Skip to main content
NCBI home page
Wiley - PMC COVID-19 Collection logoLink to Wiley - PMC COVID-19 Collection
. 2010 Mar 24;82(5):727–734. doi: 10.1002/jmv.21667

The route of inoculation determines the tissue tropism of modified vaccinia tiantan expressing the spike glycoprotein of SARS‐CoV in mice†, ‡

Huan Liu 1, Wenbo Yu 2, Xian Tang 2, Haibo Wang 2, Wenjie Ouyang 1, Jingying Zhou 2, Zhiwei Chen 2,✉
PMCID: PMC7166938  PMID: 20336714

Abstract

The live replication‐competent modified vaccinia virus Tiantan (MVTT) is an attractive vaccine vector, yet little is known about its tissue tropism and pathology in vivo. Recently, we demonstrated that a recombinant MVTT expressing the spike glycoprotein of SARS‐CoV (namely MVTT‐S) is superior to the non‐replicating modified vaccinia Ankara (MVA‐S) for inducing high level of neutralizing antibodies through mucosal vaccination. In this study, we further determined the tissue tropism and safety of MVTT‐S after the vaccine was administrated through various routes including: intramuscular (i.m.), intranasal (i.n.), and intravaginal (i.vag.) inoculations, respectively. Using real‐time PCR, nested PCR, immunohistochemistry and in situ hybridization assays, we found that MVTT‐S was able to produce a transient infection in all cases within 48 hr post‐inoculation, yet the major site of viral replication in various tissues or organs was dependent on the route of viral administration. We demonstrated that i.m. injection of MVTT‐S primarily targeted draining inguinal lymph nodes, whereas mucosal inoculation had broader range of tissue infections. i.n. inoculation involved infections in lungs, kidneys, spleens and cervix lymph nodes while i.vag. administration targeted uteruses, ovaries, kidneys and spleens. Critically, the infection did not cause severe pathogenic consequences in infected tissues, which was consistent to the attenuated phenotype of MVTT‐S. Our findings have implications for the optimization of vaccination route and for studies on the correlation between the magnitude of immune responses and the extent of tissue involvement in vivo. J. Med. Virol. 82: 727–734, 2010. © 2010 Wiley‐Liss, Inc.

Keywords: vaccinia, MVTT, tissue tropism, vaccine, vaccination route

†

The authors declare no financial or commercial conflict of interest.

‡

Huan Liu and Wenbo Yu contributed equally to this work.

