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Analysis of the Th1/Th2 Reaction in the Immune Response Induced by EV71 Inactivated Vaccine in Neonatal Rhesus Monkeys

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Abstract

Although clinical trials for the enterovirus type 71 (EV71) inactivated vaccine have been progressing, the potential mechanism of EV71 infection and its associated pathogenesis are not well-characterized in terms of comprehensive analysis of the induced immune response, which is generally recognized as an important indicator of the safety of vaccines. To investigate the Th1/Th2 response following viral challenge in neonatal rhesus monkeys immunized with different doses of EV71 inactivated vaccines, the variety of different Th1 and Th2 cytokines in the organs or tissues of the monkeys were identified. The results suggest that depending on the viral challenge, the Th1/Th2 reaction induced by different doses of EV71 inactivated vaccine varies. More specifically, there is an enhanced immune response in 80EU- and 1280EU-immunized monkeys, whereas 320EU immunization induces a mild response. Although there is no direct impact on the variation in immune protection induced by the vaccine, the Th1 reaction functions in T-cell cytotoxicity, which will aid further investigation of the pathogenic characteristics of small pathological changes in the central nerves system (CNS) likely induced by the Th1 response.

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References

  1. Deaths among children during an outbreak of hand, foot, and mouth disease-Taiwan, Republic of China, April-July 1998. MMWR Morb Mortal Wkly Rep. 1998;47(30):629–32.

  2. Chan LG, Parashar UD, Lye MS, Ong FG, Zaki SR, Alexander JP, et al. Deaths of children during an outbreak of hand, foot, and mouth disease in sarawak, malaysia: clinical and pathological characteristics of the disease. For the Outbreak Study Group. Clin Infect Dis. 2000;31(3):678–83.

    Article  PubMed  CAS  Google Scholar 

  3. Shimizu H, Utama A, Yoshii K, Yoshida H, Yoneyama T, Sinniah M, et al. Enterovirus 71 from fatal and nonfatal cases of hand, foot and mouth disease epidemics in Malaysia, Japan and Taiwan in 1997–1998. Jpn J Infect Dis. 1999;52(1):12–5.

    PubMed  CAS  Google Scholar 

  4. Ooi MH, Solomon T, Podin Y, Mohan A, Akin W, Yusuf MA, et al. Evaluation of different clinical sample types in diagnosis of human enterovirus 71-associated hand-foot-and-mouth disease. J Clin Microbiol. 2007;45(6):1858–66.

    Article  PubMed  Google Scholar 

  5. Lee MS, Chang LY. Development of enterovirus 71 vaccines. Expert Rev Vaccines. 9(2):149–56.

  6. Whitton JL, Cornell CT, Feuer R. Host and virus determinants of picornavirus pathogenesis and tropism. Nat Rev Microbiol. 2005;3(10):765–76.

    Article  PubMed  CAS  Google Scholar 

  7. Wang SM, Liu CC, Tseng HW, Wang JR, Huang CC, Chen YJ, et al. Clinical spectrum of enterovirus 71 infection in children in southern Taiwan, with an emphasis on neurological complications. Clin Infect Dis. 1999;29(1):184–90.

    Article  PubMed  CAS  Google Scholar 

  8. Spellberg B, Edwards Jr JE. Type 1/Type 2 immunity in infectious diseases. Clin Infect Dis. 2001;32(1):76–102.

    Article  PubMed  CAS  Google Scholar 

  9. Infante-Duarte C, Kamradt T. Th1/Th2 balance in infection. Springer Semin Immunopathol. 1999;21(3):317–38.

    Article  PubMed  CAS  Google Scholar 

  10. Buckley RH. T-B-and NK-cells systems Nelson Textbook of Pediatrics. 2000:590–96.

  11. Imboden JB. T lymphocytes & natural killer cells. Medical Immunology. 1997:138–42.

  12. Wu CN, Lin YC, Fann C, Liao NS, Shih SR, Ho MS. Protection against lethal enterovirus 71 infection in newborn mice by passive immunization with subunit VP1 vaccines and inactivated virus. Vaccine. 2001;20(5–6):895–904.

