Cellular and Molecular Synergy in AS01-adjuvanted Vaccines Results in an Early IFNγ Response Promoting Vaccine Immunogenicity

Overview

Journal NPJ Vaccines

Date 2017 Dec 22

PMID 29263880

Citations 117

Authors

Margherita Coccia

Catherine Collignon

Caroline Herve

Aurelie Chalon

Iain Welsby

Sophie Detienne

Mary J van Helden

Sheetij Dutta

Christopher J Genito

Norman C Waters

Katrijn Van Deun

Age K Smilde

Robert A van den Berg

David Franco

Patricia Bourguignon

Sandra Morel

Nathalie Garcon

Bart N Lambrecht

Stanislas Goriely

Robbert van der Most

Arnaud M Didierlaurent

Affiliations

Soon will be listed here.

Abstract

Combining immunostimulants in adjuvants can improve the quality of the immune response to vaccines. Here, we report a unique mechanism of molecular and cellular synergy between a TLR4 ligand, 3--desacyl-4'-monophosphoryl lipid A (MPL), and a saponin, QS-21, the constituents of the Adjuvant System AS01. AS01 is part of the malaria and herpes zoster vaccine candidates that have demonstrated efficacy in phase III studies. Hours after injection of AS01-adjuvanted vaccine, resident cells, such as NK cells and CD8 T cells, release IFNγ in the lymph node draining the injection site. This effect results from MPL and QS-21 synergy and is controlled by macrophages, IL-12 and IL-18. Depletion strategies showed that this early IFNγ production was essential for the activation of dendritic cells and the development of Th1 immunity by AS01-adjuvanted vaccine. A similar activation was observed in the lymph node of AS01-injected macaques as well as in the blood of individuals receiving the malaria RTS,S vaccine. This mechanism, previously described for infections, illustrates how adjuvants trigger naturally occurring pathways to improve the efficacy of vaccines.

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References

Dendouga N, Fochesato M, Lockman L, Mossman S, Giannini S . Cell-mediated immune responses to a varicella-zoster virus glycoprotein E vaccine using both a TLR agonist and QS21 in mice. Vaccine. 2012; 30(20):3126-35. DOI: 10.1016/j.vaccine.2012.01.088. View

Mosca F, Tritto E, Muzzi A, Monaci E, Bagnoli F, Iavarone C . Molecular and cellular signatures of human vaccine adjuvants. Proc Natl Acad Sci U S A. 2008; 105(30):10501-6. PMC: 2483233. DOI: 10.1073/pnas.0804699105. View

Horowitz A, Behrens R, Okell L, Fooks A, Riley E . NK cells as effectors of acquired immune responses: effector CD4+ T cell-dependent activation of NK cells following vaccination. J Immunol. 2010; 185(5):2808-18. DOI: 10.4049/jimmunol.1000844. View

Cherwinski H, Schumacher J, Brown K, Mosmann T . Two types of mouse helper T cell clone. III. Further differences in lymphokine synthesis between Th1 and Th2 clones revealed by RNA hybridization, functionally monospecific bioassays, and monoclonal antibodies. J Exp Med. 1987; 166(5):1229-44. PMC: 2189643. DOI: 10.1084/jem.166.5.1229. View

Cauwelaert N, Desbien A, Hudson T, Pine S, Reed S, Coler R . The TLR4 Agonist Vaccine Adjuvant, GLA-SE, Requires Canonical and Atypical Mechanisms of Action for TH1 Induction. PLoS One. 2016; 11(1):e0146372. PMC: 4701231. DOI: 10.1371/journal.pone.0146372. View

Vieira P, de Jong E, Wierenga E, Kapsenberg M, Kalinski P . Development of Th1-inducing capacity in myeloid dendritic cells requires environmental instruction. J Immunol. 2000; 164(9):4507-12. DOI: 10.4049/jimmunol.164.9.4507. View

Martin-Fontecha A, Thomsen L, Brett S, Gerard C, Lipp M, Lanzavecchia A . Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming. Nat Immunol. 2004; 5(12):1260-5. DOI: 10.1038/ni1138. View

Nakaya H, Hagan T, Duraisingham S, Lee E, Kwissa M, Rouphael N . Systems Analysis of Immunity to Influenza Vaccination across Multiple Years and in Diverse Populations Reveals Shared Molecular Signatures. Immunity. 2015; 43(6):1186-98. PMC: 4859820. DOI: 10.1016/j.immuni.2015.11.012. View

Morandi B, Bougras G, Muller W, Ferlazzo G, Munz C . NK cells of human secondary lymphoid tissues enhance T cell polarization via IFN-gamma secretion. Eur J Immunol. 2006; 36(9):2394-400. DOI: 10.1002/eji.200636290. View

10.

