Yonsei Med J.  2016 Jul;57(4):809-816. 10.3349/ymj.2016.57.4.809.

In Hot Pursuit of the First Vaccine Against Respiratory Syncytial Virus

Affiliations
  • 1Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea. tcell@ewha.ac.kr

Abstract

Human respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infection, such as bronchiolitis, bronchitis, or pneumonia, in both infants and the elderly. Despite the global burden of diseases attributable to RSV infection, no clinically approved vaccine is available, and a humanized monoclonal antibody for prophylaxis is not readily affordable in developing countries. There are several hurdles to the successful development of RSV vaccines: immune-vulnerable target populations such as premature infants, pregnant women, and immunocompromised people; safety concerns associated with vaccine-enhanced diseases; repeated infection; and waning memory. To develop successful strategies for the prevention of RSV infection, it is necessary to understand the protective and pathologic roles of host immune responses to RSV infection. In this review, we will summarize the positive and negative relationship between RSV infection and host immunity and discuss strategies for the development of the first successful RSV vaccine.

Keyword

Immunity; respiratory syncytial viruses; vaccine; vaccine-enhanced diseases

MeSH Terms

Humans
Immunity
Immunocompromised Host
Respiratory Syncytial Virus Infections/immunology/*prevention & control
*Respiratory Syncytial Virus Vaccines
Respiratory Syncytial Viruses/*physiology
Respiratory Syncytial Virus Vaccines

Figure

  • Fig. 1 RSV genome, proteins, and their functions. In the schematic diagram of the RSV genome, 10 genes are indicated in the order NS1-NS2-N-P-M-SH-G-F-M2-L. Filled square, genes encoding proteins targeted by neutralizing antibodies. (A) Simplified diagram of RSV F protein-mediated membrane fusion. (B) Attachment of RSV G protein to the host cell membrane is mediated by HS and HBD and/or the CX3C-CX3CR1 interaction. Pre-fusion, pre-fusion form of the F protein; Intermediate, refolding of the F protein to initiate membrane attachment; Post-fusion, membrane fusion between RSV and the target cell; HS, heparan sulfate; HBD, heparin-binding domain; RSV, respiratory syncytial virus.


