Saponin Nanoparticle Adjuvants Incorporating Toll-Like Receptor Agonists Improve Vaccine Immunomodulation

Over the past few decades, the development of potent and safe immune-activating adjuvant technologies has become the heart of intensive research in the constant fight against highly mutative and immune evasive viruses such as influenza, SARS-CoV-2, and HIV. Herein, we developed a modular saponin-based nanoparticle platform incorporating toll-like receptor agonists (TLRas) such as TLR1/2a, TLR4a, TLR7/8a, or a mixture of TLR4a and TLR7/8a adjuvants and denoted them as TLR1/2a-SNP, TLR4a-SNP, TLR7/8a-SNP, and TLR4a-TLR7/8a-SNP respectively. These TLRa-SNPs greatly improved the potency, durability, breadth, and neutralization of both COVID-19 and HIV vaccine candidates, suggesting the potential broad application of this newly designed adjuvant technology to a range of different antigens. More importantly, in addition to their potency, different formulations of TLRa-SNPs induced unique acute cytokine and immune-signaling profiles, leading to specific Th-responses that could be of interest depending on the target disease for prevention. Overall, this work demonstrates a modular TLRa-SNP adjuvant platform which could have a major impact on modern vaccine indications.

[1]  N. King,et al.  Broad and Durable Humoral Responses Following Single Hydrogel Immunization of SARS-CoV-2 Subunit Vaccine , 2023, bioRxiv.

[2]  E. Shin,et al.  Enhanced antibody responses in fully vaccinated individuals against pan-SARS-CoV-2 variants following Omicron breakthrough infection , 2022, Cell Reports Medicine.

[3]  B. Pulendran,et al.  Durable protection against the SARS-CoV-2 Omicron variant is induced by an adjuvanted subunit vaccine , 2022, Science Translational Medicine.

[4]  Jeong-Min Kim,et al.  Neutralizing antibody responses in vaccinated and unvaccinated individuals infected with Omicron BA.1 variant. , 2022, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[5]  M. Muthana,et al.  Understanding Immune Responses to Viruses—Do Underlying Th1/Th2 Cell Biases Predict Outcome? , 2022, Viruses.

[6]  Eric A. Appel,et al.  Sustained delivery approaches to improving adaptive immune responses. , 2022, Advanced drug delivery reviews.

[7]  B. Pulendran,et al.  Adjuvanting a subunit SARS-CoV-2 vaccine with clinically relevant adjuvants induces durable protection in mice , 2022, NPJ vaccines.

[8]  M. Malim,et al.  Broad Neutralization of SARS-CoV-2 Variants, Including Omicron, following Breakthrough Infection with Delta in COVID-19-Vaccinated Individuals , 2022, mBio.

[9]  O. Cabrera-Marante,et al.  An Early Th1 Response Is a Key Factor for a Favorable COVID-19 Evolution , 2022, Biomedicines.

[10]  H. Leier,et al.  Vaccination before or after SARS-CoV-2 infection leads to robust humoral response and antibodies that effectively neutralize variants , 2022, Science Immunology.

[11]  D. Irvine,et al.  A particulate saponin/TLR agonist vaccine adjuvant alters lymph flow and modulates adaptive immunity , 2021, Science Immunology.

[12]  M. Landry,et al.  Nanomaterial Strategies for Delivery of Therapeutic Cargoes , 2021, Advanced Functional Materials.

[13]  G. Ma,et al.  Bio-mimic particles for the enhanced vaccinations: Lessons learnt from the natural traits and pathogenic invasion. , 2021, Advanced drug delivery reviews.

[14]  D. Esposito,et al.  mRNA vaccine-induced antibodies more effective than natural immunity in neutralizing SARS-CoV-2 and its high affinity variants , 2021, Scientific Reports.

[15]  Ryanne A. Brown,et al.  Injectable Nanoparticle‐Based Hydrogels Enable the Safe and Effective Deployment of Immunostimulatory CD40 Agonist Antibodies , 2021, bioRxiv.

[16]  B. Pulendran,et al.  Adjuvanting a subunit COVID-19 vaccine to induce protective immunity , 2021, Nature.

