Brief History and Characterization of Enhanced Respiratory Syncytial Virus Disease

Abstract

In 1967, infants and toddlers immunized with a formalin-inactivated vaccine against respiratory syncytial virus (RSV) experienced an enhanced form of RSV disease characterized by high fever, bronchopneumonia, and wheezing when they became infected with wild-type virus in the community. Hospitalizations were frequent, and two immunized toddlers died upon infection with wild-type RSV. The enhanced disease was initially characterized as a "peribronchiolar monocytic infiltration with some excess in eosinophils." Decades of research defined enhanced RSV disease (ERD) as the result of immunization with antigens not processed in the cytoplasm, resulting in a nonprotective antibody response and CD4؉ T helper priming in the absence of cytotoxic T lymphocytes. This response to vaccination led to a pathogenic Th2 memory response with eosinophil and immune complex deposition in the lungs after RSV infection. In recent years, the field of RSV experienced significant changes. Numerous vaccine candidates with novel designs and formulations are approaching clinical trials, defying our previous understanding of favorable parameters for ERD. This review provides a succinct analysis of these parameters and explores criteria for assessing the risk of ERD in new vaccine candidates. R espiratory syncytial virus (RSV) is the leading respiratory cause of hospitalization in infants and young children in the United States and in the world (1, 2). Most severe infections occur in young infants, with the peak incidence of lower respiratory tract illness (LRTI) occurring between 2 and 4 months of age (3-5). In the United States, hospitalization rates have risen during the last decades (6), and while premature babies and infants with chronic lung disease and/or congenital heart disease are at increased risk for severe presentations, the majority of hospitalizations occur in previously healthy infants. Recent estimates of global mortality suggest that between 66,000 and 234,000 infants and young children die every year due to RSV (1, 2). Ninety-nine percent of deaths occur in the developing world (2). A significant proportion of these fatalities are thought to occur in the community. The need for preventive interventions against the virus is indisputable.The virus. RSV is a member of the pneumovirus genus of the family Paramyxoviridae. The virus is a negative-sense RNA virus with a nonsegmented encapsidated genome and a lipid envelope (7). The envelope is a host plasma membrane-derived lipid bilayer containing three virally encoded transmembrane glycoproteins: the fusion (F) protein, the attachment (G) protein, and the small hydrophobic (SH) protein. RSV F is the main neutralizing antigen, highly conserved and essential for virus viability (7). The secondary protective antigen eliciting neutralizing antibodies is the RSV G protein. Both neutralizing antigens are the main candidates for novel vaccines and targets for monoclonal antibodies.A new scenario. The world of RSV vaccines is experiencing important changes. In recent years, epidemiologic...

Immunization with Low Doses of Recombinant Postfusion or Prefusion Respiratory Syncytial Virus F Primes for Vaccine-Enhanced Disease in the Cotton Rat Model Independently of the Presence of a Th1-Biasing (GLA-SE) or Th2-Biasing (Alum) Adjuvant

“…A study was performed comparing RSV post-F adjuvanted with GLA-SE and alum with RSV challenge 3 months post-prime immunization in which animals immunized with RSV post-F plus alum developed alveolar histopathology, similar to data reported by Murphy et al (25) and Connors et al (27). This observation is potentially associated with the induction of a Th2-biased immune response by alum adjuvant, which has been identified to play a role in ERD (12). Further investigation is required to confirm this hypothesis.…”

Progress toward a Respiratory Syncytial Virus Vaccine

“…In this issue of Clinical and Vaccine Immunology, two articles address important obstacles in the path to a successful RSV vaccine (3,4). Acosta and colleagues provide a history and perspective on the vaccine-enhanced RSV illness that occurred in the 1960s.…”

Maternal immunization: where are we now and how to move forward?

“…No vaccines are currently available to prevent RSV infections [92]. The first formalin-inactivated candidate vaccine was associated with enhanced disease in children subsequently infected naturally with RSV [91]. After these observations, boosting natural antibodies from previous RSV infections in women has acquired greater interest because these maternal antibodies are immediately present at birth and are likely to have high affinity [17,93].…”

“…RSV is the leading cause of viral lower respiratory tract infections in infants and young children [91]. RSV infections are likely to be more severe in the first months of life than in older age groups.…”