First-in-human administration of a live-attenuated RSV vaccine lacking the G-protein assessing safety, tolerability, shedding and immunogenicity: a randomized controlled trial

Background: Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in early infancy and in elderly. A pediatric vaccine against RSV would not only prevent morbidity and mortality amongst infants and young children but could also reduce transmission to elderly. The RSVDG vaccine consists of a live-attenuated RSV that lacks the G attachment protein. RSVDG is severely impaired in binding to host cells and exhibits reduced infectivity in preclinical studies. Intranasal immunization of cotton rats with RSVDG vaccine protected against replication of wildtype RSV, without inducing enhanced disease. Methods: We performed a first-in-human trial with primary objective to evaluate safety and shedding of RSV Delta G (6.5 log(10) CCID50) after intranasal administration. Healthy adults aged between 18 and 50, with RSV neutralizing serum titers below 9.6 log(2), received a single dose of either vaccine or placebo (n = 48, ratio 3:1). In addition to safety and tolerability, nasal viral load, and systemic and humoral immune responses were assessed at selected time points until 4 weeks after immunization. Results: Intranasal administration of RSV Delta G was well tolerated with no findings of clinical concern. No infectious virus was detected in nasal wash samples. Similar to other live-attenuated RSV vaccines, neutralizing antibody response following inoculation was limited in seropositive adults. Conclusions: A single dose of 6.5 log(10) CCID50 of RSV Delta G was safe and well-tolerated in seropositive healthy adults. RSV Delta G was sufficiently attenuated but there were no signs of induction of antibodies. Safety and immunogenicity can now be explored in children and eventually in seronegative infants. (C) 2020 The Author(s). Published by Elsevier Ltd.