An adjuvanted respiratory syncytial virus fusion protein induces protection in aged BALB/c mice

Immunity & Ageing

Sujin Lee¹  Martin L Moore¹  Elizabeth Stillman²  Stacie Lambert²  Kaori Sakamoto³  Howard Kuo²  Kathryn Patton²  Kate L Stokes¹  Anu Cherukuri² 

[1] Children’s Healthcare of Atlanta, Atlanta, GA, USA;Infectious Diseases/Vaccines Research, MedImmune, LLC, Mountain View, CA, USA;Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA, USA

关键词: Aged mice;    Adjuvant;    Alum;    Immunosenescence;    Respiratory Syncytial Virus;   

Others  :  817353
DOI  :  10.1186/1742-4933-9-21

 received in 2012-08-08, accepted in 2012-09-28,  发布年份 2012

【 摘 要 】

Background

Respiratory Syncytial Virus (RSV) causes significant disease in the elderly, in part, because immunosenescence impairs protective immune responses to infection in this population. Despite previous and current efforts, there is no RSV vaccine currently licensed in infants or elderly adults. Adjuvanted RSV subunit vaccines have the potential to boost waning immune responses and reduce the burden of RSV disease in the elderly population.

Results

We used an aged BALB/c mouse model to evaluate immune responses to RSV Fusion (F) protein in the absence and presence of an alum adjuvant. We demonstrate that aged BALB/c mice immunized with alum-adjuvanted RSV F protein had significantly reduced lung viral titers at day 4 following challenge with wild-type (wt) RSV. Serum neutralizing antibody titers measured on day 27 correlated with protection in both young and aged vaccinated mice, although the magnitude of antibody titers was lower in aged mice. Unlike young mice, in aged mice, alum-adjuvanted RSV F did not induce lung T_H2-type cytokines or eosinophil infiltration compared to non-adjuvanted F protein following wt RSV challenge.

Conclusion

Our studies demonstrate that neutralizing anti-RSV antibody titers correlate with protection in both young and aged BALB/c mice vaccinated with RSV F protein vaccines. The F + alum formulation mediated greater protection compared to the non-adjuvanted F protein in both young and aged mice. However, while alum can boost F-specific antibody responses in aged mice, it does not completely overcome the reduced ability of a senescent immune system to respond to the RSV F antigen. Thus, our data suggest that a stronger adjuvant may be required for the prevention of RSV disease in immunosenescent populations, to achieve the appropriate balance of protective neutralizing antibodies and effective T_H1-type cytokine response along with minimal lung immunopathology.

