Advertisement

Heterologous prime-boost vaccination against tuberculosis with recombinant Sendai virus and DNA vaccines

  • Zhidong Hu
  • Weimin Jiang
  • Ling Gu
  • Dan Qiao
  • Tsugumine Shu
  • Douglas B. Lowrie
  • Shui-Hua LuEmail author
  • Xiao-Yong FanEmail author
Original Article

Abstract

In an earlier study, a novel Sendai virus–vectored anti-tuberculosis vaccine encoding Ag85A and Ag85B (SeV85AB) was constructed and shown to elicit antigen-specific T cell responses and protection against Mycobacterium tuberculosis (Mtb) infection in a murine model. In this study, we evaluate whether the immune responses induced by this novel vaccine might be elevated by a recombinant DNA vaccine expressing the same antigen in a heterologous prime-boost vaccination strategy. The results showed that both SeV85AB prime-DNA boost (SeV85AB-DNA) and DNA prime-SeV85AB boost (DNA-SeV85AB) vaccination strategies significantly enhanced the antigen-specific T cell responses induced by the separate vaccines. The SeV85AB-DNA immunization regimen induced higher levels of recall T cell responses after Mtb infection and conferred better immune protection compared with DNA-SeV85AB or a single immunization. Collectively, our study lends strong evidence that a DNA vaccine boost might be included in a novel SeV85AB immunization strategy designed to enhance the immune protection against Mtb.

Key messages

  • A heterologous prime-boost regimen with a novel recombinant SeV85AB and a DNA vaccine increase the T cell responses above those from a single vaccine.

  • The heterologous prime-boost regimen provided protection against Mtb infection.

  • The DNA vaccine might be included in a novel SeV85AB immunization strategy designed to enhance the immune protection against Mtb.

Keywords

Tuberculosis Sendai virus DNA vaccine Prime-boost T cell responses 

Notes

Funding information

This work was supported by grants from Chinese National Mega Science and Technology Program on Infectious Diseases (2018ZX10731301, 2018ZX10302301), the National Natural and Science Foundation of China (31771004, 81873884, 81501365, 81601735, 81770011), and the Shanghai Science and Technology Commission (19XD1403100, 17ZR1423900).

Compliance with ethical standards

Conflict of interest

X.Y.F., T.S., Z.D.H., and D.B.L. are co-inventors on an SeV85AB vaccine patent application.

All animal experiments were approved by the Institutional Animal Care and Use Committee and were performed according to the guidelines of the Laboratory Animal Ethical Board of Shanghai Public Health Clinical Center.

Supplementary material

109_2019_1844_Fig7_ESM.png (423 kb)
Fig. 7

The gating strategy of IFN-γ, IL-2 and TNF-α staining. Representative flow cytometric dot plots are shown. CD4+ T cells were gated as CD3+CD4+ cells and CD8+ T cells were defined as CD3+CD4- cells. The expression of IFN-γ, IL-2 and TNF-α was determined by using appropriate antibodies and gated by respective isotype control staining. (PNG 423 kb)

109_2019_1844_MOESM1_ESM.tif (1.6 mb)
High Resolution (TIF 1597 kb)

