First-in-Human Randomized Study to Assess the Safety and Immunogenicity of an Investigational Respiratory Syncytial Virus (RSV) Vaccine Based on Chimpanzee-Adenovirus-155 Viral Vector-Expressing RSV Fusion, Nucleocapsid, and Antitermination Viral Proteins in Healthy Adults

Paola Cicconi, Claire Jones, Esha Sarkar, Laura Silva-Reyes, Paul Klenerman, Catherine de Lara, Claire Hutchings, Philippe Moris, Michel Janssens, Laurence A Fissette, Marta Picciolato, Amanda Leach, Antonio Gonzalez-Lopez, Ilse Dieussaert, Matthew D Snape, Paola Cicconi, Claire Jones, Esha Sarkar, Laura Silva-Reyes, Paul Klenerman, Catherine de Lara, Claire Hutchings, Philippe Moris, Michel Janssens, Laurence A Fissette, Marta Picciolato, Amanda Leach, Antonio Gonzalez-Lopez, Ilse Dieussaert, Matthew D Snape

Abstract

Background: Respiratory syncytial virus (RSV) disease is a major cause of infant morbidity and mortality. This Phase I, randomized, observer-blind, placebo- and active-controlled study evaluated an investigational vaccine against RSV (ChAd155-RSV) using the viral vector chimpanzee-adenovirus-155, encoding RSV fusion (F), nucleocapsid, and transcription antitermination proteins.

Methods: Healthy 18-45-year-old adults received ChAd155-RSV, a placebo, or an active control (Bexsero) at Days (D) 0 and 30. An escalation from a low dose (5 × 109 viral particles) to a high dose (5 × 1010 viral particles) occurred after the first 16 participants. Endpoints were solicited/unsolicited and serious adverse events (SAEs), biochemical/hematological parameters, cell-mediated immunogenicity by enzyme-linked immunospot, functional neutralizing antibodies, anti RSV-F immunoglobin (Ig) G, and ChAd155 neutralizing antibodies.

Results: There were 7 participants who received the ChAd155-RSV low dose, 31 who received the ChAd155-RSV high dose, 19 who received the placebo, and 15 who received the active control. No dose-related toxicity or attributable SAEs at the 1-year follow-up were observed. The RSV-A neutralizing antibodies geometric mean titer ratios (post/pre-immunization) following a high dose were 2.6 (D30) and 2.3 (D60). The ratio of the fold-rise (D0 to D30) in anti-F IgG over the fold-rise in RSV-A-neutralizing antibodies was 1.01. At D7 after the high dose of the study vaccine, the median frequencies of circulating B-cells secreting anti-F antibodies were 133.3/106 (IgG) and 16.7/106 (IgA) in peripheral blood mononuclear cells (PBMCs). The median frequency of RSV-F-specific interferon γ-secreting T-cells after a ChAd155-RSV high dose was 108.3/106 PBMCs at D30, with no increase after the second dose.

Conclusions: In adults previously naturally exposed to RSV, ChAd155-RSV generated increases in specific humoral and cellular immune responses without raising significant safety concerns.

Clinical trials registration: NCT02491463.

Keywords: RSV; first-in-human study; viral vector vaccine.

