Systems biology of vaccination for seasonal influenza in humans
Helder I Nakaya, Jens Wrammert, Eva K Lee, Luigi Racioppi, Stephanie Marie-Kunze, W Nicholas Haining, Anthony R Means, Sudhir P Kasturi, Nooruddin Khan, Gui-Mei Li, Megan McCausland, Vibhu Kanchan, Kenneth E Kokko, Shuzhao Li, Rivka Elbein, Aneesh K Mehta, Alan Aderem, Kanta Subbarao, Rafi Ahmed, Bali Pulendran, Helder I Nakaya, Jens Wrammert, Eva K Lee, Luigi Racioppi, Stephanie Marie-Kunze, W Nicholas Haining, Anthony R Means, Sudhir P Kasturi, Nooruddin Khan, Gui-Mei Li, Megan McCausland, Vibhu Kanchan, Kenneth E Kokko, Shuzhao Li, Rivka Elbein, Aneesh K Mehta, Alan Aderem, Kanta Subbarao, Rafi Ahmed, Bali Pulendran
Abstract
Here we have used a systems biology approach to study innate and adaptive responses to vaccination against influenza in humans during three consecutive influenza seasons. We studied healthy adults vaccinated with trivalent inactivated influenza vaccine (TIV) or live attenuated influenza vaccine (LAIV). TIV induced higher antibody titers and more plasmablasts than LAIV did. In subjects vaccinated with TIV, early molecular signatures correlated with and could be used to accurately predict later antibody titers in two independent trials. Notably, expression of the kinase CaMKIV at day 3 was inversely correlated with later antibody titers. Vaccination of CaMKIV-deficient mice with TIV induced enhanced antigen-specific antibody titers, which demonstrated an unappreciated role for CaMKIV in the regulation of antibody responses. Thus, systems approaches can be used to predict immunogenicity and provide new mechanistic insights about vaccines.
Conflict of interest statement
COMPETING INTERESTS STATEMENT
The authors declare no competing financial interests.
Figures
References
- Sasaki S, et al. Comparison of the influenza virus-specific effector and memory B-cell responses to immunization of children and adults with live attenuated or inactivated influenza virus vaccines. J Virol. 2007;81:215–228.
- Fiore AE, et al. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Recomm Rep. 2010;59:1–62.
- Sasaki S, et al. Influence of prior influenza vaccination on antibody and B-cell responses. PLoS One. 2008;3:e2975.
- Zeman AM, et al. Humoral and cellular immune responses in children given annual immunization with trivalent inactivated influenza vaccine. Pediatr Infect Dis J. 2007;26:107–115.
- Pulendran B, Li S, Nakaya HI. Systems vaccinology. Immunity. 2010;33:516–529.
- Querec TD, et al. Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans. Nat Immunol. 2009;10:116–125.
- Gaucher D, et al. Yellow fever vaccine induces integrated multilineage and polyfunctional immune responses. J Exp Med. 2008;205:3119–3131.
- Pulendran B. Learning immunology from the yellow fever vaccine:innate immunity to systems vaccinology. Nat Rev Immunol. 2009;9:741–747.
- Monath TP. Yellow fever vaccine. Expert Rev Vaccines. 2005;4:553–574.
- Querec T, et al. Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity. J Exp Med. 2006;203:413–424.
- Barrett AD, Teuwen DE. Yellow fever vaccine -how does it work and why do rare cases of serious adverse events take place? Curr Opin Immunol. 2009;21:308–313.
- Johnson PR, Jr, Feldman S, Thompson JM, Mahoney JD, Wright PF. Comparison of long-term systemic and secretory antibody responses in children given live, attenuated, or inactivated influenza A vaccine. J Med Virol. 1985;17:325–335.
- Beyer WE, Palache AM, de Jong JC, Osterhaus AD. Cold-adapted live influenza vaccine versus inactivated vaccine: systemic vaccine reactions, local and systemic antibody response, and vaccine efficacy. A meta-analysis. Vaccine. 2002;20:1340–1353.
- Administration, F.a.D. Guidance for Industry: Clinical Data Needed to Support the Licensure of Pandemic Influenza Vaccines. 2007.
- Wrammert J, et al. Rapid cloning of high-affinity human monoclonal antibodies against influenza virus. Nature. 2008;453:667–671.
- Takaoka A, Yanai H. Interferon signalling network in innate defence. Cell Microbiol. 2006;8:907–922.
- Tusher VG, Tibshirani R, Chu G. Significance analysis of microarrays applied to the ionizing radiation response. Proc NatlAcad Sci U S A. 2001;98:5116–5121.
- Iwakoshi NN, et al. Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1. Nat Immunol. 2003;4:321–329.
- Iwakoshi NN, Lee AH, Glimcher LH. The X-box binding protein-1 transcription factor is required for plasma cell differentiation and the unfolded protein response. Immunol Rev. 2003;194:29–38.
- Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 2007;8:519–529.
- Ueda Y, et al. Frequencies of dendritic cells (myeloid DC and plasmacytoid DC) and their ratio reduced in pregnant women: comparison with umbilical cord blood and normal healthy adults. Hum Immunol. 2003;64:1144–1151.
- Shen-Orr SS, et al. Cell type-specific gene expression differences in complex tissues. Nat Methods. 2010;7:287–289.
- Avery DT, et al. BAFF selectively enhances the survival of plasmablasts generated from human memory B cells. J Clin Invest. 2003;112:286–297.
- Park SW, et al. The regulatory subunits of PI3K, p85alpha and p85beta, interact with XBP-1 and increase its nuclear translocation. Nat Med. 2010;16:429–437.
