A phase 1, randomized, placebo-controlled study to evaluate the safety and immunogenicity of an mRNA-based RSV prefusion F protein vaccine in healthy younger and older adults

References

• 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):543–46. doi:10.1001/archpedi.1986.02140200053026.
   PubMedGoogle Scholar
• Hall CB. Respiratory syncytial virus and parainfluenza virus. N Engl J Med. 2001;344(25):1917–28. doi:10.1056/nejm200106213442507.
   PubMed Web of Science ®Google Scholar
• Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the global burden of disease study 2010. Lancet. 2012;380(9859):2095–128. doi:10.1016/s0140-6736(12)61728-0.
   PubMed Web of Science ®Google Scholar
• Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, Fukuda K. Mortality associated with influenza and respiratory syncytial virus in the United States. Jama. 2003;289(2):179–86. doi:10.1001/jama.289.2.179.
   PubMed Web of Science ®Google Scholar
• Shi T, Denouel A, Tietjen AK, Campbell I, Moran E, Li X, Campbell H, Demont C, Nyawanda BO, Chu HY, et al. Global disease burden estimates of respiratory syncytial virus-associated acute respiratory infection in older adults in 2015: A systematic review and meta-analysis. J Infect Dis. 2019. doi:10.1093/infdis/jiz059.
   Google Scholar
• Kwon YS, Park SH, Kim MA, Kim HJ, Park JS, Lee MY, Lee CW, Dauti S, Choi WI. Risk of mortality associated with respiratory syncytial virus and influenza infection in adults. BMC Infect Dis. 2017;17(1):785. doi:10.1186/s12879-017-2897-4.
   PubMedGoogle Scholar
• 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):1749–59. doi:10.1056/NEJMoa043951.
   PubMed Web of Science ®Google Scholar
• Cherukuri A, Patton K, Gasser RA, Zuo F, Woo J, Esser MT, Tang RS. Adults 65 years old and older have reduced numbers of functional memory T cells to respiratory syncytial virus fusion protein. J Clin Vacc Immunol. 2013;20(2):239–47. doi:10.1128/CVI.00580-12.
   PubMed Web of Science ®Google Scholar
• Walsh E, Falsey AR. Humoral and mucosal immunity in protection from natural respiratory syncytial virus infection in adults. J of Infect Dis. 2004;190(2):373–78. doi:10.1086/421524.
   PubMed Web of Science ®Google Scholar
• Duncan CB, Walsh EE, Peterson DR, Lee FE, Falsey AR. Risk factors for respiratory failure associated with respiratory syncytial virus infection in adults. J Infect Dis. 2009;200(8):1242–46. doi:10.1086/605948.
   PubMed Web of Science ®Google Scholar
• Walsh EE, Peterson DR, Kalkanoglu AE, Lee FE, Falsey AR. Viral shedding and immune responses to respiratory syncytial virus infection in older adults. J Infect Dis. 2013;207(9):1424–32. doi:10.1093/infdis/jit038.
   PubMed Web of Science ®Google Scholar
• Piedra PA, Jewell AM, Cron SG, Atmar RL, Glezen WP. Correlates of immunity to respiratory syncytial virus (rsv) associated-hospitalization: establishment of minimum protective threshold levels of serum neutralizing antibodies. Vaccine. 2003;21(24):3479–82. doi:10.1016/s0264-410x(03)00355-4.
   PubMed Web of Science ®Google Scholar
• Luchsinger V, Piedra PA, Ruiz M, Zunino E, Martinez MA, Machado C, Fasce R, Ulloa MT, Fink MC, Lara P, et al. Role of neutralizing antibodies in adults with community-acquired pneumonia by respiratory syncytial virus. Clin Infect Dis. 2012;54(7):905–12. doi:10.1093/cid/cir955.
   PubMed Web of Science ®Google Scholar
• Meng J, Stobart CC, Hotard AL, Moore ML. An overview of respiratory syncytial virus. PLoS Pathog. 2014;10(4):e1004016. doi:10.1371/journal.ppat.1004016.
   PubMed Web of Science ®Google Scholar
• Magro M, Mas V, Chappell K, Vazquez M, Cano O, Luque D, Terron MC, Melero JA, Palomo C. Neutralizing antibodies against the preactive form of respiratory syncytial virus fusion protein offer unique possibilities for clinical intervention. Proc Natl Acad Sci USA. 2012;109(8):3089–94. doi:10.1073/pnas.1115941109.
   PubMed Web of Science ®Google Scholar
• Ngwuta JO, Chen M, Modjarrad K, Joyce MG, Kanekiyo M, Kumar A, Yassine HM, Moin SM, Killikelly AM, Chuang GY, et al. Prefusion f-specific antibodies determine the magnitude of RSV neutralizing activity in human sera. Sci Transl Med. 2015;7(309):309ra162. doi:10.1126/scitranslmed.aac4241.