Reference

1. Hall CB, Walsh EE, Long CE, Schnabel KC. Immunity to and frequency of reinfection with respiratory syncytial virus. J Infect Dis. 1991; 163:693–698.
Article
2. Volling C, Hassan K, Mazzulli T, Green K, Al-Den A, Hunter P, et al. Respiratory syncytial virus infection-associated hospitalization in adults: a retrospective cohort study. BMC Infect Dis. 2014; 14:665.
Article
3. Bhoj VG, Sun Q, Bhoj EJ, Somers C, Chen X, Torres JP, et al. MAVS and MyD88 are essential for innate immunity but not cytotoxic T lymphocyte response against respiratory syncytial virus. Proc Natl Acad Sci U S A. 2008; 105:14046–14051.
Article
4. Kawai T, Akira S. TLR signaling. Semin Immunol. 2007; 19:24–32.
Article
5. Rudd BD, Smit JJ, Flavell RA, Alexopoulou L, Schaller MA, Gruber A, et al. Deletion of TLR3 alters the pulmonary immune environment and mucus production during respiratory syncytial virus infection. J Immunol. 2006; 176:1937–1942.
Article
6. Schlender J, Hornung V, Finke S, Günthner-Biller M, Marozin S, Brzózka K, et al. Inhibition of toll-like receptor 7- and 9-mediated alpha/beta interferon production in human plasmacytoid dendritic cells by respiratory syncytial virus and measles virus. J Virol. 2005; 79:5507–5515.
Article
7. Kurt-Jones EA, Popova L, Kwinn L, Haynes LM, Jones LP, Tripp RA, et al. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat Immunol. 2000; 1:398–401.
Article
8. Murawski MR, Bowen GN, Cerny AM, Anderson LJ, Haynes LM, Tripp RA, et al. Respiratory syncytial virus activates innate immunity through Toll-like receptor 2. J Virol. 2009; 83:1492–1500.
Article
9. Haynes LM, Moore DD, Kurt-Jones EA, Finberg RW, Anderson LJ, Tripp RA. Involvement of toll-like receptor 4 in innate immunity to respiratory syncytial virus. J Virol. 2001; 75:10730–10737.
Article
10. Ehl S, Bischoff R, Ostler T, Vallbracht S, Schulte-Mönting J, Poltorak A, et al. The role of Toll-like receptor 4 versus interleukin-12 in immunity to respiratory syncytial virus. Eur J Immunol. 2004; 34:1146–1153.
Article
11. Awomoyi AA, Rallabhandi P, Pollin TI, Lorenz E, Sztein MB, Boukhvalova MS, et al. Association of TLR4 polymorphisms with symptomatic respiratory syncytial virus infection in high-risk infants and young children. J Immunol. 2007; 179:3171–3177.
Article
12. Tulic MK, Hurrelbrink RJ, Prêle CM, Laing IA, Upham JW, Le Souef P, et al. TLR4 polymorphisms mediate impaired responses to respiratory syncytial virus and lipopolysaccharide. J Immunol. 2007; 179:132–140.
Article
13. Glezen WP, Taber LH, Frank AL, Kasel JA. Risk of primary infection and reinfection with respiratory syncytial virus. Am J Dis Child. 1986; 140:543–546.
Article
14. Falsey AR, Singh HK, Walsh EE. Serum antibody decay in adults following natural respiratory syncytial virus infection. J Med Virol. 2006; 78:1493–1497.
Article
15. Habibi MS, Jozwik A, Makris S, Dunning J, Paras A, DeVincenzo JP, et al. Impaired antibody-mediated protection and defective IgA B-cell memory in experimental infection of adults with respiratory syncytial virus. Am J Respir Crit Care Med. 2015; 191:1040–1049.
Article
16. McLellan JS, Ray WC, Peeples ME. Structure and function of respiratory syncytial virus surface glycoproteins. Curr Top Microbiol Immunol. 2013; 372:83–104.
Article
17. Graham BS, Modjarrad K, McLellan JS. Novel antigens for RSV vaccines. Curr Opin Immunol. 2015; 35:30–38.
Article
18. Feldman SA, Hendry RM, Beeler JA. Identification of a linear heparin binding domain for human respiratory syncytial virus attachment glycoprotein G. J Virol. 1999; 73:6610–6617.
Article
19. Tripp RA, Jones LP, Haynes LM, Zheng H, Murphy PM, Anderson LJ. CX3C chemokine mimicry by respiratory syncytial virus G glycoprotein. Nat Immunol. 2001; 2:732–738.
Article
20. Oshansky CM, Zhang W, Moore E, Tripp RA. The host response and molecular pathogenesis associated with respiratory syncytial virus infection. Future Microbiol. 2009; 4:279–297.