- Liu B, Li Z. Endoplasmic reticulum HSP90b1 (gp96, grp94) optimizes B-cell function via chaperoning integrin and TLR but not immunoglobulin. Blood. 2008;112:1223–1230.
- Apostolou A, Shen Y, Liang Y, Luo J, Fang S. Armet, a UPR-upregulated protein, inhibits cell proliferation and ER stress-induced cell death. Exp Cell Res. 2008;314:2454–2467.
- Huleatt JW, et al. Potent immunogenicity and efficacy of a universal influenza vaccine candidate comprising a recombinant fusion protein linking influenza M2e to the TLR5 ligand flagellin. Vaccine. 2008;26:201–214.
- Treanor JJ, et al. Safety and immunogenicity of a recombinant hemagglutinin influenza-flagellin fusion vaccine (VAX125) in healthy young adults. Vaccine. 2010;28:8268–8274.
- Talbot HK, et al. Immunopotentiation of trivalentinfluenza vaccine when given with VAX102, a recombinant influenza M2e vaccine fused to the TLR5 ligand flagellin. PLoS One. 2010;5:e14442.
- He XS, et al. Cellular immune responses in children and adults receiving inactivated or live attenuated influenza vaccines. J Virol. 2006;80:11756–11766.
- Le Bon A, et al. Cutting edge: enhancement of antibody responses through direct stimulation of B and T cells by type I IFN. J Immunol. 2006;176:2074–2078.
- Lee EK. Large-scale optimization-basedclassification models in medicine and biology. Ann Biomed Eng. 2007;35:1095–1109.
- Brooks JP, Lee EK. Analysis of the consistency of a mixed integer programming-based multi-category constrained discriminant model. Annals of Operations Research. 2010;174:147–168.
- Sullivan SJ, Jacobson R, Poland GA. Advances in the vaccination of the elderly against influenza: role of a high-dose vaccine. Expert Rev Vaccines. 2010;9:1127–1133.
- Anderson KJ, Allen RL. Regulation of T-cell immunity by leucocyte immunoglobulin-like receptors: innate immune receptors for self on antigen-presenting cells. Immunology. 2009;127:8–17.
- Thomas R, Matthias T, Witte T. Leukocyte immunoglobulin-like receptors as new players in autoimmunity. Clin Rev Allergy Immunol. 2010;38:159–162.
- Brown D, Trowsdale J, Allen R. The LILR family: modulators of innate and adaptive immune pathways in health and disease. Tissue Antigens. 2004;64:215–225.
- Krebs J, Wilson A, Kisielow P. Calmodulin-dependent protein kinase IV during T-cell development. Biochem Biophys Res Commun. 1997;241:383–389.
- Wang SL, Ribar TJ, Means AR. Expression of Ca(2+)/calmodulin-dependent protein kinase IV (caMKIV) messenger RNA during murine embryogenesis. Cell Growth Differ. 2001;12:351–361.
- Anderson KA, Means AR. Defective signaling in a subpopulation of CD4(+) T cells in the absence of Ca(2+)/calmodulin-dependent protein kinase IV. Mol Cell Biol. 2002;22:23–29.
- Illario M, et al. Calmodulin-dependent kinase IV links Toll-like receptor 4 signaling with survival pathway of activated dendritic cells. Blood. 2008;111:723–731.
- Sato K, et al. Regulation of osteoclast differentiation and function by the CaMK-CREB pathway. Nat Med. 2006;12:1410–1416.
- Kitsos CM, et al. Calmodulin-dependent protein kinase IV regulates hematopoietic stem cell maintenance. J Biol Chem. 2005;280:33101–33108.
- Pulendran B, Ahmed R. Immunological mechanisms of vaccination. Nat Immunol. 2011;131:509–517.
- Moldoveanu Z, Clements ML, Prince SJ, Murphy BR, Mestecky J. Human immune responses to influenza virus vaccines administered by systemic or mucosal routes. Vaccine. 1995;13:1006–1012.
- Shubinsky G, Schlesinger M. The CD38 lymphocyte differentiation marker: new insight into its ectoenzymatic activity and its role as a signal transducer. Immunity. 1997;7:315–324.
- Deaglio S, Mehta K, Malavasi F. Human CD38: a (r)evolutionary story of enzymes and receptors. Leuk Res. 2001;25:1–12.
- Clements ML, Betts RF, Tierney EL, Murphy BR. Serum and nasal wash antibodies associated with resistance to experimental challenge with influenza A wild-type virus. J Clin Microbiol. 1986;24:157–160.
- Potter CW, Oxford JS. Determinants of immunity to influenza infection in man. Br Med Bull. 1979;35:69–75.
- Hirota Y, et al. Antibody efficacy as a keen index to evaluate influenza vaccine effectiveness. Vaccine. 1997;15:962–967.
- Belshe RB. Current status of live attenuated influenza virus vaccine in the US. Virus Res. 2004;103:177–185.
- Chen GL, Lamirande EW, Jin H, Kemble G, Subbarao K. Safety, immunogencity, and efficacy of a cold-adapted A/Ann Arbor/6/60 (H2N2) vaccine in mice and ferrets. Virology. 2010;398:109–114.
- Crotty S, et al. Cutting edge: long-term B cell memory in humans after smallpox vaccination. J Immunol. 2003;171:4969–4973.
- Wu JY, et al. Spermiogenesis and exchange of basic nuclear proteins are impaired in male germ cells lacking Camk4. Nat Genet. 2000;25:448–452.
Source: PubMed