References

  1. 1.
    World Health Organization, Global tuberculosis report (2018) http://apps.who.int/medicinedocs/en/m/abstract/Js23553en/
  2. 2.
    Colditz GA, Brewer TF, Berkey CS, Wilson ME, Burdick E, Fineberg HV, Mosteller F (1994) Efficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literature. JAMA 271:698–702CrossRefPubMedGoogle Scholar
  3. 3.
    Jasenosky LD, Scriba TJ, Hanekom WA, Goldfeld AE (2015) T cells and adaptive immunity to Mycobacterium tuberculosis in humans. Immunol Rev 264:74–87PubMedCrossRefGoogle Scholar
  4. 4.
    Lewinsohn DA, Lewinsohn DM, Scriba TJ (2017) Polyfunctional CD4(+) T cells as targets for tuberculosis vaccination. Front Immunol 8:1262PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Ernst JD (2018) Mechanisms of M. tuberculosis immune evasion as challenges to TB vaccine design. Cell Host Microbe 24:34–42PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    O'Garra A, Redford PS, McNab FW, Bloom CI, Wilkinson RJ, Berry MP (2013) The immune response in tuberculosis. Annu Rev Immunol 31:475–527PubMedCrossRefGoogle Scholar
  7. 7.
    Orme IM, Robinson RT, Cooper AM (2015) The balance between protective and pathogenic immune responses in the TB-infected lung. Nat Immunol 16:57–63PubMedCrossRefGoogle Scholar
  8. 8.
    Khademi F, Derakhshan M, Yousefi-Avarvand A, Tafaghodi M, Soleimanpour S (2018) Multi-stage subunit vaccines against Mycobacterium tuberculosis: an alternative to the BCG vaccine or a BCG-prime boost? Expert Rev Vaccines 17:31–44PubMedCrossRefGoogle Scholar
  9. 9.
    Dalmia N, Ramsay AJ (2012) Prime-boost approaches to tuberculosis vaccine development. Expert Rev Vaccines 11:1221–1233PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Ertl HC (2016) Viral vectors as vaccine carriers. Curr Opin Virol 21:1–8PubMedCrossRefGoogle Scholar
  11. 11.
    Nakanishi M, Otsu M (2012) Development of Sendai virus vectors and their potential applications in gene therapy and regenerative medicine. Curr Gene Ther 12:410–416PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Le TV, Mironova E, Garcin D, Compans RW (2011) Induction of influenza-specific mucosal immunity by an attenuated recombinant Sendai virus. PLoS One 6:e18780.  https://doi.org/10.1371/journal.pone.0018780 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Zhang X, Sobue T, Isshiki M, Makino S, Inoue M, Kato K, Shioda T, Ohashi T, Sato H, Komano J, Hanabusa H, Shida H (2012) Elicitation of both anti HIV-1 Env humoral and cellular immunities by replicating vaccinia prime Sendai virus boost regimen and boosting by CD40Lm. PLoS One 7:e51633.  https://doi.org/10.1371/journal.pone.0051633 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Voges B, Vallbracht S, Zimmer G, Bossow S, Neubert WJ, Richter K, Hobeika E, Herrler G, Ehl S (2007) Recombinant Sendai virus induces T cell immunity against respiratory syncytial virus that is protective in the absence of antibodies. Cell Immunol 247:85–94PubMedCrossRefGoogle Scholar
  15. 15.
    Ewer KJ, Lambe T, Rollier CS, Spencer AJ, Hill AV, Dorrell L (2016) Viral vectors as vaccine platforms: from immunogenicity to impact. Curr Opin Immunol 41:47–54PubMedCrossRefGoogle Scholar
  16. 16.
    Moriya C, Horiba S, Inoue M, Iida A, Hara H, Shu T, Hasegawa M, Matano T (2008) Antigen-specific T-cell induction by vaccination with a recombinant Sendai virus vector even in the presence of vector-specific neutralizing antibodies in rhesus macaques. Biochem Biophys Res Commun 371:850–854PubMedCrossRefGoogle Scholar
  17. 17.
