Cellular Immune Responses to Live Attenuated Japanese Encephalitis (JE) Vaccine SA14-14-2 in Adults in a JE/Dengue Co-Endemic Area
Lance Turtle, Filippo Tatullo, Tanushka Bali, Vasanthapuram Ravi, Mohammed Soni, Sajesh Chan, Savita Chib, Manjunatha M Venkataswamy, Prachi Fadnis, Mansour Yaïch, Stefan Fernandez, Paul Klenerman, Vijaya Satchidanandam, Tom Solomon, Lance Turtle, Filippo Tatullo, Tanushka Bali, Vasanthapuram Ravi, Mohammed Soni, Sajesh Chan, Savita Chib, Manjunatha M Venkataswamy, Prachi Fadnis, Mansour Yaïch, Stefan Fernandez, Paul Klenerman, Vijaya Satchidanandam, Tom Solomon
Abstract
Background: Japanese encephalitis (JE) virus (JEV) causes severe epidemic encephalitis across Asia, for which the live attenuated vaccine SA14-14-2 is being used increasingly. JEV is a flavivirus, and is closely related to dengue virus (DENV), which is co-endemic in many parts of Asia, with clinically relevant interactions. There is no information on the human T cell response to SA14-14-2, or whether responses to SA14-14-2 cross-react with DENV. We used live attenuated JE vaccine SA14-14-2 as a model for studying T cell responses to JEV infection in adults, and to determine whether these T cell responses are cross-reactive with DENV, and other flaviviruses.
Methods: We conducted a single arm, open label clinical trial (registration: clinicaltrials.gov NCT01656200) to study T cell responses to SA14-14-2 in adults in South India, an area endemic for JE and dengue.
Results: Ten out of 16 (62.5%) participants seroconverted to JEV SA14-14-2, and geometric mean neutralising antibody (NAb) titre was 18.5. Proliferation responses were commonly present before vaccination in the absence of NAb, indicating a likely high degree of previous flavivirus exposure. Thirteen of 15 (87%) participants made T cell interferon-gamma (IFNγ) responses against JEV proteins. In four subjects tested, at least some T cell epitopes mapped cross-reacted with DENV and other flaviviruses.
Conclusions: JEV SA14-14-2 was more immunogenic for T cell IFNγ than for NAb in adults in this JE/DENV co-endemic area. The proliferation positive, NAb negative combination may represent a new marker of long term immunity/exposure to JE. T cell responses can cross-react between JE vaccine and DENV in a co-endemic area, illustrating a need for greater knowledge on such responses to inform the development of next-generation vaccines effective against both diseases.
Trial registration: clinicaltrials.gov (NCT01656200).
Conflict of interest statement
MY is an employee of Vaxyn Consulting. Vaxyn Consulting has no financial interest in JE vaccine SA14-14-2. The other authors have declared that no competing interests exist.
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References
- Campbell GL, Hills SL, Fischer M, Jacobson JA, Hoke CH, Hombach JM, et al. Estimated global incidence of Japanese encephalitis: a systematic review. Bull World Health Organ. 2011;89(10):766–74. 10.2471/BLT.10.085233
- Sumiyoshi H, Mori C, Fuke I, Morita K, Kuhara S, Kondou J, et al. Complete nucleotide sequence of the Japanese encephalitis virus genome RNA. Virology. 1987;161(2):497–510.
- Solomon T. Control of Japanese encephalitis—within our grasp? N Engl J Med. 2006;355(9):869–71. 10.1056/NEJMp058263
- Beasley DW, Lewthwaite P, Solomon T. Current use and development of vaccines for Japanese encephalitis. Expert Opin Biol Ther. 2008;8(1):95–106. 10.1517/14712598.8.1.95
- Hoke CH, Nisalak A, Sangawhipa N, Jatanasen S, Laorakapongse T, Innis BL, et al. Protection against Japanese encephalitis by inactivated vaccines. N Engl J Med. 1988;319(10):608–14. 10.1056/NEJM198809083191004
- Gatchalian S, Yao Y, Zhou B, Zhang L, Yoksan S, Kelly K, et al. Comparison of the immunogenicity and safety of measles vaccine administered alone or with live, attenuated Japanese encephalitis SA 14-14-2 vaccine in Philippine infants. Vaccine. 2008;26(18):2234–41. 10.1016/j.vaccine.2008.02.042
- Wijesinghe PR, Abeysinghe MR, Yoksan S, Yao Y, Zhou B, Zhang L, et al. Safety and immunogenicity of live-attenuated Japanese encephalitis SA 14-14-2 vaccine co-administered with measles vaccine in 9-month-old infants in Sri Lanka. Vaccine. 2014;32(37):4751–7. 10.1016/j.vaccine.2014.06.036
- Zaman K, Naser AM, Power M, Yaich M, Zhang L, Ginsburg AS, et al. Lot-to-lot consistency of live attenuated SA 14-14-2 Japanese encephalitis vaccine manufactured in a good manufacturing practice facility and non-inferiority with respect to an earlier product. Vaccine. 2014;32(46):6061–6. 10.1016/j.vaccine.2014.09.012
- Bista MB, Banerjee MK, Shin SH, Tandan JB, Kim MH, Sohn YM, et al. Efficacy of single-dose SA 14-14-2 vaccine against Japanese encephalitis: a case control study. Lancet. 2001;358(9284):791–5.
