Molecular Signatures of a TLR4 Agonist-Adjuvanted HIV-1 Vaccine Candidate in Humans

Systems biology approaches have recently provided new insights into the mechanisms of action of human vaccines and adjuvants. Here, we investigated early transcriptional signatures induced in whole blood of healthy subjects following vaccination with a recombinant HIV-1 envelope glycoprotein subunit CN54gp140 adjuvanted with the TLR4 agonist glucopyranosyl lipid adjuvant-aqueous formulation (GLA-AF) and correlated signatures to CN54gp140-specific serum antibody responses. Fourteen healthy volunteers aged 18–45 years were immunized intramuscularly three times at 1-month intervals and whole blood samples were collected at baseline, 6 h, and 1, 3, and 7 days post first immunization. Subtle changes in the transcriptomic profiles were observed following immunization, ranging from over 300 differentially expressed genes (DEGs) at day 1 to nearly 100 DEGs at day 7 following immunization. Functional pathway analysis revealed blood transcription modules (BTMs) related to general cell cycle activation, and innate immune cell activation at early time points, as well as BTMs related to T cells and B cell activation at the later time points post-immunization. Diverse CN54gp140-specific serum antibody responses of the subjects enabled their categorization into high or low responders, at early (<1 month) and late (up to 6 months) time points post vaccination. BTM analyses revealed repression of modules enriched in NK cells, and the mitochondrial electron chain, in individuals with high or sustained antigen-specific antibody responses. However, low responders showed an enhancement of BTMs associated with enrichment in myeloid cells and monocytes as well as integrin cell surface interactions. Flow cytometry analysis of peripheral blood mononuclear cells obtained from the subjects revealed an enhanced frequency of CD56dim NK cells in the majority of vaccines 14 days after vaccination as compared with the baseline. These results emphasize the utility of a systems biology approach to enhance our understanding on the mechanisms of action of TLR4 adjuvanted human vaccines.

[1]  Lindsay N. Carpp,et al.  A Systems Vaccinology Approach Reveals Temporal Transcriptomic Changes of Immune Responses to the Yellow Fever 17D Vaccine , 2017, The Journal of Immunology.

[2]  S. Kent,et al.  A Phase 1 Human Immunodeficiency Virus Vaccine Trial for Cross-Profiling the Kinetics of Serum and Mucosal Antibody Responses to CN54gp140 Modulated by Two Homologous Prime-Boost Vaccine Regimens , 2017, Front. Immunol..

[3]  S. McCormack,et al.  A Comparative Phase I Study of Combination, Homologous Subtype-C DNA, MVA, and Env gp140 Protein/Adjuvant HIV Vaccines in Two Immunization Regimes , 2017, Front. Immunol..

[4]  Eva K. Lee,et al.  Systems analysis of protective immune responses to RTS,S malaria vaccination in humans , 2017, Proceedings of the National Academy of Sciences.

[5]  E. Zoratti,et al.  HIV-1 Env associates with HLA-C free-chains at the cell membrane modulating viral infectivity , 2017, Scientific Reports.

[6]  Intawat Nookaew,et al.  Comparative Systems Analyses Reveal Molecular Signatures of Clinically tested Vaccine Adjuvants , 2016, Scientific Reports.

[7]  J. Chamberland,et al.  NECAP2 controls clathrin coat recruitment to early endosomes for fast endocytic recycling , 2016, Journal of Cell Science.

[8]  S. McCormack,et al.  Comparative Immunogenicity of HIV-1 gp140 Vaccine Delivered by Parenteral, and Mucosal Routes in Female Volunteers; MUCOVAC2, A Randomized Two Centre Study , 2016, PloS one.

[9]  Helder I. Nakaya,et al.  Systems biology of immunity to MF59-adjuvanted versus nonadjuvanted trivalent seasonal influenza vaccines in early childhood , 2016, Proceedings of the National Academy of Sciences.

[10]  R. Coler,et al.  The TLR4 Agonist Vaccine Adjuvant, GLA-SE, Requires Canonical and Atypical Mechanisms of Action for TH1 Induction , 2016, PloS one.