    Martinez-Gil L, Goff PH, Hai R, Garcia-Sastre A, Shaw ML, Palese P (2013) A Sendai virus-derived RNA agonist of RIG-I as a virus vaccine adjuvant. J Virol 87:1290–1300PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Hu Z, Wong KW, Zhao HM, Wen HL, Ji P, Ma H, Wu K, Lu SH, Li F, Li ZM, Shu T, Xu JQ, Lowrie DB, Fan XY (2017) Sendai virus mucosal vaccination establishes lung-resident memory CD8 T cell immunity and boosts BCG-primed protection against TB in mice. Mol Ther 25:1222–1233PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Hu Z, Gu L, Li CL, Shu T, Lowrie DB, Fan XY (2018) The profile of T cell responses in Bacille Calmette-Guerin-primed mice boosted by a novel sendai virus vectored anti-tuberculosis vaccine. Front Immunol 9:1796PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Suschak JJ, Williams JA, Schmaljohn CS (2017) Advancements in DNA vaccine vectors, non-mechanical delivery methods, and molecular adjuvants to increase immunogenicity. Hum Vaccin Immunother 13:2837–2848PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Li L, Petrovsky N (2016) Molecular mechanisms for enhanced DNA vaccine immunogenicity. Expert Rev Vaccines 15:313–329PubMedCrossRefGoogle Scholar
  22. 22.
    Abdulhaqq SA, Weiner DB (2008) DNA vaccines: developing new strategies to enhance immune responses. Immunol Res 42:219–232PubMedCrossRefGoogle Scholar
  23. 23.
    Wu J, Ma H, Qu Q, Zhou WJ, Luo YP, Thangaraj H, Lowrie DB, Fan XY (2011) Incorporation of immunostimulatory motifs in the transcribed region of a plasmid DNA vaccine enhances Th1 immune responses and therapeutic effect against Mycobacterium tuberculosis in mice. Vaccine 29:7624–7630PubMedCrossRefGoogle Scholar
  24. 24.
    Kang H, Yuan Q, Ma H, Hu ZD, Han DP, Wu K, Lowrie DB, Fan XY (2014) Enhanced protective efficacy against Mycobacterium tuberculosis afforded by BCG prime-DNA boost regimen in an early challenge mouse model is associated with increased splenic interleukin-2-producing CD4 T-cell frequency post-vaccination. Immunology 143:661–669PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Ji P, Hu ZD, Kang H, Yuan Q, Ma H, Wen HL, Wu J, Li ZM, Lowrie DB, Fan XY (2016) Boosting BCG-primed mice with chimeric DNA vaccine HG856A induces potent multifunctional T cell responses and enhanced protection against Mycobacterium tuberculosis. Immunol Res 64:64–72PubMedCrossRefGoogle Scholar
  26. 26.
    Lousberg EL, Diener KR, Brown MP, Hayball JD (2011) Innate immune recognition of poxviral vaccine vectors. Expert Rev Vaccines 10:1435–1449PubMedCrossRefGoogle Scholar
  27. 27.
    Hu Z, Wang J, Wan Y, Zhu L, Ren X, Qiu S, Ren Y, Yuan S, Ding X, Chen J, Qiu C, Sun J, Zhang X, Xiang J, Qiu C, Xu J (2014) Boosting functional avidity of CD8+ T cells by vaccinia virus vaccination depends on intrinsic T-cell MyD88 expression but not the inflammatory milieu. J Virol 88:5356–5368PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Hu Z, Zhu L, Wang J, Wan Y, Yuan S, Chen J, Ding X, Qiu C, Zhang X, Qiu C, Xu J (2017) Immune signature of enhanced functional avidity CD8(+) T cells in vivo induced by vaccinia vectored vaccine. Sci Rep 7:41558PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    You Q, Wu Y, Wu Y, Wei W, Wang C, Jiang D, Yu X, Zhang X, Wang Y, Tang Z, Jiang C, Kong W (2012) Immunogenicity and protective efficacy of heterologous prime-boost regimens with mycobacterial vaccines and recombinant adenovirus- and poxvirus-vectored vaccines against murine tuberculosis. Int J Infect Dis 16:e816–e825PubMedCrossRefGoogle Scholar
