Human rhinovirus (RV) infections are the principle cause of common colds and precipitate asthma and COPD exacerbations. There is currently no RV vaccine, largely due to the existence of ~150 strains. We aimed to define highly conserved areas of the RV proteome and test their usefulness as candidate antigens for a broadly cross-reactive vaccine, using a mouse infection model. Regions of the VP0 (VP4+VP2) capsid protein were identified as having high homology across RVs. Immunization with a recombinant VP0 combined with a Th1 promoting adjuvant induced systemic, antigen specific, cross-serotype, cellular and humoral immune responses. Similar cross-reactive responses were observed in the lungs of immunized mice after infection with heterologous RV strains. Immunization enhanced the generation of heterosubtypic neutralizing antibodies and lung memory T cells, and caused more rapid virus clearance. Conserved domains of the RV capsid therefore induce cross-reactive immune responses and represent candidates for a subunit RV vaccine.
References
[1]
Makela MJ, Puhakka T, Ruuskanen O, Leinonen M, Saikku P, et al. (1998) Viruses and bacteria in the etiology of the common cold. J Clin Microbiol 36: 539–542.
[2]
Johnston SL, Pattemore PK, Sanderson G, Smith S, Lampe F, et al. (1995) Community study of role of viral infections in exacerbations of asthma in 9–11 year old children. Bmj 310: 1225–1229. doi: 10.1136/bmj.310.6989.1225
[3]
Nicholson KG, Kent J, Ireland DC (1993) Respiratory viruses and exacerbations of asthma in adults. Bmj 307: 982–986. doi: 10.1136/bmj.307.6910.982
[4]
Papi A, Bellettato CM, Braccioni F, Romagnoli M, Casolari P, et al. (2006) Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations. Am J Respir Crit Care Med 173: 1114–1121. doi: 10.1164/rccm.200506-859oc
[5]
Alper CM, Doyle WJ, Skoner DP, Buchman CA, Seroky JT, et al. (1996) Prechallenge antibodies: moderators of infection rate, signs, and symptoms in adults experimentally challenged with rhinovirus type 39. Laryngoscope 106: 1298–1305. doi: 10.1097/00005537-199610000-00025
[6]
Alper CM, Doyle WJ, Skoner DP, Buchman CA, Cohen S, et al. (1998) Prechallenge antibodies moderate disease expression in adults experimentally exposed to rhinovirus strain hanks. Clin Infect Dis 27: 119–128. doi: 10.1086/514634
[7]
Barclay WS, al-Nakib W, Higgins PG, Tyrrell DA (1989) The time course of the humoral immune response to rhinovirus infection. Epidemiol Infect 103: 659–669. doi: 10.1017/s095026880003106x
[8]
Perkins JC, Tucker DN, Knope HL, Wenzel RP, Hornick RB, et al. (1969) Evidence for protective effect of an inactivated rhinovirus vaccine administered by the nasal route. Am J Epidemiol 90: 319–326.