[17]  B. Pulendran,et al.  Emerging concepts in the science of vaccine adjuvants , 2021, Nature reviews. Drug discovery.

[18]  B. Pulendran,et al.  Hydrogel-based slow release of a receptor-binding domain subunit vaccine elicits neutralizing antibody responses against SARS-CoV-2 , 2021, bioRxiv.

[19]  R. Díaz-Simón,et al.  T-Helper Cell Subset Response Is a Determining Factor in COVID-19 Progression , 2021, Frontiers in Cellular and Infection Microbiology.

[20]  Lisa E. Gralinski,et al.  Elicitation of potent neutralizing antibody responses by designed protein nanoparticle vaccines for SARS-CoV-2. Walls, Fiala et al. , 2020 .

[21]  Mark M. Davis,et al.  Injectable Hydrogels for Sustained Codelivery of Subunit Vaccines Enhance Humoral Immunity , 2020, ACS central science.

[22]  W. Chiu,et al.  A single immunization with spike-functionalized ferritin vaccines elicits neutralizing antibody responses against SARS-CoV-2 in mice , 2020, bioRxiv.

[23]  D. Irvine,et al.  Controlling timing and location in vaccines , 2020, Advanced Drug Delivery Reviews.

[24]  D. Burton,et al.  Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model , 2020, Science.

[25]  H. Maecker,et al.  A Novel Utility to Correct for Plate/Batch/Lot and Nonspecific Binding Artifacts in Luminex Data , 2020, The Journal of Immunology.

[26]  M. Ansems,et al.  Tumor ablation plus co-administration of CpG and saponin adjuvants affects IL-1 production and multifunctional T cell numbers in tumor draining lymph nodes , 2020, Journal for immunotherapy of cancer.

[27]  J. Bloom,et al.  Protocol and Reagents for Pseudotyping Lentiviral Particles with SARS-CoV-2 Spike Protein for Neutralization Assays , 2020, bioRxiv.

[28]  J. Mascola,et al.  Novel vaccine technologies for the 21st century , 2019, Nature Reviews Immunology.

[29]  H. Maecker,et al.  Penalized Supervised Star Plots: Example Application in Influenza-Specific CD4+ T Cells. , 2019, Viral immunology.

[30]  D. E. Parks,et al.  A combination of TLR-4 agonist and saponin adjuvants increases antibody diversity and protective efficacy of a recombinant West Nile Virus antigen , 2018, npj Vaccines.

[31]  W. Schrödl,et al.  Comparative analysis of humoral immune responses and pathologies of BALB/c and C57BL/6 wildtype mice experimentally infected with a highly virulent Rodentibacter pneumotropicus (Pasteurella pneumotropica) strain , 2018, BMC Microbiology.

[32]  W. N. Arifin,et al.  Sample Size Calculation in Animal Studies Using Resource Equation Approach. , 2017, The Malaysian journal of medical sciences : MJMS.

[33]  A. Didierlaurent,et al.  Adjuvant system AS01: helping to overcome the challenges of modern vaccines , 2017, Expert review of vaccines.

[34]  T. Xia,et al.  Nanomaterial-Based Vaccine Adjuvants. , 2016, Journal of materials chemistry. B.

[35]  Edmond J. Breen,et al.  The Statistical Value of Raw Fluorescence Signal in Luminex xMAP Based Multiplex Immunoassays , 2016, Scientific Reports.

[36]  D. Irvine,et al.  Synthetic Nanoparticles for Vaccines and Immunotherapy. , 2015, Chemical reviews.

[37]  J. Mascola,et al.  Primate immune responses to HIV-1 Env formulated in the saponin-based adjuvant AbISCO-100 in the presence or absence of TLR9 co-stimulation , 2015, Scientific Reports.

[38]  Adriana Baz Morelli,et al.  The Combination of ISCOMATRIX Adjuvant and TLR Agonists Induces Regression of Established Solid Tumors In Vivo , 2015, The Journal of Immunology.

[39]  M. Garenne,et al.  Sexist Diseases , 2015, Perspectives in biology and medicine.

[40]  M. Cooke,et al.  Rational design of small molecules as vaccine adjuvants , 2014, Science Translational Medicine.