Kastenmuller W, Torabi-Parizi P, Subramanian N, Lammermann T, Germain R . A spatially-organized multicellular innate immune response in lymph nodes limits systemic pathogen spread. Cell. 2012; 150(6):1235-48. PMC: 3514884. DOI: 10.1016/j.cell.2012.07.021. View

11.

Kupz A, Curtiss 3rd R, Bedoui S, Strugnell R . In vivo IFN-γ secretion by NK cells in response to Salmonella typhimurium requires NLRC4 inflammasomes. PLoS One. 2014; 9(5):e97418. PMC: 4020851. DOI: 10.1371/journal.pone.0097418. View

12.

Casella C, Mitchell T . Putting endotoxin to work for us: monophosphoryl lipid A as a safe and effective vaccine adjuvant. Cell Mol Life Sci. 2008; 65(20):3231-40. PMC: 2647720. DOI: 10.1007/s00018-008-8228-6. View

13.

Porter M, Nicki J, Pool C, DeBot M, Illam R, Brando C . Transgenic parasites stably expressing full-length Plasmodium falciparum circumsporozoite protein as a model for vaccine down-selection in mice using sterile protection as an endpoint. Clin Vaccine Immunol. 2013; 20(6):803-10. PMC: 3675977. DOI: 10.1128/CVI.00066-13. View

14.

Steain M, Sutherland J, Rodriguez M, Cunningham A, Slobedman B, Abendroth A . Analysis of T cell responses during active varicella-zoster virus reactivation in human ganglia. J Virol. 2013; 88(5):2704-16. PMC: 3958057. DOI: 10.1128/JVI.03445-13. View

15.

Marty-Roix R, Vladimer G, Pouliot K, Weng D, Buglione-Corbett R, West K . Identification of QS-21 as an Inflammasome-activating Molecular Component of Saponin Adjuvants. J Biol Chem. 2015; 291(3):1123-36. PMC: 4714196. DOI: 10.1074/jbc.M115.683011. View

16.

Narni-Mancinelli E, Chaix J, Fenis A, Kerdiles Y, Yessaad N, Reynders A . Fate mapping analysis of lymphoid cells expressing the NKp46 cell surface receptor. Proc Natl Acad Sci U S A. 2011; 108(45):18324-9. PMC: 3215049. DOI: 10.1073/pnas.1112064108. View

17.

Kastenmuller W, Brandes M, Wang Z, Herz J, Egen J, Germain R . Peripheral prepositioning and local CXCL9 chemokine-mediated guidance orchestrate rapid memory CD8+ T cell responses in the lymph node. Immunity. 2013; 38(3):502-13. PMC: 3793246. DOI: 10.1016/j.immuni.2012.11.012. View

18.

Didierlaurent A, Laupeze B, Di Pasquale A, Hergli N, Collignon C, Garcon N . Adjuvant system AS01: helping to overcome the challenges of modern vaccines. Expert Rev Vaccines. 2016; 16(1):55-63. DOI: 10.1080/14760584.2016.1213632. View

19.

Van Deun K, Thorrez L, van den Berg R, Smilde A, Van Mechelen I . Not Just a Sum? Identifying Different Types of Interplay between Constituents in Combined Interventions. PLoS One. 2015; 10(5):e0125334. PMC: 4429013. DOI: 10.1371/journal.pone.0125334. View

20.

Van Braeckel E, Bourguignon P, Koutsoukos M, Clement F, Janssens M, Carletti I . An adjuvanted polyprotein HIV-1 vaccine induces polyfunctional cross-reactive CD4+ T cell responses in seronegative volunteers. Clin Infect Dis. 2011; 52(4):522-31. PMC: 3060898. DOI: 10.1093/cid/ciq160. View