Safety and immunogenicity of novel respiratory syncytial virus (RSV) vaccines based on the RSV viral proteins F, N and M2-1 encoded by simian adenovirus (PanAd3-RSV) and MVA (MVA-RSV); protocol for an open-label, dose-escalation, single-centre, phase 1 clinical trial in healthy adults

C A Green, E Scarselli, M Voysey, S Capone, A Vitelli, A Nicosia, R Cortese, A J Thompson, C S Sande, Catherine de Lara, P Klenerman, A J Pollard, C A Green, E Scarselli, M Voysey, S Capone, A Vitelli, A Nicosia, R Cortese, A J Thompson, C S Sande, Catherine de Lara, P Klenerman, A J Pollard

Abstract

Introduction: Respiratory syncytial virus (RSV) infection causes respiratory disease throughout life, with infants and the elderly at risk of severe disease and death. RSV001 is a phase 1 (first-in-man), open-label, dose-escalation, clinical trial of novel genetic viral-vectored vaccine candidates PanAd3-RSV and modified vaccinia virus Ankara (MVA)-RSV. The objective of RSV001 is to characterise the (primary objective) safety and (secondary objective) immunogenicity of these vaccines in healthy younger and older adults.

Methods and analysis: Heterologous and homologous 'prime'/boost combinations of PanAd3-RSV and single-dose MVA-RSV are evaluated in healthy adults. 40 healthy adults aged 18-50 years test one of four combinations of intramuscular (IM) or intranasal (IN) PanAd3-RSV prime and IM PanAd3 or IM MVA-RSV boost vaccination, starting at a low dose for safety. The following year an additional 30 healthy adults aged 60-75 years test either a single dose of IM MVA-RSV, one of three combinations of IN or IM PanAd3-RSV prime and PanAd3-RSV or MVA-RSV boost vaccination used in younger volunteers, and a non-vaccinated control group. Study participants are self-selected volunteers who satisfy the eligibility criteria and are assigned to study groups by sequential allocation. Safety assessment includes the daily recording of solicited and unsolicited adverse events for 1 week after vaccination, as well as visit (nursing) observations and safety bloods obtained at all scheduled attendances. Laboratory measures of RSV-specific humoral and cellular immune responses after vaccination will address the secondary end points. All study procedures are performed at the Centre for Clinical Vaccinology and Tropical Medicine (CCVTM), Oxford, UK.

Ethics and dissemination: RSV001 has clinical trial authorisation from the Medicines and Healthcare Products Regulatory Agency (MHRA) and ethics approval from NRES Berkshire (reference 13/SC/0023). All study procedures adhere to International Conference on Harmonisation (ICH) Good Clinical Practice guidelines. The results of the trial are to be published in peer-reviewed journals, conferences and academic forums.

Trial registration number: NCT01805921.

Keywords: IMMUNOLOGY.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Figures

Figure 1
Figure 1
The single DNA fragment insertion for the expression of RSV proteins by PanAd3 and MVA. The same codon-optimised DNA fragment was inserted into replication-defective PanAd3 and MVA viral vectors. After transfection into a mammalian cell, cleavage of a Foot and Mouth Disease Virus 2A region releases a soluble truncated F protein while the N and M2-1 proteins remain intracellular. MVA, modified vaccinia virus Ankara; RSV, respiratory syncytial virus.
Figure 2
Figure 2
Schematic for dose and group size escalation for adults aged 18–50 years, enrolled in 2013. (n=number of volunteers). At each dose, prime vaccination with IM and IN PanAd3-RSV was performed in one individual and safety assessed for a minimum of 48 h before the remaining prime vaccinations were administered. Formal DSMC approval was required before administration of the low-dose booster and high-dose prime vaccinations, and again for the high-dose boost vaccinations. For older adults aged 60–75 years, enrolled in 2014, there is no low dose of vaccine and no group size escalation. DSMC, data safety monitoring committee; IM, intramuscular; IN, intranasal; RSV, respiratory syncytial virus.