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Overview of staggered design and safety evaluation. SE up to D7/D37: safety evaluation by an Internal Safety Review Committee based on all available safety data, and at least safety data up to 7 days after vaccination (including hematology/biochemistry parameters). The placebo was a saline solution and the active dose was an active control. Abbreviations: ChAd155, chimpanzee-adenovirus-155 vaccine; D, day; HD, high dose; LD, low dose; RSV, respiratory syncytial virus; SE, standard error.
Figure 2.
Figure 2.
Flow diagram of the cohort. The placebo was a saline solution and the active dose was an active control. *Consent withdrawal (not due to AEs), n = 1; migrated to the study area, n = 1. **Consent withdrawal (not due to AEs), n = 2; migrated to the study area, n = 5; lost to follow-up (vaccination course completed), n = 3. ^Migrated to the study area, n = 1; lost to follow-up (vaccination course completed), n = 3. ^^Migrated to the study area, n = 1. Abbreviations: AE, adverse event; ATP, according-to-protocol; ChAd155, chimpanzee-adenovirus-155 vaccine; D, day; HD, high dose; LD, low dose; RSV, respiratory syncytial virus.
Figure 3.
Figure 3.
Incidence and nature of local and general solicited adverse events (AEs) during the 7-day postvaccination period following each dose. Absolute number of participants reporting AEs is indicated above each column. The placebo was a saline solution and the active dose was an active control. Abbreviations: AE, adverse event; ChAd155, chimpanzee-adenovirus-155 vaccine; D, day; HD, high dose; LD, low dose; RSV, respiratory syncytial virus.
Figure 4.
Figure 4.
Boxplots with individual data of (A) RSV-F–, (B) RSV-N–, and (C) RSV-M2-1–specific IFN γ–secreting T-cells (per million of PBMCs) by ELISpot (ATP cohort for immunogenicity). The placebo was a saline solution and the active dose was an active control. Abbreviations: ATP, according-to-protocol; ChAd155, chimpanzee-adenovirus-155 vaccine; D, day; F, fusion protein; HD, high dose; IFN, interferon; LD, low dose; M2-1, antitermination protein; N, nucleocapsid protein; PMBCs, peripheral blood mononuclear cells; RSV, respiratory syncytial virus.
Figure 5.
Figure 5.
Boxplots with individual data of (A) anti-F IgG and (B) anti-F IgA antibody secreting B-cells (per million of PBMCs) by ELISpot (ATP cohort for immunogenicity). The placebo was a saline solution and the active dose was an active control. Abbreviations: anti-F, anti RSV F; ATP, according-to-protocol; ChAd155, chimpanzee-adenovirus-155 vaccine; D, day; HD, high dose; Ig, immunoglobulin; LD, low dose; PMBCs, peripheral blood mononuclear cells; RSV, respiratory syncytial virus.
Figure 6.
Figure 6.
GMTs of the individual ratios of anti-RSV-A neutralizing antibody titers at each timepoint, compared to prevaccination (D0). The placebo was a saline solution and the active dose was an active control. Abbreviations: ChAd155, chimpanzee-adenovirus-155 vaccine; CI, confidence interval; D, day; GMT, geometric mean titers; HD, high dose; LD, low dose; RSV, respiratory syncytial virus.
Figure 7.
Figure 7.
GMTs of the anti-F IgG at each timepoint. The placebo was a saline solution and the active dose was an active control. Abbreviations: anti-F, anti RSV F; ChAd155, chimpanzee-adenovirus-155 vaccine; CI, confidence interval; D, day; GMT, geometric mean titers; HD, high dose; Ig, immunoglobin; LD, low dose; RSV, respiratory syncytial virus.