[9]
Mitchison DA (1965) Prevention of Colds by Vaccination against a Rhinovirus: A Report by the Scientific Committee on Common Cold Vaccines. Br Med J 1: 1344–1349. doi: 10.1136/bmj.1.5446.1344
[10]
Hamparian VV, Colonno RJ, Cooney MK, Dick EC, Gwaltney JM Jr, et al. (1987) A collaborative report: rhinoviruses–extension of the numbering system from 89 to 100. Virology 159: 191–192. doi: 10.1016/0042-6822(87)90367-9
[11]
Palmenberg AC, Spiro D, Kuzmickas R, Wang S, Djikeng A, et al. (2009) Sequencing and analyses of all known human rhinovirus genomes reveal structure and evolution. Science 324: 55–59. doi: 10.1126/science.1165557
[12]
Uncapher CR, DeWitt CM, Colonno RJ (1991) The major and minor group receptor families contain all but one human rhinovirus serotype. Virology 180: 814–817. doi: 10.1016/0042-6822(91)90098-v
[13]
Bochkov YA, Palmenberg AC, Lee WM, Rathe JA, Amineva SP, et al. (2011) Molecular modeling, organ culture and reverse genetics for a newly identified human rhinovirus C. Nat Med 17: 627–632. doi: 10.1038/nm.2358
[14]
Lau SK, Yip CC, Tsoi HW, Lee RA, So LY, et al. (2007) Clinical features and complete genome characterization of a distinct human rhinovirus (HRV) genetic cluster, probably representing a previously undetected HRV species, HRV-C, associated with acute respiratory illness in children. J Clin Microbiol 45: 3655–3664. doi: 10.1128/jcm.01254-07
Hillaire ML, Osterhaus AD, Rimmelzwaan GF (2011) Induction of virus-specific cytotoxic T lymphocytes as a basis for the development of broadly protective influenza vaccines. J Biomed Biotechnol 2011: 939860. doi: 10.1155/2011/939860
[17]
Lee LY, Ha do LA, Simmons C, de Jong MD, Chau NV, et al. (2008) Memory T cells established by seasonal human influenza A infection cross-react with avian influenza A (H5N1) in healthy individuals. J Clin Invest 118: 3478–3490. doi: 10.1172/jci32460
[18]
Richards KA, Topham D, Chaves FA, Sant AJ (2010) Cutting edge: CD4 T cells generated from encounter with seasonal influenza viruses and vaccines have broad protein specificity and can directly recognize naturally generated epitopes derived from the live pandemic H1N1 virus. J Immunol 185: 4998–5002. doi: 10.4049/jimmunol.1001395
[19]
Gern JE, Dick EC, Kelly EA, Vrtis R, Klein B (1997) Rhinovirus-specific T cells recognize both shared and serotype-restricted viral epitopes. J Infect Dis 175: 1108–1114. doi: 10.1086/516449
[20]
Wimalasundera SS, Katz DR, Chain BM (1997) Characterization of the T cell response to human rhinovirus in children: implications for understanding the immunopathology of the common cold. J Infect Dis 176: 755–759. doi: 10.1086/514101
[21]
Hastings GZ, Francis MJ, Rowlands DJ, Chain BM (1993) Epitope analysis of the T cell response to a complex antigen: proliferative responses to human rhinovirus capsids. Eur J Immunol 23: 2300–2305. doi: 10.1002/eji.1830230937
[22]
Parry DE, Busse WW, Sukow KA, Dick CR, Swenson C, et al. (2000) Rhinovirus-induced PBMC responses and outcome of experimental infection in allergic subjects. J Allergy Clin Immunol 105: 692–698. doi: 10.1067/mai.2000.104785
[23]
Bartlett NW, Walton RP, Edwards MR, Aniscenko J, Caramori G, et al. (2008) Mouse models of rhinovirus-induced disease and exacerbation of allergic airway inflammation. Nat Med 14: 199–204. doi: 10.1038/nm1713
[24]
Eichelberger M, Allan W, Zijlstra M, Jaenisch R, Doherty PC (1991) Clearance of influenza virus respiratory infection in mice lacking class I major histocompatibility complex-restricted CD8+ T cells. J Exp Med 174: 875–880. doi: 10.1084/jem.174.4.875
[25]
Hussell T, Openshaw PJ (1998) Intracellular IFN-gamma expression in natural killer cells precedes lung CD8+ T cell recruitment during respiratory syncytial virus infection. J Gen Virol 79 (Pt 11) 2593–2601.
[26]
Hou S, Doherty PC, Zijlstra M, Jaenisch R, Katz JM (1992) Delayed clearance of Sendai virus in mice lacking class I MHC-restricted CD8+ T cells. J Immunol 149: 1319–1325.
