Individualized flu immune responses revealed by high-throughput sequencing

By Sally Robertson, B.Sc.Feb 11 2013

Researchers have shown that it is possible to create personalized, individual-specific measurements of the antibody repertoire in response to influenza vaccination using high-throughput DNA sequencing technology.

Furthermore, they have provided molecular characterization of defects in the humoral immune response as a result of aging.

Stephen Quake (Stanford University School of Medicine, California, USA) and colleagues analyzed over 5 million antibody heavy chains and compared isotype diversity, lineage structure, and mutational activity in different age groups before and 1 week and 1 month after influenza vaccination.

As reported in Science Translational Medicine, the team amplified influenza-specific antibody sequences from single-sorted plasmablasts for two separate individuals. This showed that in one person, heavy-chain plasmablast sequences overlapped with antibody lineages with smaller numbers of sequencing reads compared with those from the other individual, in whom many plasmablast sequences were in the top lineage containing the majority of the sequencing reads.

"This may reflect structural differences in repertoire between these two subjects because one has a dominant lineage and the other one has a more even distribution," say the researchers, who add that "the detailed topology of each lineage may contain information about how antigen selection and antibody affinity maturation work in concert in shaping the antibody repertoire."

Further analysis showed that between 1 week and 1 month after vaccination, there was a decrease in the abundance of the immunoglobulin (Ig)M isotype on naïve B (NB) cells in 16 of 17 participants. This decrease coincided with an increase in isotypes IgA and IgG, suggesting "that a portion of the NB cells may have undergone switching and the antibody transcript copy numbers of these isotypes may also have increased as a result of the vaccine stimulation."

Interestingly, the extent of the reduction in IgM decreased with age, with mean reductions of 11.1% in those aged 8 to 17 years, 6.5% in those aged 18 to 30 years, and 6.0% in those aged 70 to 100 years. In addition, analyses of flow cytometry sequence data showed that the number of lineages with isotype switches decreased with age.

The researchers also report that elderly individuals (aged 70 to 100 years) had significantly fewer lineages than other age groups both before and after vaccination. This indicates an "altered repertoire structure and potentially a smaller pool of diversity for the immune repertoire to draw upon in vaccine response."

Finally, the elderly had the highest number of amino acid mutations in the IgG fraction both at 1 week and 1 month after vaccination, while they remained low and similar to the IgM fraction in other age groups at both time points.

"This approach to immune system characterization may be generally applicable to the development of new vaccines and may also help identify which individuals respond to a given vaccine," say Quake et al.

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