  30. 30.
    Vuola JM, Keating S, Webster DP, Berthoud T, Dunachie S, Gilbert SC, Hill AV (2005) Differential immunogenicity of various heterologous prime-boost vaccine regimens using DNA and viral vectors in healthy volunteers. J Immunol 174:449–455PubMedCrossRefGoogle Scholar
  31. 31.
    Glynn A, Freytag LC, Clements JD (2005) Effect of homologous and heterologous prime-boost on the immune response to recombinant plague antigens. Vaccine 23:1957–1965PubMedCrossRefGoogle Scholar
  32. 32.
    Radcliffe JN, Roddick JS, Friedmann PS, Stevenson FK, Thirdborough SM (2006) Prime-boost with alternating DNA vaccines designed to engage different antigen presentation pathways generates high frequencies of peptide-specific CD8+ T cells. J Immunol 177:6626–6633PubMedCrossRefGoogle Scholar
  33. 33.
    Skinner MA, Wedlock DN, de Lisle GW, Cooke MM, Tascon RE, Ferraz JC, Lowrie DB, Vordermeier HM, Hewinson RG, Buddle BM (2005) The order of prime-boost vaccination of neonatal calves with Mycobacterium bovis BCG and a DNA vaccine encoding mycobacterial proteins Hsp65, Hsp70, and Apa is not critical for enhancing protection against bovine tuberculosis. Infect Immun 73:4441–4444PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Tameris MD, Hatherill M, Landry BS, Scriba TJ, Snowden MA, Lockhart S, Shea JE, McClain JB, Hussey GD, Hanekom WA, Mahomed H, McShane H (2013) Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial. Lancet 381:1021–1028PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Aguilo N, Alvarez-Arguedas S, Uranga S, Marinova D, Monzon M, Badiola J, Martin C (2016) Pulmonary but not subcutaneous delivery of BCG vaccine confers protection to tuberculosis-susceptible mice by an interleukin 17-dependent mechanism. J Infect Dis 213:831–839PubMedCrossRefGoogle Scholar
  36. 36.
    Verreck F, Tchilian EZ, Vervenne R, Sombroek CC, Kondova I, Eissen OA, Sommandas V, van der Werff NM, Verschoor E, Braskamp G, Bakker J, Langermans J, Heidt PJ, Ottenhoff T, van Kralingen KW, Thomas AW, Beverley P, Kocken C (2017) Variable BCG efficacy in rhesus populations: pulmonary BCG provides protection where standard intra-dermal vaccination fails. Tuberculosis (Edinb) 104:46–57CrossRefGoogle Scholar
  37. 37.
    Goonetilleke NP, McShane H, Hannan CM, Anderson RJ, Brookes RH, Hill AV (2003) Enhanced immunogenicity and protective efficacy against Mycobacterium tuberculosis of Bacille Calmette-Guerin vaccine using mucosal administration and boosting with a recombinant modified vaccinia virus Ankara. J Immunol 171:1602–1609PubMedCrossRefGoogle Scholar
  38. 38.
    Florido M, Muflihah H, Lin L, Xia Y, Sierro F, Palendira M, Feng CG, Bertolino P, Stambas J, Triccas JA, Britton WJ (2018) Pulmonary immunization with a recombinant influenza A virus vaccine induces lung-resident CD4(+) memory T cells that are associated with protection against tuberculosis. Mucosal Immunol 11:1743–1752PubMedCrossRefGoogle Scholar
  39. 39.
    Perdomo C, Zedler U, Kuhl AA, Lozza L, Saikali P, Sander LE, Vogelzang A, Kaufmann SH, Kupz A (2016) Mucosal BCG vaccination induces protective lung-resident memory T cell populations against tuberculosis. MBIO 7.  https://doi.org/10.1128/mBio.01686-16
  40. 40.
    Bull NC, Stylianou E, Kaveh DA, Pinpathomrat N, Pasricha J, Harrington-Kandt R, Garcia-Pelayo MC, Hogarth PJ, McShane H (2019) Enhanced protection conferred by mucosal BCG vaccination associates with presence of antigen-specific lung tissue-resident PD-1(+) KLRG1(-) CD4(+) T cells. Mucosal Immunol 12:555–564PubMedCrossRefGoogle Scholar
