Abstract
Respiratory Syncytial Virus (RSV) is a major cause of viral brochiolitis in infants and young children and is also a significant problem in elderly and immuno-compromised adults. To date there is no efficacious and safe RSV vaccine, partially because of the outcome of a clinical trial in the 1960s with a formalin-inactivated RSV vaccine (FI-RSV). This vaccine caused enhanced respiratory disease upon exposure to the live virus, leading to increased morbidity and the death of two children. Subsequent analyses of this incident showed that FI-RSV induces a Th2-skewed immune response together with poorly neutralizing antibodies. As a new approach, we used reconstituted RSV viral envelopes, i.e. virosomes, with incorporated monophosphoryl lipid A (MPLA) adjuvant to enhance immunogenicity and to skew the immune response towards a Th1 phenotype. Incorporation of MPLA stimulated the overall immunogenicity of the virosomes compared to non-adjuvanted virosomes in mice. Intramuscular administration of the vaccine led to the induction of RSV-specific IgG2a levels similar to those induced by inoculation of the animals with live RSV. These antibodies were able to neutralize RSV in vitro. Furthermore, MPLA-adjuvanted RSV virosomes induced high amounts of IFNγ and low amounts of IL5 in both spleens and lungs of immunized and subsequently challenged animals, compared to levels of these cytokines in animals vaccinated with FI-RSV, indicating a Th1-skewed response. Mice vaccinated with RSV-MPLA virosomes were protected from live RSV challenge, clearing the inoculated virus without showing signs of lung pathology. Taken together, these data demonstrate that RSV-MPLA virosomes represent a safe and efficacious vaccine candidate which warrants further evaluation.
Highlights
Respiratory Syncytial Virus (RSV) is a major cause of viral brochiolitis in infants and young children and is a significant problem in elderly and immuno-compromised adults
Since a large proportion of the monophosphoryl lipid A (MPLA) was associated with the virosomal fraction, as judged by phosphate analysis and TLR4activating capacity of the fractions of the gradient, subsequent experiments were performed with non-fractionated virosomes
Inactivated virus vaccines appear to be hard to advance to the clinic because of the safety concerns related to the outcome of the 1960’s formalin-inactivated RSV vaccine (FI-RSV) trial
Summary
Respiratory Syncytial Virus (RSV) is a major cause of viral brochiolitis in infants and young children and is a significant problem in elderly and immuno-compromised adults. Each year, RSV leads to 3.4 million hospitalizations of children [2]. At old age, the immune system weakens, RSV infections become more severe, leading to, for example, approximately 10,000 deaths in nursing homes in the US each year [3,4]. Current treatment of RSV infection in highrisk infants consists of prophylactic administration of the monoclonal antibody Palivizumab [5]. The high costs of monoclonal antibody therapy and the limited duration of efficacy of this treatment warrant the development of an RSV vaccine [6,7] In elderly, treatment is mainly supportive and consists of administration of fluids, oxygen and antipyretics [8]. Aerosolized Ribavirin is registered for use in some infant groups no significant effect has been reported in the elderly [8]
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