【 授权许可】

   
2012 Cherukuri et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE: Respiratory syncytial virus infection in elderly and high-risk adults. N Engl J Med 2005, 352(17):1749-1759.
• [2]Glezen WP, Taber LH, Frank AL, Kasel JA: Risk of primary infection and reinfection with respiratory syncytial virus. Am J Dis Child 1986, 140(6):543-546.
• [3]Falsey AR, Walsh EE: Respiratory syncytial virus infection in elderly adults. Drugs Aging 2005, 22(7):577-587.
• [4]Elliot AJ, Fleming DM: Influenza and respiratory syncytial virus in the elderly. Expert Rev Vaccines 2008, 7(2):249-258.
• [5]Graham BS: Biological challenges and technological opportunities for respiratory syncytial virus vaccine development. Immunol Rev 2011, 239(1):149-166.
• [6]Neuzil KM, Johnson JE, Tang YW, Prieels JP, Slaoui M, Gar N, Graham BS: Adjuvants influence the quantitative and qualitative immune response in BALB/c mice immunized with respiratory syncytial virus FG subunit vaccine. Vaccine 1997, 15(5):525-532.
• [7]Welliver RC, Tristram DA, Batt K, Sun M, Hogerman D, Hildreth S: Respiratory syncytial virus-specific cell-mediated immune responses after vaccination with a purified fusion protein subunit vaccine. J Infect Dis 1994, 170(2):425-428.
• [8]Falsey AR, Walsh EE: Safety and immunogenicity of a respiratory syncytial virus subunit vaccine (PFP-2) in the institutionalized elderly. Vaccine 1997, 15(10):1130-1132.
• [9]Falsey AR, Walsh EE: Safety and immunogenicity of a respiratory syncytial virus subunit vaccine (PFP-2) in ambulatory adults over age 60. Vaccine 1996, 14(13):1214-1218.
• [10]Murata Y: Respiratory syncytial virus vaccine development. Clin Lab Med 2009, 29(4):725-739.
• [11]Empey KM, Peebles RS Jr, Kolls JK: Pharmacologic advances in the treatment and prevention of respiratory syncytial virus. Clin Infect Dis 2010, 50(9):1258-1267.
• [12]Murphy BR, Sotnikov AV, Lawrence LA, Banks SM, Prince GA: Enhanced pulmonary histopathology is observed in cotton rats immunized with formalin-inactivated respiratory syncytial virus (RSV) or purified F glycoprotein and challenged with RSV 3–6 months after immunization. Vaccine 1990, 8(5):497-502.
• [13]Vaux-Peretz F, Chapsal JM, Meignier B: Comparison of the ability of formalin-inactivated respiratory syncytial virus, immunopurified F, G and N proteins and cell lysate to enhance pulmonary changes in Balb/c mice. Vaccine 1992, 10(2):113-118.
• [14]Baylor NW, Egan W, Richman P: Aluminum salts in vaccines–US perspective. Vaccine 2002, 20(Suppl 3):S18-S23.
• [15]Falsey AR, Walsh EE, Capellan J, Gravenstein S, Zambon M, Yau E, Gorse GJ, Edelman R, Hayden FG, McElhaney JE, et al.: Comparison of the safety and immunogenicity of 2 respiratory syncytial virus (rsv) vaccines–nonadjuvanted vaccine or vaccine adjuvanted with alum–given concomitantly with influenza vaccine to high-risk elderly individuals. J Infect Dis 2008, 198(9):1317-1326.
• [16]Langley JM, Sales V, McGeer A, Guasparini R, Predy G, Meekison W, Li M, Capellan J, Wang E: A dose-ranging study of a subunit Respiratory Syncytial Virus subtype A vaccine with and without aluminum phosphate adjuvantation in adults > or =65 years of age. Vaccine 2009, 27(42):5913-5919.
• [17]Prince GA, Horswood RL, Berndt J, Suffin SC, Chanock RM: Respiratory syncytial virus infection in inbred mice. Infect Immun 1979, 26(2):764-766.
• [18]Hancock GE, Hahn DJ, Speelman DJ, Hildreth SW, Pillai S, McQueen K: The pulmonary immune response of Balb/c mice vaccinated with the fusion protein of respiratory syncytial virus. Vaccine 1994, 12(3):267-274.
• [19]Graham BS, Bunton LA, Wright PF, Karzon DT: Role of T lymphocyte subsets in the pathogenesis of primary infection and rechallenge with respiratory syncytial virus in mice. J Clin Invest 1991, 88(3):1026-1033.
• [20]Romanowski B, Schwarz TF, Ferguson LM, Peters K, Dionne M, Schulze K, Ramjattan B, Hillemanns P, Catteau G, Dobbelaere K, et al.: Immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine administered as a 2-dose schedule compared with the licensed 3-dose schedule: results from a randomized study. Hum Vaccin 2011, 7(12):1374-1386.
• [21]Collins PD, Marleau S, Griffiths-Johnson DA, Jose PJ, Williams TJ: Cooperation between interleukin-5 and the chemokine eotaxin to induce eosinophil accumulation in vivo. J Exp Med 1995, 182(4):1169-1174.
• [22]Kariyawasam HH, Robinson DS: The eosinophil: the cell and its weapons, the cytokines, its locations. Semin Respir Crit Care Med 2006, 27(2):117-127.
• [23]Zhang Y, Wang Y, Gilmore X, Xu K, Wyde PR, Mbawuike IN: An aged mouse model for RSV infection and diminished CD8(+) CTL responses. Exp Biol Med (Maywood) 2002, 227(2):133-140.
• [24]Marichal T, Ohata K, Bedoret D, Mesnil C, Sabatel C, Kobiyama K, Lekeux P, Coban C, Akira S, Ishii KJ, et al.: DNA released from dying host cells mediates aluminum adjuvant activity. Nat Med 2011, 17(8):996-1002.
• [25]Flach TL, Ng G, Hari A, Desrosiers MD, Zhang P, Ward SM, Seamone ME, Vilaysane A, Mucsi AD, Fong Y, et al.: Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity. Nat Med 2011, 17(4):479-487.
• [26]Moore ML, Chi MH, Luongo C, Lukacs NW, Polosukhin VV, Huckabee MM, Newcomb DC, Buchholz UJ, Crowe JE Jr, Goleniewska K, et al.: A chimeric A2 strain of respiratory syncytial virus (RSV) with the fusion protein of RSV strain line 19 exhibits enhanced viral load, mucus, and airway dysfunction. J Virol 2009, 83(9):4185-4194.
• [27]Stokes KL, Chi MH, Sakamoto K, Newcomb DC, Currier MG, Huckabee MM, Lee S, Goleniewska K, Pretto C, Williams JV, et al.: Differential pathogenesis of respiratory syncytial virus clinical isolates in BALB/c mice. J Virol 2011, 85(12):5782-5793.