1887

Abstract

FluMist has been used in children and adults for more than 10 years. As pre-existing CD8 T cell memory pools can provide heterologous immunity against distinct influenza viruses, it is important to understand influenza-specific CD8 T cell responses elicited by different live attenuated influenza virus (LAIV) regimens. In this study, we immunized mice intranasally with two different doses of live-attenuated PR8 virus (PR8 ts, H1N1), low and high, and then assessed protective efficacy by challenging animals with heterosubtypic X31-H3N2 virus at 6 weeks post-vaccination. Different LAIV doses elicited influenza-specific CD8 T cell responses in lungs and spleen, but unexpectedly not in bronchoalveolar lavage. Interestingly, the immunodominance hierarchy at the acute phase after immunization varied depending on the LAIV dose; however, these differences disappeared at 6 weeks post-vaccination, resulting in generation of comparable CD8 T cell memory pools. After vaccination with either dose, sufficient numbers of specific CD8 T cells were generated for recall and protection of mice against heterosubtypic H1N1→H3N2 challenge. As a result, immunized mice displayed reduced weight loss, diminished inflammatory responses and lower viral titres in lungs, when compared to unvaccinated animals. Interestingly, the higher dose led to enhanced viral clearance on day 5 post-challenge, though this was not associated with increased CD8 T cell responses, but with higher levels of non-neutralizing antibodies against the priming virus. Our study suggests that, while different LAIV doses result in distinct immune profiles, even a low dose produces sufficient protective CD8 T cell memory against challenge infection, though the high dose results in more rapid viral clearance and reduced inflammation.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.000651
2016-12-16
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/jgv/97/12/3205.html?itemId=/content/journal/jgv/10.1099/jgv.0.000651&mimeType=html&fmt=ahah

References

  1. Baker S. F., Guo H., Albrecht R. A., García-Sastre A., Topham D. J., Martínez-Sobrido L. 2013; Protection against lethal influenza with a viral mimic. J Virol 87:8591–8605 [View Article][PubMed]
    [Google Scholar]
  2. Bird N. L., Olson M. R., Hurt A. C., Oshansky C. M., Oh D. Y., Reading P. C., Chua B. Y., Sun Y., Tang L. et al. 2015; Oseltamivir prophylaxis reduces inflammation and facilitates establishment of cross-strain protective T cell memory to influenza viruses. PLoS One 10:e0129768 [View Article][PubMed]
    [Google Scholar]
  3. Carragher D. M., Kaminski D. A., Moquin A., Hartson L., Randall T. D. 2008; A novel role for non-neutralizing antibodies against nucleoprotein in facilitating resistance to influenza virus. J Immunol 181:4168–4176 [View Article][PubMed]
    [Google Scholar]
  4. Carter N. J., Curran M. P. 2011; Live attenuated influenza vaccine (FluMist(R); Fluenz): a review of its use in the prevention of seasonal influenza in children and adults. Drugs 71:1591–1622 [View Article][PubMed]
    [Google Scholar]
  5. Chen Z., Aspelund A., Kemble G., Jin H. 2006; Genetic mapping of the cold-adapted phenotype of B/Ann Arbor/1/66, the master donor virus for live attenuated influenza vaccines (FluMist). Virology 345:416–423 [View Article][PubMed]
    [Google Scholar]
  6. Chen G. L., Lamirande E. W., Jin H., Kemble G., Subbarao K. 2010; Safety, immunogencity, and efficacy of a cold-adapted A/Ann Arbor/6/60 (H2N2) vaccine in mice and ferrets. Virology 398:109–114 [View Article][PubMed]
    [Google Scholar]
  7. Cukalac T., Chadderton J., Zeng W., Cullen J. G., Kan W. T., Doherty P. C., Jackson D. C., Turner S. J., La Gruta N. L. 2014; The influenza virus-specific CTL immunodominance hierarchy in mice is determined by the relative frequency of high-avidity T cells. J Immunol 192:4061–4068 [View Article][PubMed]
    [Google Scholar]
  8. Fiore A. E., Shay D. K., Broder K., Iskander J. K., Uyeki T. M., Mootrey G., Bresee J. S., Cox N. J. Centers for Disease Control and Prevention 2009; Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009. MMWR Recomm Rep 58:1–52[PubMed]
    [Google Scholar]