[11]  Eva K. Lee,et al.  Systems Analysis of Immunity to Influenza Vaccination across Multiple Years and in Diverse Populations Reveals Shared Molecular Signatures. , 2015, Immunity.

[12]  A. Harandi,et al.  Molecular signatures of vaccine adjuvants. , 2015, Vaccine.

[13]  S. Waggoner,et al.  Boosting vaccine efficacy the natural (killer) way. , 2015, Trends in immunology.

[14]  Savita Pahwa,et al.  Paediatric HIV infection in the ‘omics era: defining transcriptional signatures of viral control and vaccine responses , 2015, Journal of virus eradication.

[15]  Wanfu Hu,et al.  Influenza Vaccine Induces Intracellular Immune Memory of Human NK Cells , 2015, PloS one.

[16]  R. Welsh,et al.  Generation of cellular immune memory and B-cell immunity are impaired by natural killer cells , 2015, Nature Communications.

[17]  S. Reed,et al.  Glucopyranosyl Lipid A Adjuvant Significantly Enhances HIV Specific T and B Cell Responses Elicited by a DNA-MVA-Protein Vaccine Regimen , 2014, PloS one.

[18]  Sandra Romero-Steiner,et al.  Molecular signatures of antibody responses derived from a systems biological study of 5 human vaccines , 2013, Nature Immunology.

[19]  Chin-fen Yang,et al.  Molecular and Cellular Response Profiles Induced by the TLR4 Agonist-Based Adjuvant Glucopyranosyl Lipid A , 2012, PloS one.

[20]  T. Lehner,et al.  CN54gp140: product characteristics, peclinical and clinical use - recombinant glycoprotein for HIV immunization , 2012, Retrovirology.

[21]  Magdalini Moutaftsi,et al.  Glucopyranosyl Lipid Adjuvant (GLA), a Synthetic TLR4 Agonist, Promotes Potent Systemic and Mucosal Responses to Intranasal Immunization with HIVgp140 , 2012, PloS one.

[22]  Guido Ferrari,et al.  Immune-correlates analysis of an HIV-1 vaccine efficacy trial. , 2012, The New England journal of medicine.

[23]  Corona M. Cassidy,et al.  Microneedle mediated intradermal delivery of adjuvanted recombinant HIV-1 CN54gp140 effectively primes mucosal boost inoculations , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[24]  Eva K. Lee,et al.  Systems Biology of Seasonal Influenza Vaccination in Humans , 2011, Nature Immunology.

[25]  S. McCormack,et al.  Turning the Tide Against HIV , 2011, Science.

[26]  G. Bruyn.  Cofactors that may influence vaccine responses. , 2010 .

[27]  Eric O Long,et al.  Regulation of human NK-cell cytokine and chemokine production by target cell recognition. , 2010, Blood.

[28]  D. Scott‐Algara,et al.  Changes to the Natural Killer Cell Repertoire after Therapeutic Hepatitis B DNA Vaccination , 2010, PloS one.

[29]  G. Andrews,et al.  Vaginal delivery of the recombinant HIV-1 clade-C trimeric gp140 envelope protein CN54gp140 within novel rheologically structured vehicles elicits specific immune responses , 2009, Vaccine.

[30]  R. Strong,et al.  Structural basis for NKG2A/CD94 recognition of HLA-E , 2008, Proceedings of the National Academy of Sciences.

[31]  Eric Vivier,et al.  Functions of natural killer cells , 2008, Nature Immunology.

[32]  A. Bowie,et al.  The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling , 2007, Nature Reviews Immunology.

[33]  오윤석,et al.  Adjuvants , 2021, Visceral Leishmaniasis.

[34]  S. Taketani,et al.  Molecular characterization of a transport vesicle protein Neurensin-2, a homologue of Neurensin-1, expressed in neural cells , 2006, Brain Research.

[35]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[36]  Eric Vivier,et al.  Inhibitory NK-cell receptors on T cells: witness of the past, actors of the future , 2004, Nature Reviews Immunology.

[37]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[38]  J. Kublin,et al.  Lessons learned from HIV vaccine clinical efficacy trials. , 2013, Current HIV research.

[39]  Eva K. Lee,et al.  Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans , 2009, Nature Immunology.