Article
21. Jorquera PA, Oakley KE, Tripp RA. Advances in and the potential of vaccines for respiratory syncytial virus. Expert Rev Respir Med. 2013; 7:411–427.
Article
22. Anderson LJ, Bingham P, Hierholzer JC. Neutralization of respiratory syncytial virus by individual and mixtures of F and G protein monoclonal antibodies. J Virol. 1988; 62:4232–4238.
Article
23. Collarini EJ, Lee FE, Foord O, Park M, Sperinde G, Wu H, et al. Potent high-affinity antibodies for treatment and prophylaxis of respiratory syncytial virus derived from B cells of infected patients. J Immunol. 2009; 183:6338–6345.
Article
24. Corbeil S, Seguin C, Trudel M. Involvement of the complement system in the protection of mice from challenge with respiratory syncytial virus long strain following passive immunization with monoclonal antibody 18A2B2. Vaccine. 1996; 14:521–525.
Article
25. Kim S, Joo DH, Lee JB, Shim BS, Cheon IS, Jang JE, et al. Dual role of respiratory syncytial virus glycoprotein fragment as a mucosal immunogen and chemotactic adjuvant. PLoS One. 2012; 7:e32226.
Article
26. Yu JR, Kim S, Lee JB, Chang J. Single intranasal immunization with recombinant adenovirus-based vaccine induces protective immunity against respiratory syncytial virus infection. J Virol. 2008; 82:2350–2357.
Article
27. Jang JE, Lee JB, Kim KH, Park SM, Shim BS, Cheon IS, et al. Evaluation of protective efficacy of respiratory syncytial virus vaccine against A and B subgroup human isolates in Korea. PLoS One. 2011; 6:e23797.
Article
28. Cannon MJ, Openshaw PJ, Askonas BA. Cytotoxic T cells clear virus but augment lung pathology in mice infected with respiratory syncytial virus. J Exp Med. 1988; 168:1163–1168.
Article
29. 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; 88:1026–1033.
Article
30. Cherukuri A, Patton K, Gasser RA Jr, Zuo F, Woo J, Esser MT, et al. Adults 65 years old and older have reduced numbers of functional memory T cells to respiratory syncytial virus fusion protein. Clin Vaccine Immunol. 2013; 20:239–247.
Article
31. Hall CB, Powell KR, MacDonald NE, Gala CL, Menegus ME, Suffin SC, et al. Respiratory syncytial viral infection in children with compromised immune function. N Engl J Med. 1986; 315:77–81.
Article
32. Jozwik A, Habibi MS, Paras A, Zhu J, Guvenel A, Dhariwal J, et al. RSV-specific airway resident memory CD8+ T cells and differential disease severity after experimental human infection. Nat Commun. 2015; 6:10224.
Article
33. Openshaw PJ, Chiu C. Protective and dysregulated T cell immunity in RSV infection. Curr Opin Virol. 2013; 3:468–474.
Article
34. Munir S, Hillyer P, Le Nouën C, Buchholz UJ, Rabin RL, Collins PL, et al. Respiratory syncytial virus interferon antagonist NS1 protein suppresses and skews the human T lymphocyte response. PLoS Pathog. 2011; 7:e1001336.
Article
35. González PA, Prado CE, Leiva ED, Carreño LJ, Bueno SM, Riedel CA, et al. Respiratory syncytial virus impairs T cell activation by preventing synapse assembly with dendritic cells. Proc Natl Acad Sci U S A. 2008; 105:14999–15004.
Article
36. Wythe SE, Dodd JS, Openshaw PJ, Schwarze J. OX40 ligand and programmed cell death 1 ligand 2 expression on inflammatory dendritic cells regulates CD4 T cell cytokine production in the lung during viral disease. J Immunol. 2012; 188:1647–1655.
Article
37. Kim HW, Canchola JG, Brandt CD, Pyles G, Chanock RM, Jensen K, et al. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am J Epidemiol. 1969; 89:422–434.
Article
38. Kapikian AZ, Mitchell RH, Chanock RM, Shvedoff RA, Stewart CE. An epidemiologic study of altered clinical reactivity to respiratory syncytial (RS) virus infection in children previously vaccinated with an inactivated RS virus vaccine. Am J Epidemiol. 1969; 89:405–421.
Article
