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Antibody responses to F, G proteins in RSV show unlinked evolution
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Recent findings published in PLoS Pathogens showed that the anti-F and anti-G responses of respiratory syncytial virus had an unlinked evolution. In addition, researchers observed evidence for an immune pressure-driven evolution of the anti-G response, which declines in adulthood.
Based on these findings, the researchers believe that future RSV vaccines need to include G protein.
“Our study provides comprehensive antigenic fingerprinting of the antibody responses to RSV-F and G proteins following early RSV infection,” Surender Khurana, PhD, of the FDA’s Division of Viral Products, and colleagues wrote. “We have identified several novel epitopes in RSV F and G proteins and an immunodominant epitope in the F-p27, which is excised during processing of F0.”
While RSV is the major cause of pneumonia and bronchiolitis among infants and children, no vaccine exists to provide protection against it, the researchers wrote. Further, few conclusions have been reached regarding which antibodies correlate with protection and why protection weakens over time. Khurana and colleagues wrote that RSV isolates can be classified into two antigenic groups: A and B, with most genetic differences occurring in the attachment glycoprotein G (47%) and less differences in the fusion protein F (9%). In addition, the evolution of RSV A has generated diversity mainly in the G gene, resulting in some vaccines under development only using the F protein.
To understand the complete antibody epitope repertoire for infants with RSV, the researchers generated separate whole genome-fragment phage display libraries (GFPDL) for both F and G by using the blood serum of infants. These libraries were created in infants aged younger than 9 months and before RSV infection, and also in infants infected and aged 15 to 18 months. Based on the results of the GFPDL analysis, the researchers synthesized large peptides representing the antigenic sites spanning RSV-F and G proteins. After utilizing serums from different age groups, they used real-time Surface Plasmon Resonance-based kinetic analysis to determine the evolution of the antibody responses.
The F-GFPDL analyses surprisingly showed only “modest changes” in the anti-F epitope repertoires after RSV infection, while the G-GFPDL analyses showed a 100-fold increase in the number of bound phages, the investigators wrote. The G-reactive epitopes spanned the N- and C-terminus of the G ectodomain and had increased reactivity to the central conserved domain. The researchers observed a steady increase in RSV-F epitope repertoires from young children to adults. They identified several novel repertoires in the pre-fusion F and immunodominant epitope in the F-p27. For all age groups, antibody binding to pre-fusion F was two- to threefold greater than binding to post-fusion F, the researchers said. For RSV-G, antibody responses were high after RSV infection in children, but declined significantly in adults. Overall, the researchers identified an unlinked evolution of anti-F and anti-G responses and found evidence for an immune pressure-driven evolution of RSV-G.
“The significant drop in anti-G antibody levels in adults may be a factor in sustained susceptibility to RSV throughout life,” the researchers wrote.
“Several current subunit/particle based vaccines under development contains F protein only,” they concluded. “The implications of our findings suggest the need to include G proteins in future RSV vaccines in order to boost the anti-G responses.” – by Will Offit
Disclosure: The researchers report no relevant financial disclosures.
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