[27]
Heidema J, Rossen JW, Lukens MV, Ketel MS, Scheltens E, et al. (2008) Dynamics of human respiratory virus-specific CD8+ T cell responses in blood and airways during episodes of common cold. J Immunol 181: 5551–5559. doi: 10.4049/jimmunol.181.8.5551
[28]
Brien JD, Uhrlaub JL, Nikolich-Zugich J (2008) West Nile virus-specific CD4 T cells exhibit direct antiviral cytokine secretion and cytotoxicity and are sufficient for antiviral protection. J Immunol 181: 8568–8575. doi: 10.4049/jimmunol.181.12.8568
[29]
Brown DM, Dilzer AM, Meents DL, Swain SL (2006) CD4 T cell-mediated protection from lethal influenza: perforin and antibody-mediated mechanisms give a one-two punch. J Immunol 177: 2888–2898. doi: 10.4049/jimmunol.177.5.2888
[30]
Wilkinson TM, Li CK, Chui CS, Huang AK, Perkins M, et al. (2012) Preexisting influenza-specific CD4(+) T cells correlate with disease protection against influenza challenge in humans. Nat Med 18: 274–280. doi: 10.1038/nm.2612
[31]
McKinstry KK, Strutt TM, Kuang Y, Brown DM, Sell S, et al. (2012) Memory CD4+ T cells protect against influenza through multiple synergizing mechanisms. J Clin Invest 122: 2847–2856. doi: 10.1172/jci63689
[32]
Strutt TM, McKinstry KK, Dibble JP, Winchell C, Kuang Y, et al. (2010) Memory CD4+ T cells induce innate responses independently of pathogen. Nat Med 16: 558–564 551p following 564. doi: 10.1038/nm.2142
[33]
Message SD, Laza-Stanca V, Mallia P, Parker HL, Zhu J, et al. (2008) Rhinovirus-induced lower respiratory illness is increased in asthma and related to virus load and Th1/2 cytokine and IL-10 production. Proc Natl Acad Sci U S A 105: 13562–13567. doi: 10.1073/pnas.0804181105
[34]
O'Hagan DT, Rappuoli R, De Gregorio E, Tsai T Del Giudice G MF59 adjuvant: the best insurance against influenza strain diversity. Expert Rev Vaccines 10: 447–462. doi: 10.1586/erv.11.23
[35]
Nazareth I, Tavares F, Rosillon D, Haguinet F, Bauchau V (2013) Safety of AS03-adjuvanted split-virion H1N1 (2009) pandemic influenza vaccine: a prospective cohort study. BMJ Open 3 (2) pii: e001912. doi: 10.1136/bmjopen-2012-001912
[36]
McLean GR, Walton RP, Shetty S, Paktiawal N, Kebadze T, et al. (2012) Rhinovirus infections and immunisation induce cross-serotype reactive antibodies to VP1. Antiviral Res 95: 193–201. doi: 10.1016/j.antiviral.2013.02.004
[37]
Mallia P, Message SD, Gielen V, Contoli M, Gray K, et al. (2011) Experimental rhinovirus infection as a human model of chronic obstructive pulmonary disease exacerbation. Am J Respir Crit Care Med 183: 734–742. doi: 10.1164/rccm.201006-0833oc
[38]
Chapman TJ, Lambert K, Topham DJ (2011) Rapid reactivation of extralymphoid CD4 T cells during secondary infection. PLoS One 6: e20493. doi: 10.1371/journal.pone.0020493
[39]
Teijaro JR, Turner D, Pham Q, Wherry EJ, Lefrancois L, et al. (2011) Cutting edge: Tissue-retentive lung memory CD4 T cells mediate optimal protection to respiratory virus infection. J Immunol 187: 5510–5514. doi: 10.4049/jimmunol.1102243
[40]
Turner RB (1997) Epidemiology, pathogenesis, and treatment of the common cold. Ann Allergy Asthma Immunol 78: 531–539 quiz 539-540. doi: 10.1016/s1081-1206(10)63213-9
[41]
Edgar RC (2004) MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res 32: 1792–1797. doi: 10.1093/nar/gkh340
[42]
Galtier N, Gouy M, Gautier C (1996) SEAVIEW and PHYLO_WIN: two graphic tools for sequence alignment and molecular phylogeny. Comput Appl Biosci 12: 543–548. doi: 10.1093/bioinformatics/12.6.543
[43]
Clamp M, Cuff J, Searle SM, Barton GJ (2004) The Jalview Java alignment editor. Bioinformatics 20: 426–427. doi: 10.1093/bioinformatics/btg430