References

    1. Glezen WP, Taber LH, Frank AL et al. . Risk of primary infection and reinfection with respiratory syncytial virus. Am J Dis Child 1986;140:543–6.
    1. Hall CB, Weinberg GA, Iwane MK et al. . The burden of respiratory syncytial virus infection in young children. N Engl J Med 2009;360:588–98. 10.1056/NEJMoa0804877
    1. Deshpande SA, Northern V. The clinical and health economic burden of respiratory syncytial virus disease among children under 2 years of age in a defined geographical area. Arch Dis Child 2003;88:1065–9. 10.1136/adc.88.12.1065
    1. [No authors listed]. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. The IMpact-RSV Study Group. Pediatrics 1998;102(3 Pt 1):531–7. 10.1542/peds.102.3.531
    1. Boyce TG, Mellen BG, Mitchel EF Jr et al. . Rates of hospitalization for respiratory syncytial virus infection among children in medicaid. J Pediatr 2000;137:865–70. 10.1067/mpd.2000.110531
    1. Paediatric Intensive Care Audit Network.
    1. Collins PL, Melero JA. Progress in understanding and controlling respiratory syncytial virus: still crazy after all these years. Virus Res 2011;162:80–99. 10.1016/j.virusres.2011.09.020
    1. Szabo SM, Gooch KL, Bibby MM et al. . The risk of mortality among young children hospitalized for severe respiratory syncytial virus infection. Paediatr Respir Rev 2013;13(Suppl 2):S1–8. 10.1016/S1526-0542(12)00095-4
    1. Lozano R, Naghavi M, Foreman K 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;380:2095–128. 10.1016/S0140-6736(12)61728-0
    1. Nair H, Nokes DJ, Gessner BD et al. . Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet 2010;375:1545–55. 10.1016/S0140-6736(10)60206-1
    1. Blanken MO, Rovers MM, Molenaar JM et al. . Respiratory syncytial virus and recurrent wheeze in healthy preterm infants. N Engl J Med 2013;368:1791–9. 10.1056/NEJMoa1211917
    1. Sigurs N, Aljassim F, Kjellman B et al. . Asthma and allergy patterns over 18 years after severe RSV bronchiolitis in the first year of life. Thorax 2010;65:1045–52. 10.1136/thx.2009.121582
    1. Murray J, Bottle A, Sharland M et al. . Risk factors for hospital admission with RSV bronchiolitis in England: a population-based birth cohort study. PLoS ONE 2014;9:e89186 10.1371/journal.pone.0089186
    1. O'Shea MK, Ryan MA, Hawksworth AW et al. . Symptomatic respiratory syncytial virus infection in previously healthy young adults living in a crowded military environment. Clin Infect Dis 2005;41:311–17. 10.1086/431591
    1. Hall CB, Long CE, Schnabel KC. Respiratory syncytial virus infections in previously healthy working adults. Clin Infect Dis 2001;33:792–6. 10.1086/322657
    1. Renaud C, Xie H, Seo S et al. . Mortality rates of human metapneumovirus and respiratory syncytial virus lower respiratory tract infections in hematopoietic cell transplantation recipients. Biol Blood Marrow Transplant 2013;19:1220–6. 10.1016/j.bbmt.2013.05.005
    1. Lee N, Lui GC, Wong KT et al. . High morbidity and mortality in adults hospitalized for respiratory syncytial virus infections. Clin Infect Dis 2013;57:1069–77. 10.1093/cid/cit471
    1. Thompson WW, Shay DK, Weintraub E et al. . Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 2003;289:179–86. 10.1001/jama.289.2.179
    1. Parnes C, Guillermin J, Habersang R et al. . Palivizumab prophylaxis of respiratory syncytial virus disease in 2000–2001: results from The Palivizumab Outcomes Registry. Pediatr Pulmonol 2003;35:484–9. 10.1002/ppul.10288
    1. Falsey AR, Hennessey PA, Formica MA et al. . Respiratory syncytial virus infection in elderly and high-risk adults. N Engl J Med 2005;352:1749–59. 10.1056/NEJMoa043951
    1. Fulginiti VA, Eller JJ, Sieber OF et al. . Respiratory virus immunization. I. A field trial of two inactivated respiratory virus vaccines; an aqueous trivalent parainfluenza virus vaccine and an alum-precipitated respiratory syncytial virus vaccine. Am J Epidemiol 1969;89:435–48.
    1. Kim HW, Canchola JG, Brandt CD et al. . Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am J Epidemiol 1969;89:422–34.