39. Cohn L, Herrick C, Niu N, Homer R, Bottomly K. IL-4 promotes airway eosinophilia by suppressing IFN-gamma production: defining a novel role for IFN-gamma in the regulation of allergic airway inflammation. J Immunol. 2001; 166:2760–2767.
Article
40. Waris ME, Tsou C, Erdman DD, Zaki SR, Anderson LJ. Respiratory synctial virus infection in BALB/c mice previously immunized with formalin-inactivated virus induces enhanced pulmonary inflammatory response with a predominant Th2-like cytokine pattern. J Virol. 1996; 70:2852–2860.
Article
41. Openshaw PJ, Clarke SL, Record FM. Pulmonary eosinophilic response to respiratory syncytial virus infection in mice sensitized to the major surface glycoprotein G. Int Immunol. 1992; 4:493–500.
Article
42. Varga SM, Wang X, Welsh RM, Braciale TJ. Immunopathology in RSV infection is mediated by a discrete oligoclonal subset of antigen-specific CD4(+) T cells. Immunity. 2001; 15:637–646.
Article
43. Srikiatkhachorn A, Braciale TJ. Virus-specific CD8+ T lymphocytes downregulate T helper cell type 2 cytokine secretion and pulmonary eosinophilia during experimental murine respiratory syncytial virus infection. J Exp Med. 1997; 186:421–432.
Article
44. Chang J. Current progress on development of respiratory syncytial virus vaccine. BMB Rep. 2011; 44:232–237.
Article
45. Brandenburg AH, Kleinjan A, van Het Land B, Moll HA, Timmerman HH, de Swart RL, et al. Type 1-like immune response is found in children with respiratory syncytial virus infection regardless of clinical severity. J Med Virol. 2000; 62:267–277.
Article
46. Garofalo RP, Patti J, Hintz KA, Hill V, Ogra PL, Welliver RC. Macrophage inflammatory protein-1alpha (not T helper type 2 cytokines) is associated with severe forms of respiratory syncytial virus bronchiolitis. J Infect Dis. 2001; 184:393–399.
Article
47. Kallal LE, Hartigan AJ, Hogaboam CM, Schaller MA, Lukacs NW. Inefficient lymph node sensitization during respiratory viral infection promotes IL-17-mediated lung pathology. J Immunol. 2010; 185:4137–4147.
Article
48. Lukacs NW, Smit JJ, Mukherjee S, Morris SB, Nunez G, Lindell DM. Respiratory virus-induced TLR7 activation controls IL-17-associated increased mucus via IL-23 regulation. J Immunol. 2010; 185:2231–2239.
Article
49. Mukherjee S, Lindell DM, Berlin AA, Morris SB, Shanley TP, Hershenson MB, et al. IL-17-induced pulmonary pathogenesis during respiratory viral infection and exacerbation of allergic disease. Am J Pathol. 2011; 179:248–258.
Article
50. Fulton RB, Meyerholz DK, Varga SM. Foxp3+ CD4 regulatory T cells limit pulmonary immunopathology by modulating the CD8 T cell response during respiratory syncytial virus infection. J Immunol. 2010; 185:2382–2392.
Article
51. Lee DC, Harker JA, Tregoning JS, Atabani SF, Johansson C, Schwarze J, et al. CD25+ natural regulatory T cells are critical in limiting innate and adaptive immunity and resolving disease following respiratory syncytial virus infection. J Virol. 2010; 84:8790–8798.
Article
52. Wright PF, Karron RA, Belshe RB, Shi JR, Randolph VB, Collins PL, et al. The absence of enhanced disease with wild type respiratory syncytial virus infection occurring after receipt of live, attenuated, respiratory syncytial virus vaccines. Vaccine. 2007; 25:7372–7378.
Article
53. Karron RA, Buchholz UJ, Collins PL. Live-attenuated respiratory syncytial virus vaccines. Curr Top Microbiol Immunol. 2013; 372:259–284.
Article
54. Collins PL, Murphy BR. New generation live vaccines against human respiratory syncytial virus designed by reverse genetics. Proc Am Thorac Soc. 2005; 2:166–173.
Article
55. Malloy AM, Falsey AR, Ruckwardt TJ. Consequences of immature and senescent immune responses for infection with respiratory syncytial virus. Curr Top Microbiol Immunol. 2013; 372:211–231.
Article
56. Loomis RJ, Johnson PR. Gene-based vaccine approaches for respiratory syncytial virus. Curr Top Microbiol Immunol. 2013; 372:307–324.
Article