- Kumar R, Tripathi P, Rizvi A. Effectiveness of one dose of SA 14-14-2 vaccine against Japanese encephalitis. N Engl J Med. 2009;360(14):1465–6. 10.1056/NEJMc0808664
- Ohrr H, Tandan JB, Sohn YM, Shin SH, Pradhan DP, Halstead SB. Effect of single dose of SA 14-14-2 vaccine 1 year after immunisation in Nepalese children with Japanese encephalitis: a case-control study. Lancet. 2005;366(9494):1375–8. 10.1016/S0140-6736(05)67567-8
- Tandan JB, Ohrr H, Sohn YM, Yoksan S, Ji M, Nam CM, et al. Single dose of SA 14-14-2 vaccine provides long-term protection against Japanese encephalitis: a case-control study in Nepalese children 5 years after immunization. Vaccine. 2007;25(27):5041–5. 10.1016/j.vaccine.2007.04.052
- Riedmann EM. WHO prequalifies Chinese-produced Japanese encephalitis vaccine. Hum Vaccin Immunother. 2013;9(12):2500–1.
- Screaton G, Mongkolsapaya J, Yacoub S, Roberts C. New insights into the immunopathology and control of dengue virus infection. Nat Rev Immunol. 2015;15(12):745–59. 10.1038/nri3916
- Edelman R, Schneider RJ, Chieowanich P, Pornpibul R, Voodhikul P. The effect of dengue virus infection on the clinical sequelae of Japanese encephalitis: a one year follow-up study in Thailand. Southeast Asian J Trop Med Public Health. 1975;6(3):308–15.
- Anderson KB, Gibbons RV, Thomas SJ, Rothman AL, Nisalak A, Berkelman RL, et al. Preexisting Japanese encephalitis virus neutralizing antibodies and increased symptomatic dengue illness in a school-based cohort in Thailand. PLoS Negl Trop Dis. 2011;5(10):e1311 10.1371/journal.pntd.0001311
- Turtle L, Bali T, Buxton G, Chib S, Chan S, Soni M, et al. Human T cell responses to Japanese encephalitis virus in health and disease. J Exp Med. 2016;213(7):1331–52. 10.1084/jem.20151517
- Precopio ML, Betts MR, Parrino J, Price DA, Gostick E, Ambrozak DR, et al. Immunization with vaccinia virus induces polyfunctional and phenotypically distinctive CD8(+) T cell responses. J Exp Med. 2007;204(6):1405–16. 10.1084/jem.20062363
- Miller JD, van der Most RG, Akondy RS, Glidewell JT, Albott S, Masopust D, et al. Human effector and memory CD8+ T cell responses to smallpox and yellow fever vaccines. Immunity. 2008;28(5):710–22. 10.1016/j.immuni.2008.02.020
- Schioler KL, Samuel M, Wai KL. Vaccines for preventing Japanese encephalitis. Cochrane database of systematic reviews (Online). 2007;(3):CD004263.
- Murali-Krishna K, Ravi V, Manjunath R. Protection of adult but not newborn mice against lethal intracerebral challenge with Japanese encephalitis virus by adoptively transferred virus-specific cytotoxic T lymphocytes: requirement for L3T4+ T cells. J Gen Virol. 1996;77 (Pt 4):705–14.