  41. 41.
    D'Souza S, Rosseels V, Romano M, Tanghe A, Denis O, Jurion F, Castiglione N, Vanonckelen A, Palfliet K, Huygen K (2003) Mapping of murine Th1 helper T-Cell epitopes of mycolyl transferases Ag85A, Ag85B, and Ag85C from Mycobacterium tuberculosis. Infect Immun 71:483–493PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Giri PK, Verma I, Khuller GK (2006) Enhanced immunoprotective potential of Mycobacterium tuberculosis Ag85 complex protein based vaccine against airway Mycobacterium tuberculosis challenge following intranasal administration. FEMS Immunol Med Microbiol 47:233–241PubMedCrossRefGoogle Scholar
  43. 43.
    Wiker HG, Harboe M (1992) The antigen 85 complex: a major secretion product of Mycobacterium tuberculosis. Microbiol Rev 56:648–661PubMedPubMedCentralGoogle Scholar
  44. 44.
    Wiker HG, Sletten K, Nagai S, Harboe M (1990) Evidence for three separate genes encoding the proteins of the mycobacterial antigen 85 complex. Infect Immun 58:272–274PubMedPubMedCentralGoogle Scholar
  45. 45.
    Rosseels V, Marche S, Roupie V, Govaerts M, Godfroid J, Walravens K, Huygen K (2006) Members of the 30- to 32-kilodalton mycolyl transferase family (Ag85) from culture filtrate of Mycobacterium avium subsp. paratuberculosis are immunodominant Th1-type antigens recognized early upon infection in mice and cattle. Infect Immun 74:202–212PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Horwitz MA, Lee BW, Dillon BJ, Harth G (1995) Protective immunity against tuberculosis induced by vaccination with major extracellular proteins of Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 92:1530–1534PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Muraoka D, Kato T, Wang L, Maeda Y, Noguchi T, Harada N, Takeda K, Yagita H, Guillaume P, Luescher I, Old LJ, Shiku H, Nishikawa H (2010) Peptide vaccine induces enhanced tumor growth associated with apoptosis induction in CD8+ T cells. J Immunol 185:3768–3776PubMedCrossRefGoogle Scholar
  48. 48.
    Radcliffe JN, Roddick JS, Stevenson FK, Thirdborough SM (2007) Prolonged antigen expression following DNA vaccination impairs effector CD8+ T cell function and memory development. J Immunol 179:8313–8321PubMedCrossRefGoogle Scholar
  49. 49.
    Hanke T (2006) On DNA vaccines and prolonged expression of immunogens. Eur J Immunol 36:806–809PubMedCrossRefGoogle Scholar
  50. 50.
    Sakai S, Kauffman KD, Sallin MA, Sharpe AH, Young HA, Ganusov VV, Barber DL (2016) CD4 T cell-derived IFN-gamma plays a minimal role in control of pulmonary Mycobacterium tuberculosis infection and must be actively repressed by PD-1 to prevent lethal disease. PLoS Pathog 12:e1005667.  https://doi.org/10.1371/journal.ppat.1005667 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Zhidong Hu
    • 1
  • Weimin Jiang
    • 2
  • Ling Gu
    • 1
    • 3
    • 4
  • Dan Qiao
    • 5
  • Tsugumine Shu
    • 6
  • Douglas B. Lowrie
    • 1
    • 4
  • Shui-Hua Lu
    • 1
    • 3
    • 4
    Email author
  • Xiao-Yong Fan
    • 3
    • 4
    Email author
  1. 1.Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology of MOE/MOHFudan UniversityShanghaiChina
  2. 2.Departments of Infectious Diseases, Huashan HospitalFudan UniversityShanghaiChina
  3. 3.School of Laboratory Medicine and Life ScienceWenzhou Medical UniversityWenzhouChina
  4. 4.TB CenterShanghai Emerging and Re-emerging InstituteShanghaiChina
  5. 5.Ruijin Hospital (North)Shanghai Jiaotong UniversityShanghaiChina
  6. 6.ID PharmaIbarakiJapan

Personalised recommendations