Developing a novel vaccine for the prevention of severe disease caused by respiratory syncytial virus

Respiratory syncytial virus, or RSV, is a major global pathogen responsible for severe respiratory disease in infants, immune-compromised adults and the elderly. Infants suffer the greatest burden of disease, with up to 1 in 6 paediatric beds required each winter for cases of bronchiolitis (up to 80% caused by RSV) and 2-6% of these admissions require paediatric intensive care support. In resource poor areas of the world RSV is second only to malaria in all-cause infant mortality between the first month and first year of life. Re-infection occurs throughout life and severe immune compromise re-establishes a risk of severe disease and death, with outbreak mortality as high as 80% in haematopoietic stem cell transplant patients. Immune senescence and co-morbidities results in a 10% mortality from RSV in the elderly where estimates of hospital disease burden and death from RSV appear comparable to seasonal influenza. Despite over 50- years of clinical trials there remains no effective treatment for RSV infection and no vaccine to prevent severe disease.
The work presented in this thesis uses a logical path towards the evaluation of a novel biological platform applied as an RSV vaccine candidate for the first time. Beginning with defining the epidemiological burden of disease, time-trend analyses from multiple hospital admission datasets reported a progressive rise in emergency hospital admission rates for infants with bronchiolitis in England, and this has been sustained year-on-year over the last decade and associated with a wide variability in admission rates across regions. The next step was to further define the problem of immunity that protects from severe disease but one that fails to protect from re-infection throughout life despite repeated seasonal exposure. The first of two observational studies showed the quantity of infant RSV G-antibody and IFNγ-producing T-cells lags behind the development of RSV F-specific antibody development seen in children. The second observational study used paediatric healthcare workers and adults of presumed lesser RSV exposure, and observed the failure to maintain total and RSV F-protein specific memory IgA B-cells in peripheral circulation after the winter months of RSV transmission. The remainder of this thesis concentrates on the design, setup, execution and analysis of a phase I (first-in-man) clinical trial of two novel genetic RSV vaccine candidates in healthy younger and older adults. Chimpanzee adenovirus (PanAd3) and modified vaccinia virus Ankara (MVA) were used as genetically-modified viral vectors for the delivery of RSV antigen. The vaccines were safe, well tolerated, and proved capable of inducing desirable humoral and cellular immunity to RSV despite robust pre-existing natural immunity and PanAd3 (vector) neutralising antibody. Final explorative analysis describes the early host genetic response to vaccination with correlation to important clinical and immunological responses measured at later time points. Viral-vectored vaccines for RSV have now entered clinical stage evaluation and these data represent a new and promising approach towards meeting this global need.

Advisor: Pollard, A
Klenerman, P