    Article  PubMed  CAS  Google Scholar 

  13. Wu TC, Wang YF, Lee YP, Wang JR, Liu CC, Wang SM, et al. Immunity to avirulent enterovirus 71 and coxsackie A16 virus protects against enterovirus 71 infection in mice. J Virol. 2007;81(19):10310–5.

    Article  PubMed  CAS  Google Scholar 

  14. Chua BH, Phuektes P, Sanders SA, Nicholls PK, McMinn PC. The molecular basis of mouse adaptation by human enterovirus 71. J Gen Virol. 2008;89(Pt 7):1622–32.

    Article  PubMed  CAS  Google Scholar 

  15. Yang C, Deng C, Wan J, Zhu L, Leng Q. Neutralizing antibody response in the patients with hand, foot and mouth disease to enterovirus 71 and its clinical implications. Virol J. 8:306.

  16. Lin TY, Chang LY, Huang YC, Hsu KH, Chiu CH, Yang KD. Different proinflammatory reactions in fatal and non-fatal enterovirus 71 infections: implications for early recognition and therapy. Acta Paediatr. 2002;91(6):632–5.

    Article  PubMed  CAS  Google Scholar 

  17. Wang SM, Lei HY, Huang KJ, Wu JM, Wang JR, Yu CK, et al. Pathogenesis of enterovirus 71 brainstem encephalitis in pediatric patients: roles of cytokines and cellular immune activation in patients with pulmonary edema. J Infect Dis. 2003;188(4):564–70.

    Article  PubMed  CAS  Google Scholar 

  18. Yang KD, Yang MY, Li CC, Lin SF, Chong MC, Wang CL, et al. Altered cellular but not humoral reactions in children with complicated enterovirus 71 infections in Taiwan. J Infect Dis. 2001;183(6):850–6.

    Article  PubMed  CAS  Google Scholar 

  19. Wang SM, Lei HY, Huang MC, Su LY, Lin HC, Yu CK, et al. Modulation of cytokine production by intravenous immunoglobulin in patients with enterovirus 71-associated brainstem encephalitis. J Clin Virol. 2006;37(1):47–52.

    Article  PubMed  CAS  Google Scholar 

  20. Liu ML, Lee YP, Wang YF, Lei HY, Liu CC, Wang SM, et al. Type I interferons protect mice against enterovirus 71 infection. J Gen Virol. 2005;86(Pt 12):3263–9.

    Article  PubMed  CAS  Google Scholar 

  21. Chung YC, Ho MS, Wu JC, Chen WJ, Huang JH, Chou ST, et al. Immunization with virus-like particles of enterovirus 71 elicits potent immune responses and protects mice against lethal challenge. Vaccine. 2008;26(15):1855–62.

    Article  PubMed  CAS  Google Scholar 

  22. Liu L, Zhao H, Zhang Y, Wang J, Che Y, Dong C et al. Neonatal rhesus monkey is a potential animal model for studying pathogenesis of EV71 infection. Virology. 412(1):91–100.

  23. Zhang Y, Cui W, Liu L, Wang J, Zhao H, Liao Y et al. Pathogenesis study of enterovirus 71 infection in rhesus monkeys. Lab Invest. 91(9):1337–50.

  24. Dong C, Liu L, Zhao H, Wang J, Liao Y, Zhang X et al. Immunoprotection elicited by an enterovirus type 71 experimental inactivated vaccine in mice and rhesus monkeys. Vaccine. 29(37):6269–75.

  25. Requirements for poliomyelitis vaccine (oral). WHO Tech Rep Ser. 1990(800):30–65.

  26. Zahn J, Vallbracht A, Flehmig B. Hepatitis A-virus in cell culture. V. Neutralizing antibodies against hepatitis A-virus. Med Microbiol Immunol. 1984;173(1):9–17.

    Article  PubMed  CAS  Google Scholar 

  27. Lin MT, Wang JK, Lu FL, Wu ET, Yeh SJ, Lee WL, et al. Heart rate variability monitoring in the detection of central nervous system complications in children with enterovirus infection. J Crit Care. 2006;21(3):280–6.

    Article  PubMed  Google Scholar 

  28. Lin YW, Chang KC, Kao CM, Chang SP, Tung YY, Chen SH. Lymphocyte and antibody responses reduce enterovirus 71 lethality in mice by decreasing tissue viral loads. J Virol. 2009;83(13):6477–83.