  9. Gerhard W., Mozdzanowska K., Furchner M., Washko G., Maiese K. 1997; Role of the B-cell response in recovery of mice from primary influenza virus infection. Immunol Rev 159:95–103 [View Article][PubMed]
    [Google Scholar]
  10. Grant E. J., Quiñones-Parra S. M., Clemens E. B., Kedzierska K. 2016; Human influenza viruses and CD8+ T cell responses. Curr Opin Virol 16:132–142 [View Article][PubMed]
    [Google Scholar]
  11. Huber V. C., Lynch J. M., Bucher D. J., Le J., Metzger D. W. 2001; Fc receptor-mediated phagocytosis makes a significant contribution to clearance of influenza virus infections. J Immunol 166:7381–7388 [View Article][PubMed]
    [Google Scholar]
  12. Huber V. C., Thomas P. G., McCullers J. A. 2009; A multi-valent vaccine approach that elicits broad immunity within an influenza subtype. Vaccine 27:1192–1200 [View Article][PubMed]
    [Google Scholar]
  13. Jin H., Lu B., Zhou H., Ma C., Zhao J., Yang C. F., Kemble G., Greenberg H. 2003; Multiple amino acid residues confer temperature sensitivity to human influenza virus vaccine strains (FluMist) derived from cold-adapted A/Ann Arbor/6/60. Virology 306:18–24 [View Article][PubMed]
    [Google Scholar]
  14. Jin H., Zhou H., Lu B., Kemble G. 2004; Imparting temperature sensitivity and attenuation in ferrets to A/Puerto Rico/8/34 influenza virus by transferring the genetic signature for temperature sensitivity from cold-adapted A/Ann Arbor/6/60. J Virol 78:995–998 [View Article][PubMed]
    [Google Scholar]
  15. Kedzierska K., La Gruta N. L., Turner S. J., Doherty P. C. 2006a; Establishment and recall of CD8+ T-cell memory in a model of localized transient infection. Immunol Rev 211:133–145 [View Article]
    [Google Scholar]
  16. Kedzierska K., Venturi V., Field K., Davenport M. P., Turner S. J., Doherty P. C. 2006b; Early establishment of diverse T cell receptor profiles for influenza-specific CD8+CD62Lhi memory T cells. Proc Natl Acad Sci U S A 103:9184–9189 [View Article]
    [Google Scholar]
  17. Kedzierska K., Stambas J., Jenkins M. R., Keating R., Turner S. J., Doherty P. C. 2007; Location rather than CD62L phenotype is critical in the early establishment of influenza-specific CD8+ T cell memory. Proc Natl Acad Sci U S A 104:9782–9787 [View Article][PubMed]
    [Google Scholar]
  18. Kedzierski L., Clemens E. B., Bird N. L., Kile B. T., Belz G. T., Nicola N. A., Kedzierska K., Nicholson S. E. 2015; SOCS4 is dispensable for an efficient recall response to influenza despite being required for primary immunity. Immunol Cell Biol 93:909–913 [View Article][PubMed]
    [Google Scholar]
  19. Khattak S., K-Moghtader G., McMartin K., Barrera M., Kennedy D., Koren G. 1999; Pregnancy outcome following gestational exposure to organic solvents: a prospective controlled study. JAMA 281:1106–1109[PubMed] [CrossRef]
    [Google Scholar]
  20. La Gruta N. L., Rothwell W. T., Cukalac T., Swan N. G., Valkenburg S. A., Kedzierska K., Thomas P. G., Doherty P. C., Turner S. J. 2010; Primary CTL response magnitude in mice is determined by the extent of naive T cell recruitment and subsequent clonal expansion. J Clin Invest 120:1885–1894 [View Article][PubMed]
    [Google Scholar]
  21. LaMere M. W., Lam H. T., Moquin A., Haynes L., Lund F. E., Randall T. D., Kaminski D. A. 2011; Contributions of antinucleoprotein IgG to heterosubtypic immunity against influenza virus. J Immunol 186:4331–4339 [View Article][PubMed]
    [Google Scholar]
  22. Lanthier P. A., Huston G. E., Moquin A., Eaton S. M., Szaba F. M., Kummer L. W., Tighe M. P., Kohlmeier J. E., Blair P. J. et al. 2011; Live attenuated influenza vaccine (LAIV) impacts innate and adaptive immune responses. Vaccine 29:7849–7856 [View Article][PubMed]
    [Google Scholar]
  23. Luciani F., Sanders M. T., Oveissi S., Pang K. C., Chen W. 2013; Increasing viral dose causes a reversal in CD8+ T cell immunodominance during primary influenza infection due to differences in antigen presentation, T cell avidity, and precursor numbers. J Immunol 190:36–47 [View Article][PubMed]
    [Google Scholar]
  24. Marois I., Cloutier A., Garneau É., Lesur O., Richter M. V. 2015; The administration of oseltamivir results in reduced effector and memory CD8+ T cell responses to influenza and affects protective immunity. FASEB J 29:973–987 [View Article][PubMed]
    [Google Scholar]