    1. Kapikian AZ, Mitchell RH, Chanock RM et al. . 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;89:405–21.
    1. Chin J, Magoffin RL, Shearer LA et al. . Field evaluation of a respiratory syncytial virus vaccine and a trivalent parainfluenza virus vaccine in a pediatric population. Am J Epidemiol 1969;89:449–63.
    1. Falsey AR, Walsh EE. Safety and immunogenicity of a respiratory syncytial virus subunit vaccine (PFP-2) in ambulatory adults over age 60. Vaccine 1996;14:1214–18. 10.1016/S0264-410X(96)00030-8
    1. Falsey AR, Walsh EE. Safety and immunogenicity of a respiratory syncytial virus subunit vaccine (PFP-2) in the institutionalized elderly. Vaccine 1997;15:1130–2. 10.1016/S0264-410X(97)00002-9
    1. 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. 10.1093/intimm/4.4.493
    1. Glenn GM, Smith G, Fries L et al. . Safety and immunogenicity of a Sf9 insect cell-derived respiratory syncytial virus fusion protein nanoparticle vaccine. Vaccine 2013;31:524–32. 10.1016/j.vaccine.2012.11.009
    1. Bernstein DI, Malkin E, Abughali N et al. . 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;31:109–14. 10.1097/INF.0b013e31823386f1
    1. Yang CF, Wang CK, Malkin E 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;31:2822–7. 10.1016/j.vaccine.2013.04.006
    1. Malkin E, Yogev R, Abughali N 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 10.1371/journal.pone.0077104
    1. Karron RA, Wright PF, Belshe RB et al. . Identification of a recombinant live attenuated respiratory syncytial virus vaccine candidate that is highly attenuated in infants. J Infect Dis 2005;191:1093–104. 10.1086/427813
    1. Gilbert SC. Clinical development of Modified Vaccinia virus Ankara vaccines. Vaccine 2013;31:4241–6. 10.1016/j.vaccine.2013.03.020
    1. Rollier CS, Reyes-Sandoval A, Cottingham MG et al. . Viral vectors as vaccine platforms: deployment in sight. Curr Opin Immunol 2011;23:377–82. 10.1016/j.coi.2011.03.006
    1. Capone S, D'Alise AM, Ammendola V et al. . Development of chimpanzee adenoviruses as vaccine vectors: challenges and successes emerging from clinical trials. Expert Rev Vaccines 2013;12:379–93. 10.1586/erv.13.15
    1. Swadling L, Capone S, Antrobus RD et al. . A human vaccine strategy based on chimpanzee adenoviral and MVA vectors that primes, boosts, and sustains functional HCV-specific T cell memory. Sci Transl Med 2014;6:261ra153 10.1126/scitranslmed.3009185
    1. Taylor G, Thom M, Capone S, et al. Efficacy of a virus-vectored vaccine against human and bovine respiratory syncytial virus infections. Sci. Transl. Med. 7, 300ra127 (2015).
    1. Colloca S, Barnes E, Folgori A et al. . Vaccine vectors derived from a large collection of simian adenoviruses induce potent cellular immunity across multiple species. Sci Transl Med 2012;4:115ra2 10.1126/scitranslmed.3002925
    1. Pierantoni A, Esposito ML, Ammendola V 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 10.1038/mtm.2015.18
    1. Vitelli A, Quirion MR, Lo CY et al. . Vaccination to conserved influenza antigens in mice using a novel Simian adenovirus vector, PanAd3, derived from the bonobo Pan paniscus. PLoS ONE 2013;8:e55435 10.1371/journal.pone.0055435
    1. Schulz KF, Altman DG, Moher D et al. . CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. J Clin Epidemiol 2010;63:834–40. 10.1016/j.jclinepi.2010.02.005
    1. Damocles Study Group, NHS Health Technology Assessment Programme. A proposed charter for clinical trial data monitoring committees: helping them to do their job well. Lancet 2005;365:711–22. 10.1016/S0140-6736(05)17965-3
    1. Waris ME, Tsou C, Erdman DD et al. . Priming with live respiratory syncytial virus (RSV) prevents the enhanced pulmonary inflammatory response seen after RSV challenge in BALB/c mice immunized with formalin-inactivated RSV. J Virol 1997;71:6935–9.
    1. Olson MR, Varga SM. CD8T cells inhibit respiratory syncytial virus (RSV) vaccine-enhanced disease. J Immunol 2007;179:5415–24. 10.4049/jimmunol.179.8.5415

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