REFERENCES

  1. Bisht H, Roberts A, Vogel L, Bukreyev A, Collins PL, Murphy BR, Subbarao K, Moss B. 2004. Severe acute respiratory syndrome coronavirus spike protein expressed by attenuated vaccinia virus protectively immunizes mice. Proc Natl Acad Sci USA 101: 6641–6646. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Brenchley JM, Douek DC. 2008. The mucosal barrier and immune activation in HIV pathogenesis. Curr Opin HIV AIDS 3: 356–361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Broliden K, Haase AT, Ahuja SK, Shearer GM, Andersson J. 2009. Introduction: Back to basics: Mucosal immunity and novel HIV vaccine concepts. J Intern Med 265: 5–17. [DOI] [PubMed] [Google Scholar]
  4. Caley IJ, Betts MR, Irlbeck DM, Davis NL, Swanstrom R, Frelinger JA, Johnston RE. 1997. Humoral, mucosal, and cellular immunity in response to a human immunodeficiency virus type 1 immunogen expressed by a Venezuelan equine encephalitis virus vaccine vector. J Virol 71: 3031–3038. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chen Z, Zhang L, Qin C, Ba L, Yi CE, Zhang F, Wei Q, He T, Yu W, Yu J, Gao H, Tu X, Gettie A, Farzan M, Yuen KY, Ho DD. 2005. Recombinant modified vaccinia virus Ankara expressing the spike glycoprotein of severe acute respiratory syndrome coronavirus induces protective neutralizing antibodies primarily targeting the receptor binding region. J Virol 79: 2678–2688. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Davis NL, Brown KW, Johnston RE. 1996. A viral vaccine vector that expresses foreign genes in lymph nodes and protects against mucosal challenge. J Virol 70: 3781–3787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. de Waal L, Wyatt LS, Yuksel S, van Amerongen G, Moss B, Niesters HG, Osterhaus AD, de Swart RL. 2004. Vaccination of infant macaques with a recombinant modified vaccinia virus Ankara expressing the respiratory syncytial virus F and G genes does not predispose for immunopathology. Vaccine 22: 923–926. [DOI] [PubMed] [Google Scholar]
  8. Degano P, Schneider J, Hannan CM, Gilbert SC, Hill AV. 1999. Gene gun intradermal DNA immunization followed by boosting with modified vaccinia virus Ankara: Enhanced CD8 + T cell immunogenicity and protective efficacy in the influenza and malaria models. Vaccine 18: 623–632. [DOI] [PubMed] [Google Scholar]
  9. Demberg T, Robert‐Guroff M. 2009. Mucosal immunity and protection against HIV/SIV infection: Strategies and challenges for vaccine design. Int Rev Immunol 28: 20–48. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fennelly GJ, Khan SA, Abadi MA, Wild TF, Bloom BR. 1999. Mucosal DNA vaccine immunization against measles with a highly attenuated Shigella flexneri vector. J Immunol 162: 1603–1610. [PubMed] [Google Scholar]
  11. Forrest BD. 1992. Mucosal approaches to HIV vaccine development. AIDS Res Hum Retroviruses 8: 1523–1525. [DOI] [PubMed] [Google Scholar]
  12. Gherardi MM, Perez‐Jimenez E, Najera JL, Esteban M. 2004. Induction of HIV immunity in the genital tract after intranasal delivery of a MVA vector: Enhanced immunogenicity after DNA prime‐modified vaccinia virus Ankara boost immunization schedule. J Immunol 172: 6209–6220. [DOI] [PubMed] [Google Scholar]
  13. Girard MP, Bansal GP, Pedroza‐Martins L, Dodet B, Mehra V, Schito M, Mathieson B, Delfraissy JF, Bradac J. 2008. Mucosal immunity and HIV/AIDS vaccines. Report of an International Workshop, 28–30 October2007. Vaccine 26: 3969–3977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Haynes BF, Shattock RJ. 2008. Critical issues in mucosal immunity for HIV‐1 vaccine development. J Allergy Clin Immunol 122: 3–9 quiz 10‐11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Holmgren J, Czerkinsky C. 2005. Mucosal immunity and vaccines. Nat Med 11: S45–S53. [DOI] [PubMed] [Google Scholar]
  16. Huang X, Lu B, Yu W, Fang Q, Liu L, Zhuang K, Shen T, Wang H, Tian P, Zhang L, Chen Z. 2009. A novel replication‐competent vaccinia vector MVTT is superior to MVA for inducing high levels of neutralizing antibody via mucosal vaccination. PLoS ONE 4: e4180. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kastenmuller W, Gasteiger G, Stross L, Busch DH, Drexler I. 2009. Cutting edge: Mucosal application of a lyophilized viral vector vaccine confers systemic and protective immunity toward intracellular pathogens. J Immunol 182: 2573–2577. [DOI] [PubMed] [Google Scholar]
  18. Kent SJ, Dale CJ, Ranasinghe C, Stratov I, De Rose R, Chea S, Montefiori DC, Thomson S, Ramshaw IA, Coupar BE, Boyle DB, Law M, Wilson KM, Ramsay AJ. 2005. Mucosally‐administered human‐simian immunodeficiency virus DNA and fowlpoxvirus‐based recombinant vaccines reduce acute phase viral replication in macaques following vaginal challenge with CCR5‐tropic SHIVSF162P3. Vaccine 23: 5009–5021. [DOI] [PubMed] [Google Scholar]