   PubMed Web of Science ®Google Scholar
• McLellan JS, Chen M, Joyce MG, Sastry M, Stewart-Jones GB, Yang Y, Zhang B, Chen L, Srivatsan S, Zheng A, et al. Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus. Science. 2013;342(6158):592–98. doi:10.1126/science.1243283.
   PubMed Web of Science ®Google Scholar
• Graham BS. Immunological goals for respiratory syncytial virus vaccine development. Curr Opin Immunol. 2019:5957–64. doi:10.1016/j.coi.2019.03.005.
   Web of Science ®Google Scholar
• Crank MC, Ruckwardt TJ, Chen M, Morabito KM, Phung E, Costner PJ, Holman LA, Hickman SP, Berkowitz NM, Gordon IJ, et al. A proof of concept for structure-based vaccine design targeting rsv in humans. J Science. 2019;365(6452):505–09. doi:10.1126/science.aav9033.
   PubMed Web of Science ®Google Scholar
• Langley JM, Aggarwal N, Toma A, Halperin SA, McNeil SA, Fissette L, Dewe W, Leyssen M, Toussaint JF, Dieussaert I. A randomized, controlled, observer-blinded phase 1 study of the safety and immunogenicity of a respiratory syncytial virus vaccine with or without alum adjuvant. J Infect Dis. 2017;215(1):24–33. doi:10.1093/infdis/jiw453.
   PubMed Web of Science ®Google Scholar
• Beran J, Lickliter JD, Schwarz TF, Johnson C, Chu L, Domachowske JB, Van Damme P, Withanage K, Fissette LA, David M-P, et al. Safety and immunogenicity of 3 formulations of an investigational respiratory syncytial virus vaccine in nonpregnant women: results from 2 phase 2 trials. J of Infect Dis. 2018;217(10):1616–25. doi:10.1093/infdis/jiy065.
   PubMed Web of Science ®Google Scholar
• Schmoele-Thoma B, Falsey AR, Walsh EE, Swanson K, Zareba A, Cooper D, Gruber WC, Jansen KU, Radley D, Scott D, et al. 2755. Phase 1/2, first-in-human study of the safety, tolerability, and immunogenicity of an RSV prefusion F-based subunit vaccine candidate. Open Forum Infect Dis. 2019;6(Supplement_2):S970–S970. doi:10.1093/ofid/ofz360.2432.
   Google Scholar
• DeVincenzo J, Gymnopoulou E, De Paepe E, Murray B, Rosemary Bastian A, Haazen W, Noulin N, Comeaux C, Heijnen E, Eze K, et al. 902. A randomized, double-blind, placebo-controlled study to evaluate the efficacy of a single immunization of ad26.RSV.Pref against RSV infection in a viral challenge model in healthy adults. Open Forum Infect Dis. 2019;6(Suppl2):S27–S28. doi:10.1093/ofid/ofz359.061.
   Google Scholar
• Blanco JCG, Fernando LR, Zhang W, Kamali A, Boukhvalova MS, McGinnes-Cullen L, Morrison TG. Alternative virus-like particle-associated prefusion F proteins as maternal vaccines for respiratory syncytial virus. J Virol. 2019;93(23):e00914–19. doi:10.1128/jvi.00914-19.
   PubMed Web of Science ®Google Scholar
• Marcandalli J, Fiala B, Ols S, Perotti M, de van der Schueren W, Snijder J, Hodge E, Benhaim M, Ravichandran R, Carter L, et al. Induction of potent neutralizing antibody responses by a designed protein nanoparticle vaccine for respiratory syncytial virus. Cell. 2019;176(6):1420–1431.e1417. doi:10.1016/j.cell.2019.01.046.
   PubMed Web of Science ®Google Scholar
• Espeseth AS, Cejas PJ, Citron MP, Wang D, DiStefano DJ, Callahan C, Donnell GO, Galli JD, Swoyer R, Touch S, et al. Modified MRNA/lipid nanoparticle-based vaccines expressing respiratory syncytial virus F protein variants are immunogenic and protective in rodent models of RSV infection. NPJ Vaccines. 2020;516. doi:10.1038/s41541-020-0163-z.
   Web of Science ®Google Scholar
• Jackson NAC, Kester KE, Casimiro D, Gurunathan S, DeRosa F. The promise of MRNA vaccines: A biotech and industrial perspective. NPJ Vaccines. 2020;5(1):11. doi:10.1038/s41541-020-0159-8.
   PubMed Web of Science ®Google Scholar
• Mascola JR, Fauci AS. Novel vaccine technologies for the 21st century. Nat Rev Immunol. 2020;20(2):87–88. doi:10.1038/s41577-019-0243-3.
