Respiratory Syncytial Virus (RSV) disease
Respiratory syncytial virus (RSV) belongs to the genus Orthopneumovirus within the family Pneumoviridae and order Mononegavirales. Members of this genus include human RSV, bovine RSV and murine pneumonia virus. There are two major antigenic subtypes of human RSV (A and B) determined largely by antigenic drift and duplications in RSV-G sequences, but accompanied by genome-wide sequence divergence, including within RSV-F.
Human RSV is a globally prevalent cause of lower respiratory tract infection in all age groups. In infants and young children, the first infection may cause severe bronchiolitis that can sometimes be fatal. In older children and adults without comorbidities, repeated upper respiratory tract infections are common and range from subclinical infection to symptomatic upper respiratory tract disease. In addition to the pediatric burden of disease, RSV is increasingly being recognized as an important pathogen in older adults, with infection leading to an increase in hospitalization rates among those aged 65 years and over, and to increased mortality rates among the frail elderly that approach the rates seen with influenza. The risk of severe disease in adults is increased by the presence of underlying chronic pulmonary disease, circulatory conditions and functional disability, and is associated with higher viral loads. RSV is also a nosocomial threat both to young infants and among immunocompromised and vulnerable individuals. High mortality rates have been observed in those infected with RSV following bone marrow or lung transplantation.
RSV vaccines
RSV vaccine development began in the 1960s with an unsuccessful formalin-inactivated RSV (FI-RSV) vaccine that induced a severe – and in two cases lethal – lung inflammatory response during the first natural RSV infection after vaccination of RSV-naive infants. This response to natural RSV infection has been referred to as vaccine-associated enhanced respiratory disease (ERD). The concerns over the FI-RSV vaccine hindered the development of alternative RSV vaccines for many years. In recent years, increased understanding of the biology of RSV and associated technological advances have resulted in the entry of multiple vaccine candidates multiple vaccine candidates into clinical development, some of which may receive regulatory approval in the near future.
The information on global RSV vaccine development pipeline is regularly updated by PATH and available on the PATH website below.
RSV vaccine standardization
Written Standards
In light of the global RSV vaccine development pipeline, there is a recognized need for harmonized technical expectations to guide and facilitate the international development and assessment of candidate RSV vaccines. In response to this need, WHO convened a small group of regulatory experts (i.e. drafting group) to develop the Guidelines on the quality, safety and efficacy of respiratory syncytial virus vaccines, in consultation with international experts and stakeholders through series of informal consultation meetings and public consultations on WHO website during 2018-2019, involving experts from academic institutes, industry, regulatory authorities and other parties. The final document has been approved by the WHO Expert Committee on Biological Standardization (ECBS) at its 70th meeting during 21-25 October 2019.
These WHO Guidelines provide guidance to national regulatory authorities and vaccine manufacturers on the manufacturing processes and nonclinical and clinical evaluation of human RSV vaccines required to assure their quality, safety and efficacy. The scope of the Guidelines encompasses the leading technologies currently being used to develop prophylactic RSV vaccines at the clinical development stage, including: live-attenuated vaccines (including those based on genetically modified organisms such as chimeric virus vaccines), vaccines produced using recombinant viral and other vectored systems, and protein-based vaccines (including subunit and nanoparticle formulations with and without adjuvants). It should be noted that there remain knowledge gaps in the scientific understanding of RSV vaccines which are being addressed by ongoing research and development. This current document has been developed in the light of the available knowledge to date, and with regard to the currently most advanced candidate human RSV vaccines.
Measurement standards
WHO has been facilitating the development of international standards for RSV vaccines, in collaboration with other international agencies and expert laboratories, in order to harmonize the development and evaluation of RSV vaccines in the globe. A First WHO International Standard for antiserum to respiratory syncytial virus was established by the WHO Expert Committee on Biological Standardization (ECBS), with an assigned unitage of 1000 IU/vial for RSV subtype A and B respectively. This reference material is intended to be used in the standardization of virus neutralization methods for measuring antibody levels against RSV/A and RSV/B in human sera. The use of the reference material will allow for the standardization of RSV neutralization assays independent of assay format and will facilitate comparability of immunogenicity among RSV vaccine candidates.
The standard (Product Number: 16/284), can be ordered from WHO custodian laboratory at the National Institute for Biological Standards and Control, UK.