- Kumar P, Sulochana P, Nirmala G, Chandrashekar R, Haridattatreya M, Satchidanandam V. Impaired T helper 1 function of nonstructural protein 3-specific T cells in Japanese patients with encephalitis with neurological sequelae. The Journal of infectious diseases. 2004;189(5):880–91. 10.1086/381768
- Larena M, Regner M, Lobigs M. Cytolytic effector pathways and IFN-gamma help protect against Japanese encephalitis. Eur J Immunol. 2013;43(7):1789–98. 10.1002/eji.201243152
- Solomon T. Flavivirus encephalitis. N Engl J Med. 2004;351(4):370–8. 10.1056/NEJMra030476
- Kumar P, Uchil PD, Sulochana P, Nirmala G, Chandrashekar R, Haridattatreya M, et al. Screening for T cell-eliciting proteins of Japanese encephalitis virus in a healthy JE-endemic human cohort using recombinant baculovirus-infected insect cell preparations. Arch Virol. 2003;148(8):1569–91. 10.1007/s00705-003-0118-5
- Roederer M, Nozzi JL, Nason MC. SPICE: exploration and analysis of post-cytometric complex multivariate datasets. Cytometry A. 2011;79(2):167–74. 10.1002/cyto.a.21015
- Russell PK, Nisalak A, Sukhavachana P, Vivona S. A plaque reduction test for dengue virus neutralizing antibodies. J Immunol. 1967;99(2):285–90.
- Mathew A, Kurane I, Green S, Stephens HA, Vaughn DW, Kalayanarooj S, et al. Predominance of HLA-restricted cytotoxic T-lymphocyte responses to serotype-cross-reactive epitopes on nonstructural proteins following natural secondary dengue virus infection. J Virol. 1998;72(5):3999–4004.
- Zivny J, DeFronzo M, Jarry W, Jameson J, Cruz J, Ennis FA, et al. Partial agonist effect influences the CTL response to a heterologous dengue virus serotype. J Immunol. 1999;163(5):2754–60.
- Nielsen M, Lundegaard C, Blicher T, Lamberth K, Harndahl M, Justesen S, et al. NetMHCpan, a method for quantitative predictions of peptide binding to any HLA-A and -B locus protein of known sequence. PLoS One. 2007;2(8):e796 10.1371/journal.pone.0000796
- Hoof I, Peters B, Sidney J, Pedersen LE, Sette A, Lund O, et al. NetMHCpan, a method for MHC class I binding prediction beyond humans. Immunogenetics. 2009;61(1):1–13. 10.1007/s00251-008-0341-z
- Friberg H, Burns L, Woda M, Kalayanarooj S, Endy TP, Stephens HA, et al. Memory CD8+ T cells from naturally acquired primary dengue virus infection are highly cross-reactive. Immunol Cell Biol. 2011;89(1):122–9. 10.1038/icb.2010.61
- Feroldi E, Pancharoen C, Kosalaraksa P, Chokephaibulkit K, Boaz M, Meric C, et al. Primary immunization of infants and toddlers in Thailand with Japanese encephalitis chimeric virus vaccine in comparison with SA14-14-2: a randomized study of immunogenicity and safety. Pediatr Infect Dis J. 2014;33(6):643–9. 10.1097/INF.0000000000000276
- Sohn YM, Park MS, Rho HO, Chandler LJ, Shope RE, Tsai TF. Primary and booster immune responses to SA14-14-2 Japanese encephalitis vaccine in Korean infants. Vaccine. 1999;17(18):2259–64.
- Singh A, Mitra M, Sampath G, Venugopal P, Rao JV, Krishnamurthy B, et al. A Japanese Encephalitis Vaccine From India Induces Durable and Cross-protective Immunity Against Temporally and Spatially Wide-ranging Global Field Strains. The Journal of infectious diseases. 2015;212(5):715–25. 10.1093/infdis/jiv023
- Konishi E, Yamaoka M, Khin Sane W, Kurane I, Takada K, Mason PW. The anamnestic neutralizing antibody response is critical for protection of mice from challenge following vaccination with a plasmid encoding the Japanese encephalitis virus premembrane and envelope genes. J Virol. 1999;73(7):5527–34.