   PubMed Web of Science ®Google Scholar
• Zhang C, Maruggi G, Shan H, Li J. Advances in MRNA vaccines for infectious diseases.  Frontiers in Immunol. 2019;10:594. doi:10.3389/fimmu.2019.00594.
   Google Scholar
• Jackson LA, Anderson EJ, Rouphael NG, Roberts PC, Makhene M, Coler RN, McCullough MP, Chappell JD, Denison MR, Stevens LJ, et al. An MRNA vaccine against SARS-COV-2 - preliminary report. N Engl J Med. 2020. doi:10.1056/NEJMoa2022483.
   Web of Science ®Google Scholar
• Feldman RA, Fuhr R, Smolenov I, Mick Ribeiro A, Panther L, Watson M, Senn JJ, Smith M, Almarsson O, Pujar HS, et al. MRNA vaccines against H10nN and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials. Vaccine. 2019;37(25):3326–34. doi:10.1016/j.vaccine.2019.04.074.
   PubMed Web of Science ®Google Scholar
• Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research (US). Guidance for industry: toxicity grading scale for healthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials. Research CfBEa, ed. 2007.
   Google Scholar
• Citron MP, Patel M, Purcell M, Lin SA, Rubins DJ, McQuade P, Callahan C, Gleason A, Petrescu I, Knapp W, et al. A novel method for strict intranasal delivery of non-replicating RSV vaccines in cotton rats and non-human primates. Vaccine. 2018;36(20):2876–85. doi:10.1016/j.vaccine.2018.02.110.
   PubMed Web of Science ®Google Scholar
• Dubey S, Clair J, Fu T-M, Guan L, Long R, Mogg R, Anderson K, Collins KB, Gaunt C, Fernandez VR, et al. Detection of HIV vaccine-induced cell-mediated immunity in HIV-seronegative clinical trial participants using an optimized and validated enzyme-linked immunospot assay. JAIDS. 2007;45(1):20–27. doi:10.1097/QAI.0b013e3180377b5b.
   Google Scholar
• Gilman MS, Castellanos CA, Chen M, Ngwuta JO, Goodwin E, Moin SM, Mas V, Melero JA, Wright PF, Graham BS, et al. Rapid profiling of RSV antibody repertoires from the memory B cells of naturally infected adult donors. Sci Immunol. 2016;1(6). doi:10.1126/sciimmunol.aaj1879.
   PubMed Web of Science ®Google Scholar
• Graham BS. Vaccine development for respiratory syncytial virus. Curr Opin Virol. 2017;23:107–12. doi:10.1016/j.coviro.2017.03.012.
   PubMed Web of Science ®Google Scholar
• Osterholm MT, Kelley NS, Sommer A, Belongia EA. Efficacy and effectiveness of influenza vaccines: A systematic review and meta-analysis. Lancet Infect Dis. 2012;12(1):36–44. doi:10.1016/s1473-3099(11)70295-x.
   PubMed Web of Science ®Google Scholar
• Weinberger B. Vaccines for the elderly: current use and future challenges. Immun Ageing. 2018;15:3. doi:10.1186/s12979-017-0107-2.
   PubMed Web of Science ®Google Scholar
• Ciabattini A, Nardini C, Santoro F, Garagnani P, Franceschi C, Medaglini D. Vaccination in the elderly: the challenge of immune changes with aging. Semin Immunol. 2018:4083–94. doi:10.1016/j.smim.2018.10.010.
   Web of Science ®Google Scholar
• McDonald JU, Rigsby P, Dougall T, Engelhardt OG. Establishment of the first WHO international standard for antiserum to respiratory syncytial virus: report of an international collaborative study. Vaccine. 2018;36(50):7641–49. doi:10.1016/j.vaccine.2018.10.087.
   PubMed Web of Science ®Google Scholar
• Guess HA, Broughton DD, Melton LJ 3rd, Kurland LT. Population-based studies of varicella complications. Pediatrics. 1986;78(4 Pt 2):723–27. PMID: 3763290. https://www.ncbi.nlm.nih.gov/pubmed/3763290.
   PubMed Web of Science ®Google Scholar
• Williams K, Bastian AR, Feldman RA, Omoruyi E, de Paepe E, Hendriks J, van Zeeburg H, Godeaux O, Langedijk JPM, Schuitemaker H, et al. Phase 1 safety and immunogenicity study of a respiratory syncytial virus vaccine with an adenovirus 26 vector encoding pre-fusion f (ad26.RSV.Pref) in adults 60 years and older. J Infect Dis. 2020;222(6):979–88. doi:10.1093/infdis/jiaa193.
   PubMed Web of Science ®Google Scholar