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

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.

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.

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.

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.

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.

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.

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.

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.