Belfast M, Soung G et al (2009) Effect of the strength of adsorption of hepatitis B surface antigen to aluminum hydroxide adjuvant on the immune response. Vaccine 27:888–892

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Hayashi M, Aoshi T, Kogai Y et al (2016) Optimization of physiological properties of hydroxyapatite as a vaccine adjuvant. Vaccine 34:306–312

    Article  CAS  PubMed  Google Scholar 

  • Heil F, Hemmi H, Hochrein H et al (2004) Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 303:1526–1529

    Article  CAS  PubMed  Google Scholar 

  • Herck SV, Feng B, Tang L (2021) Delivery of STING agonists for adjuvanting subunit vaccines. Adv Drug Deliv Rev 179:114020

    Article  PubMed  Google Scholar 

  • HogenEsch H, O'Hagan DT, Fox CB (2018) Optimizing the utilization of aluminum adjuvants in vaccines: you might just get what you want. NPJ Vaccines 3:51

    Article  PubMed  PubMed Central  Google Scholar 

  • Hong X, Zhong X, Du G et al (2020) The pore size of mesoporous silica nanoparticles regulates their antigen delivery efficiency. Sci Adv 6:eaaz4462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Immunization Dashboard (n.d.). https://immunizationdata.who.int/. Accessed 14 Oct 2022

  • Iyer S, HogenEsch H, Hem SL (2003) Effect of the degree of phosphate substitution in aluminum hydroxide adjuvant on the adsorption of phosphorylated proteins. Pharm Dev Technol 8:81–86

    Article  CAS  PubMed  Google Scholar 

  • Janjua TI, Cao Y, Yu C et al (2021) Clinical translation of silica nanoparticles. Nat Rev Mater 6:1072–1074

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kariko K, Ni H, Capodici J et al (2004) mRNA is an endogenous ligand for toll-like receptor 3. J Biol Chem 279:12542–12550

    Article  CAS  PubMed  Google Scholar 

  • Klinman DM (2004) Immunotherapeutic uses of CpG oligodeoxynucleotides. Nat Rev Immunol 4:249–258

    Article  CAS  PubMed  Google Scholar 

  • Klinman DM, Currie D, Lee G et al (2007) Systemic but not mucosal immunity induced by AVA prevents inhalational anthrax. Microbes Infect 9:1478–1483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kwon S, Kwon M, Im S et al (2022) mRNA vaccines: the most recent clinical applications of synthetic mRNA. Arch Pharm Res 45:245–262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lange T, Schilling AF, Peters F et al (2009) Proinflammatory and osteoclastogenic effects of beta-tricalciumphosphate and hydroxyapatite particles on human mononuclear cells in vitro. Biomaterials 30:5312–5318

    Article  CAS  PubMed  Google Scholar 

  • Lebre F, Sridharan R, Sawkins MJ et al (2017) The shape and size of hydroxyapatite particles dictate inflammatory responses following implantation. Sci Rep 7:2922

    Article  PubMed  PubMed Central  Google Scholar 

  • Li X, Aldayel AM, Cui Z (2014) Aluminum hydroxide nanoparticles show a stronger vaccine adjuvant activity than traditional aluminum hydroxide microparticles. J Control Release 173:148–157

    Article  CAS  PubMed  Google Scholar 

  • Li M, Cheng F, Xue C et al (2019) Surface modification of Stober silica nanoparticles with controlled moiety densities determines their cytotoxicity profiles in macrophages. Langmuir 35:14688–14695

    Article  CAS  PubMed  Google Scholar 

  • Li M, Liang Z, Chen C et al (2022) Virus-like particle-templated silica-adjuvanted nanovaccines with enhanced humoral and cellular immunity. ACS Nano 16:10482–10495

    Article  CAS  PubMed  Google Scholar 

  • Liang Z, Yang Y, Yu G et al (2021) Engineering aluminum hydroxyphosphate nanoparticles with well-controlled surface property to enhance humoral immune responses as vaccine adjuvants. Biomaterials 275:120960

    Article  CAS  PubMed  Google Scholar 

  • Liang Z, Wang X, Yu G et al (2022) Mechanistic understanding of the aspect ratio-dependent adjuvanticity of engineered aluminum oxyhydroxide nanorods in prophylactic vaccines. Nano Today 43:101445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin Y, Wang X, Huang X et al (2017) Calcium phosphate nanoparticles as a new generation vaccine adjuvant. Expert Rev Vaccines 16:895–906

    Article  CAS  PubMed  Google Scholar 

  • Lin LC, Huang CY, Yao BY et al (2019) Viromimetic STING agonist-loaded hollow polymeric nanoparticles for safe and effective vaccination against middle east respiratory syndrome coronavirus. Adv Funct Mater 29:1807616

