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 RSVΔG vaccine consists of a live-attenuated RSV that lacks the G attachment protein. RSVΔG is severely impaired in binding to host cells and exhibits reduced infectivity in preclinical studies. Intranasal immunization of cotton rats with RSVΔG 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 RSVΔG (6.5 log10 CCID50) after intranasal administration. Healthy adults aged between 18 and 50, with RSV neutralizing serum titers below 9.6 log2, 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 RSVΔG 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 log10 CCID50 of RSVΔG was safe and well-tolerated in seropositive healthy adults. RSVΔG 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. Clinical trial register: NTR7173/EudraCT number 2016-002437-30.
['Verdijk|Pauline|P|', 'van der Plas|Johan L|JL|', 'van Brummelen|Emilie M J|EMJ|', 'Jeeninga|Rienk E|RE|', 'de Haan|Cornelis A M|CAM|', 'Roestenberg|Meta|M|', 'Burggraaf|Jacobus|J|', 'Kamerling|Ingrid M C|IMC|']
D000328:Adult D000368:Aged D000818:Animals D057134:Antibodies, Neutralizing D000914:Antibodies, Viral D002648:Child D002675:Child, Preschool D019204:GTP-Binding Proteins D006801:Humans D018357:Respiratory Syncytial Virus Infections D022261:Respiratory Syncytial Virus Vaccines D018113:Respiratory Syncytial Virus, Human
Safety Immunogenicity Respiratory Syncytial Virus Intranasal Live-attenuated vaccine phase I trial