    Article  PubMed  CAS  Google Scholar 

  29. Khong WX, Foo DG, Trasti SL, Tan EL, Alonso S. Sustained high levels of interleukin-6 contribute to the pathogenesis of enterovirus 71 in a neonate mouse model. J Virol. 85(7):3067–76.

  30. Lin TY, Hsia SH, Huang YC, Wu CT, Chang LY. Proinflammatory cytokine reactions in enterovirus 71 infections of the central nervous system. Clin Infect Dis. 2003;36(3):269–74.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by the Grant of Basic Research of CASMS (2010IPB109) and the National Basic Research Program (2011CB504903,2012CB518901).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Institute Of Medical Biology, Chinese Academy of Medical Sciences, Peking Union Medical College, 935# Jiaoling Rd, Kunming, 650118, People’s Republic of China

    Yan Liang, Xiaofang Zhou, Erxia Yang, Jing Pu, Yanchun Che, JingJing Wang, Na Ma, Longding Liu, Dong Ding, Donghong Tang, Dong Sheng, Lixian Yang, Hongling Zhao, Chenghong Dong & Qihan Li

  2. Department of Viral Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences, Peking Union Medical College, 935 Jiaoling Road, Kunming, Yunnan, People’s Republic of China

    Qihan Li

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  1. Yan Liang
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Correspondence to Qihan Li.

Additional information

Yan Liang and Xiaofang Zhou contributed to this work equally.

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Supplemental Fig. 1

Viral load detection in peripheral blood at days 0, 4, 7, 10 and 14 of immunized monkeys challenged with 104CCID50/0.5 ml FY-23 EV71, as determined by real-time RT-PCR. Blood samples were collected on 0, 4, 7 (4 monkeys each group), 10 and 14 (2 monkeys each group) days post virus infection for detecting the viral load. Viral copy number was quantified according to an EV71 RNA standard. The results are presented as the mean ± S.D. based on three separate experiments. The asterisks indicate values with significant differences (P < 0.05). *P < 0.05, between live virus and 80EU, 320EU, 1280EU at 4, 7 days post challenge. (JPEG 36 kb)

Supplemental Fig. 2

The blood cell analysis using FCM and number statistic measure of immunized monkeys challenged with 104 CCID50/0.5 ml FY-23 EV71, containing (a) leucocyte neutrophil, (b) lymphocytes and (c) monocytes. The percentages of normal cells ranging (data collected from two negative monkeys and referring Sibley, 1974) were shown as dot line. Blood samples were collected in days 0, 4, 7, 10, 14 post-infection for detecting the presence of certain inflammatory markers. (JPEG 72 kb)

Supplemental Fig. 3

Pathological changes in lung, thalamus and spinal cord of immunized monkeys challenged with 104CCID50/0.5 ml FY-23 EV71. (a) The typical features of pathological changes in lung of immunized monkeys challenged with FY-23 EV71. Infiltration of inflammatory cells (black arrow), edema (white arrow) and hemorrhage (green arrow). Images are shown at 100× magnification. Bar, 30 μm. (b) The typical features of pathological changes in thalamus of immunized monkeys challenged with FY-23 EV71. glial cells aggregation (blue arrow), neuron retrogression (yellow arrow) and neuronal cell nuclei disappearance (brown arrow) . Images are shown at 200× magnification. Bar, 30 μm. (c) The typical features of pathological changes in spinal cord of immunized monkeys challenged with FY-23 EV71. glial cells aggregation (blue arrow), neuron retrogression (yellow arrow) and neuronal cell nuclei disappearance (brown arrow) . Images are shown at 200× magnification. Bar, 30 μm. Samples were collected on day 7 post-infection. The histopathological examinations were performed on 4-μm sections of paraffin-embedded tissue or organ stained with H&E according to the protocol. (JPEG 288 kb)

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Liang, Y., Zhou, X., Yang, E. et al. Analysis of the Th1/Th2 Reaction in the Immune Response Induced by EV71 Inactivated Vaccine in Neonatal Rhesus Monkeys. J Clin Immunol 32, 1048–1058 (2012). https://doi.org/10.1007/s10875-012-9690-3

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  • DOI: https://doi.org/10.1007/s10875-012-9690-3

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