    Article  PubMed  PubMed Central  Google Scholar 

  • Martins KA, Bavari S, Salazar AM (2015) Vaccine adjuvant uses of poly-IC and derivatives. Expert Rev Vaccines 14:447–459

    Article  CAS  PubMed  Google Scholar 

  • Moderna COVID-19 Vaccines (n.d.). https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/moderna-covid-19-vaccines. Accessed 14 Oct 2022

  • Moyer TJ, Kato Y, Abraham W et al (2020) Engineered immunogen binding to alum adjuvant enhances humoral immunity. Nat Med 26:430–440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • O’Neill CL, Shrimali PC, Clapacs ZP et al (2021) Peptide-based supramolecular vaccine systems. Acta Biomater 133:153–167

    Article  PubMed  PubMed Central  Google Scholar 

  • Orr MT, Khandhar AP, Seydoux E et al (2019) Reprogramming the adjuvant properties of aluminum oxyhydroxide with nanoparticle technology. NPJ Vaccines 4:1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oss CJV (1995) Hydrophobic, hydrophilic and other interactions in epitope-paratope binding. Mol Immunol 32:199–211

    Article  PubMed  Google Scholar 

  • Pardi N, Tuyishime S, Muramatsu H et al (2015) Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes. J Control Release 217:345–351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peng S, Cao F, Xia Y et al (2020) Particulate alum via Pickering emulsion for an enhanced COVID-19 vaccine adjuvant. Adv Mater 32:e2004210

    Article  PubMed  Google Scholar 

  • Pfizer-BioNTech COVID-19 Vaccines (n.d.). https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/pfizer-biontech-covid-19-vaccines. Accessed 14 Oct 2022

  • Pollet J, Chen WH, Strych U (2021) Recombinant protein vaccines, a proven approach against coronavirus pandemics. Adv Drug Deliv Rev 170:71–82

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rodrigues KA, Rodriguez-Aponte SA, Dalvie NC et al (2021) Phosphate-mediated coanchoring of RBD immunogens and molecular adjuvants to alum potentiates humoral immunity against SARS-CoV-2. Sci Adv 7

    Google Scholar 

  • Roy R, Kumar S, Verma AK et al (2014) Zinc oxide nanoparticles provide an adjuvant effect to ovalbumin via a Th2 response in Balb/c mice. Int Immunol 26:159–172

    Article  CAS  PubMed  Google Scholar 

  • Rudra JS, Banasik BN, Milligan GN (2018) A combined carrier-adjuvant system of peptide nanofibers and toll-like receptor agonists potentiates robust CD8+ T cell responses. Vaccine 36:438–441

    Article  CAS  PubMed  Google Scholar 

  • Ruwona TB, Xu H, Li X et al (2016) Toward understanding the mechanism underlying the strong adjuvant activity of aluminum salt nanoparticles. Vaccine 34:3059–3067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scheiermann J, Klinman DM (2014) Clinical evaluation of CpG oligonucleotides as adjuvants for vaccines targeting infectious diseases and cancer. Vaccine 32:6377–6389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schmidlin H, Diehl SA, Blom B (2009) New insights into the regulation of human B-cell differentiation. Trends Immunol 30:277–285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shi S, Zhu H, Xia X et al (2019) Vaccine adjuvants: understanding the structure and mechanism of adjuvanticity. Vaccine 37:3167–3178

    Article  CAS  PubMed  Google Scholar 

  • Shirai S, Shibuya M, Kawai A et al (2019) Lipid nanoparticles potentiate CpG-oligodeoxynucleotide-based vaccine for influenza virus. Front Immunol 10:3018

    Article  CAS  PubMed  Google Scholar 

  • Sugai T, Mori M, Nakazawa M et al (2005) A CpG-containing oligodeoxynucleotide as an efficient adjuvant counterbalancing the Th1/Th2 immune response in diphtheria-tetanus-pertussis vaccine. Vaccine 23:5450–5456

    Article  CAS  PubMed  Google Scholar 

  • Sun B, Xia T (2016) Nanomaterial-based vaccine adjuvants. J Mater Chem B 4:5496–5509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun B, Ji Z, Liao YP et al (2013) Engineering an effective immune adjuvant by designed control of shape and crystallinity of aluminum oxyhydroxide nanoparticles. ACS Nano 7:10834–10849

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun B, Pokhrel S, Dunphy DR et al (2015) Reduction of acute inflammatory effects of fumed silica nanoparticles in the lung by adjusting silanol display through calcination and metal doping. ACS Nano 9:9357–9372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun B, Ji Z, Liao YP et al (2017) Enhanced immune adjuvant activity of aluminum oxyhydroxide nanorods through cationic surface functionalization. ACS Appl Mater Interfaces 9:21697–21705

    Article  CAS  PubMed  Google Scholar 

  • Ulrich JT, Myers KR (1995) Monopbospboryl lipid a as an adjuvant, vol 6. Springer, Boston