  19. Lehner T, Hussain L, Wilson J, Chapman M. 1991. Mucosal transmission of HIV. Nature 353: 709. [DOI] [PubMed] [Google Scholar]
  20. Mestecky J. 2005. Mucosal immunology 3rd edition San Diego: Academic Press. [Google Scholar]
  21. Miller CJ, McGhee JR, Gardner MB. 1993. Mucosal immunity, HIV transmission, and AIDS. Lab Invest 68: 129–145. [PubMed] [Google Scholar]
  22. Moldoveanu Z, Mestecky J. 2009. Mucosal antibody responses to HIV. Methods Mol Biol 485: 333–345. [DOI] [PubMed] [Google Scholar]
  23. O'Hagan DT. 1991. HIV and mucosal immunity. Lancet 337: 1289. [DOI] [PubMed] [Google Scholar]
  24. Olszewska W, Suezer Y, Sutter G, Openshaw PJ. 2004. Protective and disease‐enhancing immune responses induced by recombinant modified vaccinia Ankara (MVA) expressing respiratory syncytial virus proteins. Vaccine 23: 215–2221. [DOI] [PubMed] [Google Scholar]
  25. Osorio JE, Frank RS, Moss K, Taraska T, Powell T, Stinchcomb DT. 2003. Raccoon poxvirus as a mucosal vaccine vector for domestic cats. J Drug Target 11: 463–470. [DOI] [PubMed] [Google Scholar]
  26. Pascual DW, White MD, Larson T, Walters N. 2001. Impaired mucosal immunity in L‐selectin‐deficient mice orally immunized with a Salmonella vaccine vector. J Immunol 167: 407–415. [DOI] [PubMed] [Google Scholar]
  27. Ramirez JC, Finke D, Esteban M, Kraehenbuhl JP, Acha‐Orbea H. 2003. Tissue distribution of the Ankara strain of vaccinia virus (MVA) after mucosal or systemic administration. Arch Virol 148: 827–839. [DOI] [PubMed] [Google Scholar]
  28. Schlereth B, Buonocore L, Tietz A, Meulen Vt V, Rose JK, Niewiesk S. 2003. Successful mucosal immunization of cotton rats in the presence of measles virus‐specific antibodies depends on degree of attenuation of vaccine vector and virus dose. J Gen Virol 84: 2145–2151. [DOI] [PubMed] [Google Scholar]
  29. Sertl K, Takemura T, Tschachler E, Ferrans VJ, Kaliner MA, Shevach EM. 1986. Dendritic cells with antigen‐presenting capability reside in airway epithelium, lung parenchyma, and visceral pleura. J Exp Med 163: 436–451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Shacklett BL. 2008. Mucosal immunity to HIV: A review of recent literature. Curr Opin HIV AIDS 3: 541–547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Shata MT, Reitz MS, Jr , DeVico AL, Lewis GK, Hone DM. 2001. Mucosal and systemic HIV‐1 Env‐specific CD8(+) T‐cells develop after intragastric vaccination with a Salmonella Env DNA vaccine vector. Vaccine 20: 623–629. [DOI] [PubMed] [Google Scholar]
  32. Shattock RJ, Haynes BF, Pulendran B, Flores J, Esparza J. 2008. Improving defences at the portal of HIV entry: Mucosal and innate immunity. PLoS Med 5: e81. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Stevenson A, Roberts M. 2002. Use of a rationally attenuated Bordetella bronchiseptica as a live mucosal vaccine and vector for heterologous antigens. Vaccine 20: 2325–2335. [DOI] [PubMed] [Google Scholar]
  34. Stolte‐Leeb N, Bieler K, Kostler J, Heeney J, Haaft PT, Suh YS, Hunsmann G, Stahl‐Hennig C, Wagner R. 2008. Better protective effects in rhesus macaques by combining systemic and mucosal application of a dual component vector vaccine after rectal SHIV89.6P challenge compared to systemic vaccination alone. Viral Immunol 21: 235–246. [DOI] [PubMed] [Google Scholar]
  35. Sutter G, Wyatt LS, Foley PL, Bennink JR, Moss B. 1994. A recombinant vector derived from the host range‐restricted and highly attenuated MVA strain of vaccinia virus stimulates protective immunity in mice to influenza virus. Vaccine 12: 1032–1040. [DOI] [PubMed] [Google Scholar]
  36. Wang SW, Bertley FM, Kozlowski PA, Herrmann L, Manson K, Mazzara G, Piatak M, Johnson RP, Carville A, Mansfield K, Aldovini A. 2004. An SHIV DNA/MVA rectal vaccination in macaques provides systemic and mucosal virus‐specific responses and protection against AIDS. AIDS Res Hum Retroviruses 20: 846–859. [DOI] [PubMed] [Google Scholar]
  37. Wu L. 2008. Biology of HIV mucosal transmission. Curr Opin HIV AIDS 3: 534–540. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Wyatt LS, Whitehead SS, Venanzi KA, Murphy BR, Moss B. 1999. Priming and boosting immunity to respiratory syncytial virus by recombinant replication‐defective vaccinia virus MVA. Vaccine 18: 392–397. [DOI] [PubMed] [Google Scholar]
  39. Xu Q, Pichichero ME, Simpson LL, Elias M, Smith LA, Zeng M. 2009. An adenoviral vector‐based mucosal vaccine is effective in protection against botulism. Gene Ther 16: 367–375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Zhu W, Fang Q, Zhuang K, Wang H, Yu W, Zhou J, Liu L, Tien P, Zhang L, Chen Z. 2007. The attenuation of vaccinia Tian Tan strain by the removal of the viral M1L‐K2L genes. J Virol Methods 144: 17–26. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Medical Virology are provided here courtesy of Wiley

RESOURCES