- Monath TP, Guirakhoo F, Nichols R, Yoksan S, Schrader R, Murphy C, et al. Chimeric live, attenuated vaccine against Japanese encephalitis (ChimeriVax-JE): phase 2 clinical trials for safety and immunogenicity, effect of vaccine dose and schedule, and memory response to challenge with inactivated Japanese encephalitis antigen. The Journal of infectious diseases. 2003;188(8):1213–30. 10.1086/378356
- Ward SM, Phalora P, Bradshaw D, Leyendeckers H, Klenerman P. Direct ex vivo evaluation of long-lived protective antiviral memory B cell responses against hepatitis B virus. The Journal of infectious diseases. 2008;198(6):813–7. 10.1086/591094
- Weiskopf D, Angelo MA, Bangs DJ, Sidney J, Paul S, Peters B, et al. The human CD8+ T cell responses induced by a live attenuated tetravalent dengue vaccine are directed against highly conserved epitopes. J Virol. 2015;89(1):120–8. 10.1128/JVI.02129-14
- Mongkolsapaya J, Dejnirattisai W, Xu XN, Vasanawathana S, Tangthawornchaikul N, Chairunsri A, et al. Original antigenic sin and apoptosis in the pathogenesis of dengue hemorrhagic fever. Nat Med. 2003;9(7):921–7. 10.1038/nm887
- Hatch S, Endy TP, Thomas S, Mathew A, Potts J, Pazoles P, et al. Intracellular cytokine production by dengue virus-specific T cells correlates with subclinical secondary infection. The Journal of infectious diseases. 2011;203(9):1282–91. 10.1093/infdis/jir012
- Weiskopf D, Angelo MA, de Azeredo EL, Sidney J, Greenbaum JA, Fernando AN, et al. Comprehensive analysis of dengue virus-specific responses supports an HLA-linked protective role for CD8+ T cells. Proc Natl Acad Sci U S A. 2013;110(22):E2046–53. 10.1073/pnas.1305227110
- Sabchareon A, Wallace D, Sirivichayakul C, Limkittikul K, Chanthavanich P, Suvannadabba S, et al. Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial. Lancet. 2012;380(9853):1559–67. 10.1016/S0140-6736(12)61428-7
- Hadinegoro SR, Arredondo-Garcia JL, Capeding MR, Deseda C, Chotpitayasunondh T, Dietze R, et al. Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease. N Engl J Med. 2015;373(13):1195–206. 10.1056/NEJMoa1506223
- Weiskopf D, Angelo MA, Sidney J, Peters B, Shresta S, Sette A. Immunodominance changes as a function of the infecting dengue virus serotype and primary versus secondary infection. J Virol. 2014;88(19):11383–94. 10.1128/JVI.01108-14
- Weiskopf D, Cerpas C, Angelo MA, Bangs DJ, Sidney J, Paul S, et al. Human CD8+ T-Cell Responses Against the 4 Dengue Virus Serotypes Are Associated With Distinct Patterns of Protein Targets. The Journal of infectious diseases. 2015;212(11):1743–51. 10.1093/infdis/jiv289
- Li XF, Deng YQ, Yang HQ, Zhao H, Jiang T, Yu XD, et al. A chimeric dengue virus vaccine using Japanese encephalitis virus vaccine strain SA14-14-2 as backbone is immunogenic and protective against either parental virus in mice and nonhuman primates. J Virol. 2013;87(24):13694–705. 10.1128/JVI.00931-13
- Gromowski GD, Firestone CY, Hanson CT, Whitehead SS. Japanese encephalitis virus vaccine candidates generated by chimerization with dengue virus type 4. Vaccine. 2014;32(25):3010–8. 10.1016/j.vaccine.2014.03.062
- Ravi V, Parida S, Desai A, Chandramuki A, Gourie-Devi M, Grau GE. Correlation of tumor necrosis factor levels in the serum and cerebrospinal fluid with clinical outcome in Japanese encephalitis patients. J Med Virol. 1997;51(2):132–6.
- Shyu WR, Wang YC, Chin C, Chen WJ. Assessment of neutralizing antibodies elicited by a vaccine (Nakayama) strain of Japanese encephalitis virus in Taiwan. Epidemiol Infect. 1997;119(1):79–83.
- Sallusto F, Geginat J, Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol. 2004;22:745–63. 10.1146/annurev.immunol.22.012703.104702
- Markoff L. Points to consider in the development of a surrogate for efficacy of novel Japanese encephalitis virus vaccines. Vaccine. 2000;18 Suppl 2:26–32.
- Hombach J, Solomon T, Kurane I, Jacobson J, Wood D. Report on a WHO consultation on immunological endpoints for evaluation of new Japanese encephalitis vaccines, WHO, Geneva, 2–3 September, 2004. Vaccine. 2005;23(45):5205–11. 10.1016/j.vaccine.2005.07.002
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