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Rapid profiling of RSV antibody repertoires from the memory B cells of naturally infected adult donors.

ABSTRACT: Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in young children and the elderly. There are currently no licensed RSV vaccines, and passive prophylaxis with the monoclonal antibody palivizumab is restricted to high-risk infants in part due to its modest efficacy. Although it is widely agreed that an effective RSV vaccine will require the induction of a potent neutralizing antibody response against the RSV fusion (F) glycoprotein, little is known about the specificities and functional activities of RSV F-specific antibodies induced by natural infection. Here, we have comprehensively profiled the human antibody response to RSV F by isolating and characterizing 364 RSV F-specific monoclonal antibodies from the memory B cells of three healthy adult donors. In all donors, the antibody response to RSV F is comprised of a broad diversity of clones that target several antigenic sites. Nearly half of the most potent antibodies target a previously undefined site of vulnerability near the apex of the prefusion conformation of RSV F (preF), providing strong support for the development of RSV vaccine candidates that preserve the membrane-distal hemisphere of the preF protein. Additionally, the antibodies targeting this new site display convergent sequence features, thus providing a future means to rapidly detect the presence of these antibodies in human vaccine samples. Many of the antibodies that bind preF-specific surfaces are over 100 times more potent than palivizumab, and several cross-neutralize human metapneumovirus (HMPV). Taken together, the results have implications for the design and evaluation of RSV vaccine candidates and offer new options for passive prophylaxis.

SUBMITTER: Gilman MS

PROVIDER: S-EPMC5244814 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Rapid profiling of RSV antibody repertoires from the memory B cells of naturally infected adult donors.

Gilman Morgan S A MS Castellanos Carlos A CA Chen Man M Ngwuta Joan O JO Goodwin Eileen E Moin Syed M SM Mas Vicente V Melero José A JA Wright Peter F PF Graham Barney S BS McLellan Jason S JS Walker Laura M LM

Science immunology 20161209 6

Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in young children and the elderly. There are currently no licensed RSV vaccines, and passive prophylaxis with the monoclonal antibody palivizumab is restricted to high-risk infants in part due to its modest efficacy. Although it is widely agreed that an effective RSV vaccine will require the induction of a potent neutralizing antibody response against the RSV fusion (F) glycoprotein, little is known about the specificit ...[more]

PMID: 28111638

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Project description:Although high-throughput sequencing and associated bioinformatics technologies have enabled the in-depth, sequence-based characterization of human immune repertoires, only a few studies on a relatively small number of sequences explored the characteristics of antibody repertoires in neonates, with contradictory conclusions. To gain a more comprehensive understanding of the human IgM antibody repertoire, we performed Illumina sequencing and IMGT/HighV-QUEST analysis of IgM heavy chain repertoire of the B lymphocytes from the cord blood (CB) of neonates, as well as the repertoire from peripheral blood of healthy human adults (HH). The comparative study revealed unexpectedly high levels of similarity between the neonatal and adult repertoires. In both repertoires, the VDJ gene usage showed no significant difference, and the most frequently used VDJ gene was IGHV4-59, IGHD3-10, and IGHJ3. The average amino acid (aa) length of CDR1 (CB: 8.5, HH: 8.4) and CDR2 (CB: 7.6, HH: 7.5), as well as the aa composition and the average hydrophobicity of the CDR3 demonstrated no significant difference between the two repertories. However, the average aa length of CDR3 was longer in the HH repertoire than the CB repertoire (CB: 14.5, HH: 15.5). Besides, the frequencies of aa mutations in CDR1 (CB: 19.33%, HH: 25.84%) and CDR2 (CB: 9.26%, HH: 17.82%) were higher in the HH repertoire compared to the CB repertoire. Interestingly, the most prominent difference between the two repertoires was the occurrence of N2 addition (CB: 64.87%, HH: 85.69%), a process that occurs during V-D-J recombination for introducing random nucleotide additions between D- and J-gene segments. The antibody repertoire of healthy adults was more diverse than that of neonates largely due to the higher occurrence of N2 addition. These findings may lead to a better understanding of antibody development and evolution pathways and may have potential practical value for facilitating the generation of more effective antibody therapeutics and vaccines.

Dataset Information

Rapid profiling of RSV antibody repertoires from the memory B cells of naturally infected adult donors.

Publications

Rapid profiling of RSV antibody repertoires from the memory B cells of naturally infected adult donors.

Similar Datasets

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