57. Gomez M, Mufson MA, Dubovsky F, Knightly C, Zeng W, Losonsky G. Phase-I study MEDI-534, of a live, attenuated intranasal vaccine against respiratory syncytial virus and parainfluenza-3 virus in seropositive children. Pediatr Infect Dis J. 2009; 28:655–658.
Article
58. Bernstein DI, Malkin E, Abughali N, Falloon J, Yi T, Dubovsky F. MI-CP149 Investigators. Phase 1 study of the safety and immunogenicity of a live, attenuated respiratory syncytial virus and parainfluenza virus type 3 vaccine in seronegative children. Pediatr Infect Dis J. 2012; 31:109–114.
Article
59. Yang CF, Wang CK, Malkin E, Schickli JH, Shambaugh C, Zuo F, et al. Implication of respiratory syncytial virus (RSV) F transgene sequence heterogeneity observed in Phase 1 evaluation of MEDI-534, a live attenuated parainfluenza type 3 vectored RSV vaccine. Vaccine. 2013; 31:2822–2827.
Article
60. Schickli JH, Kaur J, Tang RS. Nonclinical phenotypic and genotypic analyses of a Phase 1 pediatric respiratory syncytial virus vaccine candidate MEDI-559 (rA2cp248/404/1030ΔSH) at permissive and non-permissive temperatures. Virus Res. 2012; 169:38–47.
Article
61. Malkin E, Yogev R, Abughali N, Sliman J, Wang CK, Zuo F, et al. Safety and immunogenicity of a live attenuated RSV vaccine in healthy RSV-seronegative children 5 to 24 months of age. PLoS One. 2013; 8:e77104.
Article
62. Bermingham A, Collins PL. The M2-2 protein of human respiratory syncytial virus is a regulatory factor involved in the balance between RNA replication and transcription. Proc Natl Acad Sci U S A. 1999; 96:11259–11264.
Article
63. Karron RA, Luongo C, Thumar B, Loehr KM, Englund JA, Collins PL, et al. A gene deletion that up-regulates viral gene expression yields an attenuated RSV vaccine with improved antibody responses in children. Sci Transl Med. 2015; 7:312ra175.
Article
64. Luongo C, Winter CC, Collins PL, Buchholz UJ. Respiratory syncytial virus modified by deletions of the NS2 gene and amino acid S1313 of the L polymerase protein is a temperature-sensitive, liveattenuated vaccine candidate that is phenotypically stable at physiological temperature. J Virol. 2013; 87:1985–1996.
Article
65. Luongo C, Winter CC, Collins PL, Buchholz UJ. Increased genetic and phenotypic stability of a promising live-attenuated respiratory syncytial virus vaccine candidate by reverse genetics. J Virol. 2012; 86:10792–10804.
Article
66. Calder LJ, González-Reyes L, García-Barreno B, Wharton SA, Skehel JJ, Wiley DC, et al. Electron microscopy of the human respira tory syncytial virus fusion protein and complexes that it forms with monoclonal antibodies. Virology. 2000; 271:122–131.
Article
67. Collins PL, Mottet G. Post-translational processing and oligomerization of the fusion glycoprotein of human respiratory syncytial virus. J Gen Virol. 1991; 72(Pt 12):3095–3101.
Article
68. López JA, Bustos R, Orvell C, Berois M, Arbiza J, García-Barreno B, et al. Antigenic structure of human respiratory syncytial virus fusion glycoprotein. J Virol. 1998; 72:6922–6928.
Article
69. Glenn GM, Smith G, Fries L, Raghunandan R, Lu H, Zhou B, et al. Safety and immunogenicity of a Sf9 insect cell-derived respiratory syncytial virus fusion protein nanoparticle vaccine. Vaccine. 2013; 31:524–532.
Article
70. Pierantoni A, Esposito ML, Ammendola V, Napolitano F, Grazioli F, Abbate A, et al. Mucosal delivery of a vectored RSV vaccine is safe and elicits protective immunity in rodents and nonhuman primates. Mol Ther Methods Clin Dev. 2015; 2:15018.
Article
71. Widjojoatmodjo MN, Bogaert L, Meek B, Zahn R, Vellinga J, Custers J, et al. Recombinant low-seroprevalent adenoviral vectors Ad26 and Ad35 expressing the respiratory syncytial virus (RSV) fusion protein induce protective immunity against RSV infection in cotton rats. Vaccine. 2015; 33:5406–5414.
Article
Full Text Links
  • YMJ
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr