How immunity to RSV develops in childhood but deteriorates in adults

Respiratory Syncytial Virus A leading infectious cause of severe respiratory disease in infants, respiratory syncytial virus (RSV), is also a major cause of respiratory illness in the elderly. Approved vaccines do not yet exist, and despite the development of partial immunity following infection during childhood, individuals remain susceptible to RSV reinfection life-long.

RSV is nearly ubiquitous, and most children are born with some protective immunity conveyed by maternal antibodies. As the maternal antibodies wane over time, infants become susceptible, and are often infected for the first time between nine months and two years of age. Studies over the past three decades have explored the antibody responses before and after RSV infection in different age groups. We know that human antibodies that can mediate the destruction (or neutralization) of the virus target the two major proteins on the virus surface, namely the attachment protein G and the fusion protein F. However, which antibody combination conveys the best immune protection, and why RSV infections recur throughout life remain open questions. This study of the antibody-response to RSV advances our understanding of the human immune response against RSV and has implications for vaccine design.

The blood of young infants contains maternal antibodies that recognize several parts of both the F and G proteins. In older infants that had been infected with RSV, they saw a dramatic expansion in both quantity and diversity of the antibodies that recognized the G protein. Surprisingly, infection prompted only a modest increase in the antibody repertoire against the F protein. Looking at changes over time, the researchers found that the antibodies against the F protein continued to expand with age whereas those against the G protein weakened. Because the G protein sequence varies between RSV strains, whereas the F protein is highly conserved among strains, some vaccines under development use only the more tractable F protein as a vaccine antigen. The results suggest that such a vaccine design might be problematic. On the other hand, the fact that the strong anti-G responses seen in children target a relatively conserved region in the G protein suggest that variability in other parts of the G protein does not necessarily compromise G’s utility as a vaccine antigen.

 

Antigenic Fingerprinting following Primary RSV Infection in Young Children Identifies Novel Antigenic Sites and Reveals Unlinked Evolution of Human Antibody Repertoires to Fusion and Attachment Glycoproteins. (2016) PLoS Pathog 12(4): e1005554. doi:10.1371/journal.ppat.1005554
Respiratory syncytial virus (RSV) is the major cause of pneumonia and bronchiolitis among infants and children globally. In the United States, RSV infections lead to 57,000 hospitalizations among young children, especially in those less than one year old. Further- more, despite the development of immunity following RSV infection during childhood, individuals remain susceptible to RSV upper respiratory tract reinfection. In the current study we explored the antibody repertoires following primary RSV infection and their evo- lution in adolescents and adults. Whole genome-fragment phage display libraries (GFPDL) expressing linear and conformational epitopes from RSV fusion protein (F) and attachment protein (G) were used for unbiased epitope profiling of sera prior to and fol- lowing RSV infection. In addition, Plasmon Surface Resonance (SPR) was used to measure antibody binding to F and G peptides and proteins. A steady increase in RSV-F epitope repertoires from young children to adults was observed. Several novel epitopes were iden- tified in pre-fusion F and an immunodominant epitope in F0-p27. For RSV-G, antibody responses were high following RSV infection in children, but declined in adults. This study identified unlinked evolution of anti-F and anti G responses that could help development of better RSV vaccines and therapies.

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