    Google Scholar 

  • Vandepapeliere P, Horsmans Y, Moris P et al (2008) Vaccine adjuvant systems containing monophosphoryl lipid A and QS21 induce strong and persistent humoral and T cell responses against hepatitis B surface antigen in healthy adult volunteers. Vaccine 26:1375–1386

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Ihara S, Li X et al (2019) Si-doping increases the adjuvant activity of hydroxyapatite nanorods. Colloids Surf B Biointerfaces 174:300–307

    Article  CAS  PubMed  Google Scholar 

  • Wang YQ, Bazin-Lee H, Evans JT et al (2020a) MPL adjuvant contains competitive antagonists of human TLR4. Front Immunol 11:577823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang J, Li P, Yu Y et al (2020b) Pulmonary surfactant-biomimetic nanoparticles potentiate heterosubtypic influenza immunity. Science 367

    Google Scholar 

  • Wang Y, Xie Y, Luo J et al (2021a) Engineering a self-navigated MnARK nanovaccine for inducing potent protective immunity against novel coronavirus. Nano Today 38:101139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Zhang Z, Luo J et al (2021b) mRNA vaccine: a potential therapeutic strategy. Mol Cancer 20:33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weeratna RD, McCluskie MJ, Xu Y et al (2000) CpG DNA induces stronger immune responses with less toxicity than other adjuvants. Vaccine 18:1755–1762

    Article  CAS  PubMed  Google Scholar 

  • Wen Y, Waltman A, Han H et al (2016) Switching the immunogenicity of peptide assemblies using surface properties. ACS Nano 10:9274–9286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xia Y, Wu J, Wei W et al (2018) Exploiting the pliability and lateral mobility of Pickering emulsion for enhanced vaccination. Nat Mater 17:187–194

    Article  CAS  PubMed  Google Scholar 

  • Yang Y, Jambhrunkar M, Abbaraju PL et al (2017a) Understanding the effect of surface chemistry of mesoporous silica nanorods on their vaccine adjuvant potency. Adv Healthc Mater 6

    Google Scholar 

  • Yang Y, Fang Z, Chen X et al (2017b) An overview of Pickering emulsions: solid-particle materials, classification, morphology, and applications. Front Pharmacol 8:287

    Article  PubMed  PubMed Central  Google Scholar 

  • Yang Y, Tang J, Song H et al (2020) Dendritic mesoporous silica nanoparticle adjuvants modified with binuclear aluminum complex: coordination chemistry dictates adjuvanticity. Angew Chem Int Ed Engl 59:19610–19617

    Article  CAS  PubMed  Google Scholar 

  • Yu G, Liang Z, Yu Z et al (2022) Engineering the hydroxyl content on aluminum oxyhydroxide nanorod for elucidating the antigen adsorption behavior. NPJ Vaccines 7:62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang L, Liang Z, Chen C et al (2021a) Engineered hydroxyapatite nanoadjuvants with controlled shape and aspect ratios reveal their immunomodulatory potentials. ACS Appl Mater Interfaces 13:59662–59672

    Article  CAS  PubMed  Google Scholar 

  • Zhang R, Wang C, Guan Y et al (2021b) Manganese salts function as potent adjuvants. Cell Mol Immunol 18:1222–1234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao H, Han Q, Yang A et al (2022) CpG-C ODN M362 as an immunoadjuvant for HBV therapeutic vaccine reverses the systemic tolerance against HBV. Int J Biol Sci 18:154–165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (U22A20455), National Key Research and Development Program of China (2022YFC2304305), Dalian Science and Technology Innovation Fund (2020JJ25CY015), and Fundamental Research Funds for the Central Universities (DUT21ZD216, DUT22LAB601, and DUT22QN225).

Author information

Authors and Affiliations

  1. State Key Laboratory of Fine Chemicals, School of Chemical Engineering and Frontiers Science Center for Smart Materials Oriented Chemical Engineering, Dalian University of Technology, Dalian, China

    Bingbing Sun, Min Li, Zhiying Yao, Ge Yu & Yubin Ma

Authors
  1. Bingbing Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Min Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhiying Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ge Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yubin Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bingbing Sun .

Editor information

Editors and Affiliations

  1. Pharmacology and Toxicology, Freie Universität Berlin, Berlin, Germany

    Monika Schäfer-Korting

  2. Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Jena, Germany

    Ulrich S. Schubert

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Sun, B., Li, M., Yao, Z., Yu, G., Ma, Y. (2023). Advances in Vaccine Adjuvants: Nanomaterials and Small Molecules. In: Schäfer-Korting, M., Schubert, U.S. (eds) Drug Delivery and Targeting. Handbook of Experimental Pharmacology, vol 284. Springer, Cham. https://doi.org/10.1007/164_2023_652

Download citation

Publish with us

Policies and ethics

Search

Navigation