References

    1. Shi T, McAllister DA, O’Brien KL, et al. . Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study. Lancet 2017; 390:946–58.
    1. Kutsaya A, Teros-Jaakkola T, Kakkola L, et al. . Prospective clinical and serological follow-up in early childhood reveals a high rate of subclinical RSV infection and a relatively high reinfection rate within the first 3 years of life. Epidemiol Infect 2016; 144:1622–33.
    1. Nyiro JU, Kombe IK, Sande CJ, et al. . Defining the vaccination window for respiratory syncytial virus (RSV) using age-seroprevalence data for children in Kilifi, Kenya. PLOS One 2017; 12:e0177803.
    1. Fauroux B, Simões EAF, Checchia PA, et al. . The burden and long-term respiratory morbidity associated with respiratory syncytial virus infection in early childhood. Infect Dis Ther 2017; 6:173–97.
    1. Higgins D, Trujillo C, Keech C. Advances in RSV vaccine research and development - a global agenda. Vaccine 2016; 34:2870–5.
    1. Galvez NMS, Soto JA, Kalergis AM. New insights contributing to the development of effective vaccines and therapies to reduce the pathology caused by hRSV. Int J Mol Sci 2017; 18:1753.
    1. Polack FP, Teng MN, Collins PL, et al. . A role for immune complexes in enhanced respiratory syncytial virus disease. J Exp Med 2002; 196:859–65.
    1. Castilow EM, Legge KL, Varga SM. Cutting edge: eosinophils do not contribute to respiratory syncytial virus vaccine-enhanced disease. J Immunol 2008; 181:6692–6.
    1. Russell CD, Unger SA, Walton M, Schwarze J. The human immune response to respiratory syncytial virus infection. Clin Microbiol Rev 2017; 30:481–502.
    1. Liniger M, Zuniga A, Naim HY. Use of viral vectors for the development of vaccines. Expert Rev Vaccines 2007; 6:255–66.
    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.
    1. Cheng T, Wang X, Song Y, et al. . Chimpanzee adenovirus vector-based avian influenza vaccine completely protects mice against lethal challenge of H5N1. Vaccine 2016; 34:4875–83.
    1. Emmer KL, Wieczorek L, Tuyishime S, Molnar S, Polonis VR, Ertl HC. Antibody responses to prime-boost vaccination with an HIV-1 gp145 envelope protein and chimpanzee adenovirus vectors expressing HIV-1 gp140. AIDS 2016; 30:2405–14.
    1. Zhang C, Chi Y, Zhou D. Development of novel vaccines against infectious diseases based on chimpanzee adenoviral vector. Methods Mol Biol 2017; 1581:3–13.
    1. Ewer K, Rampling T, Venkatraman N, et al. . A monovalent chimpanzee adenovirus ebola vaccine boosted with MVA. N Engl J Med 2016; 374:1635–46.
    1. Zhao M, Zheng Z-Z, Chen M, et al. . Discovery of a prefusion respiratory syncytial virus f-specific monoclonal antibody that provides greater in vivo protection than the murine precursor of palivizumab. J Virol 2017; 91 pii:e00176–17.
    1. Mcdermott DS, Knudson CJ, Varga SM. Determining the breadth of the respiratory syncytial virus-specific. J Virol 2014; 88:3135–3143.
    1. US Department of Health and Human Services Food and Drug Administration. Center for biologics evaluation and research September 2007. Guidance for industry. Toxicity grading scale for healthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials. Available at: . Accessed 18 November 2018.
    1. US Department of Health and Human Services, National Institute of Health, National Cancer Institute. Common terminology criteria for diverse events (CTCAE). Version 4.0. Available at: . Accessed 18 November 2018.
    1. Green CA, Scarselli E, Sande CJ, et al. . Chimpanzee adenovirus- and MVA-vectored respiratory syncytial virus vaccine is safe and immunogenic in adults. Sci Transl Med 2015; 7:300ra126.
    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.
    1. Capella C, Chaiwatpongsakorn S, Gorrell E, et al. . Prefusion F, postfusion F, G antibodies, and disease severity in infants and young children with acute respiratory syncytial virus infection. J Infect Dis 2017; 216:1398–406.
    1. Cullen LM, Schmidt MR, Morrison TG. The importance of RSV F protein conformation in VLPs in stimulation of neutralizing antibody titers in mice previously infected with RSV. Hum Vaccin Immunother 2017; 13:2814–23.
    1. Acosta PL, Caballero MT, Polack FP. Brief history and characterization of enhanced respiratory syncytial virus disease. Clin Vaccine Immunol 2015; 23:189–95.
    1. Graham BS. Vaccine development for respiratory syncytial virus. Curr Opin Virol 2017; 23:107–12.
    1. Ewer KJ, Lambe T, Rollier CS, Spencer AJ, Hill AV, Dorrell L. Viral vectors as vaccine platforms: from immunogenicity to impact. Curr Opin Immunol 2016; 41:47–54.
    1. Dieussaert I. GSK’s Pediatric RSV vaccine program. Available from: . Accessed 01 August 2019.
    1. Broberg Eeva K, Waris M, Johansen K, Snacken R, Penttinen P; European Influenza Surveillance Network. Seasonality and geographical spread of respiratory syncytial virus epidemics in 15 European countries, 2010 to 2016. Euro Surveill 2018; 23:pii: 17-00284.

Source: PubMed

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