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An In vitro Model to Study Immune Responses of Human Peripheral Blood Mononuclear Cells to Human Respiratory Syncytial Virus Infection
Published on: December 10, 2013
First-in-human administration of a live-attenuated RSV vaccine lacking the G-protein assessing safety, tolerability,
Pauline Verdijk1, Johan L van der Plas2, Emilie M J van Brummelen3
1Institute for Translational Vaccinology (Intravacc), Bilthoven, The Netherlands.
Insights
The novel RSVΔG vaccine, a live-attenuated virus lacking the G protein, demonstrated safety and tolerability in adults. Further studies are planned to assess its potential in children and infants.
Area of Science:
- Virology
- Vaccinology
- Immunology
Background:
- Human respiratory syncytial virus (RSV) causes significant respiratory illness in infants and the elderly.
- A pediatric RSV vaccine could reduce infant morbidity/mortality and transmission to vulnerable populations.
- The RSVΔG vaccine is a live-attenuated RSV lacking the G attachment protein, designed for reduced infectivity.
Purpose of the Study:
- To evaluate the safety and shedding of the intranasally administered RSVΔG vaccine in healthy adults.
- To assess viral load and immune responses following vaccination.
Main Methods:
- A first-in-human, randomized, placebo-controlled trial was conducted.
- Healthy adults (18-50 years) with low RSV neutralizing antibody titers received a single intranasal dose of RSVΔG or placebo.
- Safety, tolerability, viral shedding, and immune responses were monitored for 4 weeks.
Main Results:
- Intranasal RSVΔG was well-tolerated with no safety concerns.
- No infectious virus was detected in nasal wash samples, indicating sufficient attenuation.
- Limited neutralizing antibody responses were observed in seropositive adults.
Conclusions:
- A single intranasal dose of RSVΔG vaccine (6.5 log10 CCID50) is safe and well-tolerated in seropositive healthy adults.
- The vaccine is sufficiently attenuated, though antibody induction was limited.
- Further evaluation of RSVΔG safety and immunogenicity in children and seronegative infants is warranted.
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.