  25. Matrosovich M., Matrosovich T., Garten W., Klenk H. D. 2006; New low-viscosity overlay medium for viral plaque assays. Virol J 3:63 [View Article][PubMed]
    [Google Scholar]
  26. McMaster S. R., Wilson J. J., Wang H., Kohlmeier J. E. 2015; Airway-resident memory CD8 T cells provide antigen-specific protection against respiratory virus challenge through rapid IFN-γ production. J Immunol 195:203–209 [View Article][PubMed]
    [Google Scholar]
  27. Neirynck S., Deroo T., Saelens X., Vanlandschoot P., Jou W. M., Fiers W. 1999; A universal influenza A vaccine based on the extracellular domain of the M2 protein. Nat Med 5:1157–1163 [View Article][PubMed]
    [Google Scholar]
  28. Powell T. J., Strutt T., Reome J., Hollenbaugh J. A., Roberts A. D., Woodland D. L., Swain S. L., Dutton R. W. 2007; Priming with cold-adapted influenza A does not prevent infection but elicits long-lived protection against supralethal challenge with heterosubtypic virus. J Immunol 178:1030–1038 [View Article][PubMed]
    [Google Scholar]
  29. Quiñones-Parra S. M., Clemens E. B., Wang Z., Croom H. A., Kedzierski L., McVernon J., Vijaykrishna D., Kedzierska K. 2016; A role of influenza virus exposure history in determining pandemic susceptibility and CD8+ T cell responses. J Virol 90:6936–6947 [View Article][PubMed]
    [Google Scholar]
  30. Rangel-Moreno J., Carragher D. M., Misra R. S., Kusser K., Hartson L., Moquin A., Lund F. E., Randall T. D. 2008; B cells promote resistance to heterosubtypic strains of influenza via multiple mechanisms. J Immunol 180:454–463 [View Article][PubMed]
    [Google Scholar]
  31. Slepushkin V. A., Katz J. M., Black R. A., Gamble W. C., Rota P. A., Cox N. J. 1995; Protection of mice against influenza A virus challenge by vaccination with baculovirus-expressed M2 protein. Vaccine 13:1399–1402 [View Article][PubMed]
    [Google Scholar]
  32. Slütter B., Pewe L. L., Lauer P., Harty J. T. 2013; Cutting edge: rapid boosting of cross-reactive memory CD8 T cells broadens the protective capacity of the FluMist vaccine. J Immunol 190:3854–3858 [View Article][PubMed]
    [Google Scholar]
  33. Suguitan A. L. Jr, McAuliffe J., Mills K. L., Jin H., Duke G., Lu B., Luke C. J., Murphy B., Swayne D. E. et al. 2006; Live, attenuated influenza A H5N1 candidate vaccines provide broad cross-protection in mice and ferrets. PLoS Med 3:e360 [View Article][PubMed]
    [Google Scholar]
  34. Thomas P. G., Keating R., Hulse-Post D. J., Doherty P. C. 2006; Cell-mediated protection in influenza infection. Emerg Infect Dis 12:48–54 [View Article][PubMed]
    [Google Scholar]
  35. Valkenburg S. A., Gras S., Guillonneau C., La Gruta N. L., Thomas P. G., Purcell A. W., Rossjohn J., Doherty P. C., Turner S. J., Kedzierska K. 2010; Protective efficacy of cross-reactive CD8+ T cells recognising mutant viral epitopes depends on peptide–MHC-I structural interactions and T cell activation threshold. PLoS Pathog 6:e1001039 [View Article][PubMed]
    [Google Scholar]
  36. Wakim L. M., Smith J., Caminschi I., Lahoud M. H., Villadangos J. A. 2015; Antibody-targeted vaccination to lung dendritic cells generates tissue-resident memory CD8 T cells that are highly protective against influenza virus infection. Mucosal Immunol 8:1060–1071 [View Article][PubMed]
    [Google Scholar]
  37. Wang Z., Robb N. C., Lenz E., Wolff T., Fodor E., Pleschka S. 2010; NS reassortment of an H7-type highly pathogenic avian influenza virus affects its propagation by altering the regulation of viral RNA production and antiviral host response. J Virol 84:11323–11335 [View Article][PubMed]
    [Google Scholar]
  38. Wang Z., Chua B. Y., Ramos J. V., Parra S. M., Fairmaid E., Brown L. E., Jackson D. C., Kedzierska K. 2015a; Establishment of functional influenza virus-specific CD8+ T cell memory pools after intramuscular immunization. Vaccine 33:5148–5154 [View Article][PubMed]
    [Google Scholar]
  39. Wang Z., Wan Y., Qiu C., Quiñones-Parra S., Zhu Z., Loh L., Tian D., Ren Y., Hu Y. et al. 2015b; Recovery from severe H7N9 disease is associated with diverse response mechanisms dominated by CD8+ T cells. Nat Commun 6:6833 [View Article]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.000651
Loading
/content/journal/jgv/10.1099/jgv.0.000651
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error