[41]  S. Bertholet,et al.  Unleashing the potential of NOD- and Toll-like agonists as vaccine adjuvants , 2014, Proceedings of the National Academy of Sciences.

[42]  M. Liedtke,et al.  Effects of serum and plasma matrices on multiplex immunoassays , 2014, Immunologic Research.

[43]  Gregory L. Szeto,et al.  Structure-based programming of lymph-node targeting in molecular vaccines , 2014, Nature.

[44]  Jaykaran Charan,et al.  How to calculate sample size in animal studies? , 2013, Journal of pharmacology & pharmacotherapeutics.

[45]  I. Toth,et al.  Modern Subunit Vaccines: Development, Components, and Research Opportunities , 2013, ChemMedChem.

[46]  H. M. Nielsen,et al.  Structure of immune stimulating complex matrices and immune stimulating complexes in suspension determined by small-angle x-ray scattering. , 2012, Biophysical journal.

[47]  B. Pulendran,et al.  Distinct TLR adjuvants differentially stimulate systemic and local innate immune responses in nonhuman primates. , 2012, Blood.

[48]  J. Schmidt,et al.  Vaccine adjuvant activity of 3M-052: an imidazoquinoline designed for local activity without systemic cytokine induction. , 2011, Vaccine.

[49]  S. Reed,et al.  Use of defined TLR ligands as adjuvants within human vaccines , 2011, Immunological reviews.

[50]  John Steel,et al.  Programming the magnitude and persistence of antibody responses with innate immunity , 2010, Nature.

[51]  R. Coffman,et al.  Vaccine adjuvants: putting innate immunity to work. , 2010, Immunity.

[52]  J. A. Rod Blais,et al.  Least Squares for Practitioners , 2010 .

[53]  S. Plotkin.  Correlates of Protection Induced by Vaccination , 2010, Clinical and Vaccine Immunology.

[54]  E. Maraskovsky,et al.  Development of prophylactic and therapeutic vaccines using the ISCOMATRIX adjuvant , 2009, Immunology and cell biology.

[55]  Kyung In Kim,et al.  Effects of dependence in high-dimensional multiple testing problems , 2008, BMC Bioinformatics.

[56]  W. Hooper,et al.  Interference in microsphere flow cytometric multiplexed immunoassays for human cytokine estimation. , 2006, Cytokine.

[57]  Rolan D. Davis,et al.  Detection of Cellular Immunity to Rabies Antigens in Human Vaccinees , 2006, Journal of Clinical Immunology.

[58]  Y. Benjamini,et al.  Adaptive linear step-up procedures that control the false discovery rate , 2006 .

[59]  David N Mastronarde,et al.  Automated electron microscope tomography using robust prediction of specimen movements. , 2005, Journal of structural biology.

[60]  L. Brown,et al.  ISCOMTM‐based vaccines: The second decade , 2005, Immunology and cell biology.

[61]  M. Pearse,et al.  ISCOMATRIX adjuvant for antigen delivery. , 2005, Advanced drug delivery reviews.

[62]  Conrad C. Huang,et al.  UCSF Chimera—A visualization system for exploratory research and analysis , 2004, J. Comput. Chem..

[63]  T. Mosmann,et al.  The expanding universe of T-cell subsets: Th1, Th2 and more. , 1996, Immunology today.

[64]  Michael Y. Gerner,et al.  Supplementary Text and Figures to In vivo characterization of the physicochemical properties of polymer-linked TLR agonists that enhance vaccine immunogenicity , 2015 .

[65]  T. Kamradt,et al.  Th1/Th2 balance in infection , 2004, Springer Seminars in Immunopathology.

[66]  D. O’hagan.  Vaccine adjuvants : preparation methods and research protocols , 2000 .

[67]  Douglas J. Miller,et al.  Maximum entropy econometrics: robust estimation with limited data , 1996 .

[68]  J R Kremer,et al.  Computer visualization of three-dimensional image data using IMOD. , 1996, Journal of structural biology.

[69]  A. Osterhaus,et al.  Iscom, a novel structure for antigenic presentation of membrane proteins from enveloped viruses , 1984, Nature.