Investigating the effect of AS03 adjuvant on the plasma cell repertoire following pH1N1 influenza vaccination

Abstract

Influenza pandemics require rapid deployment of effective vaccines for control. Adjuvants such as AS03 improve vaccine immunogenicity, but this mechanism is poorly understood. We used high-throughput B cell receptor sequencing of plasma cells produced following AS03-adjuvanted and non-adjuvanted 2009 pandemic H1N1 vaccination, as well as pre-pandemic seasonal influenza vaccination to elucidate the effect of the adjuvant on the humoral immune response. By analyzing mutation levels, it was possible to distinguish sequences from cells that were recently activated from naïve B cells from those that were activated by memory recall. We show that the adjuvant functions through two mechanisms. First, the adjuvant stimulates increased activation of naïve B cells, thus reducing immune interference with previous vaccine responses. Second, the adjuvant is able to increase the adaptability of the recalled cells to give improved specificity to the new vaccine antigen. We thus show how AS03 enhances pH1N1 immune responses, and reduces immune interference.

AS03-adjuvanted H5N1 vaccine promotes antibody diversity and affinity maturation, NAI titers, cross-clade H5N1 neutralization, but not H1N1 cross-subtype neutralization

“…Previous studies in humans using AS03-adjuvanted H1N1pdm09 vaccine combined with B-cell receptor (BCR) sequencing of isolated of plasma blasts on day 7 provided evidence for improved recruitment of total antibody secreting cells, that included naïve (unmutated BCR) B cells and recalled preexisting memory B cells in the adjuvanted group compared to the unadjuvanted group. 60 In a separate study, subjects receiving AS03-adjuvanted H1N1pdm09 46 showed an increase in both anti-head and anti-stem antibodies. A significant increase in HI titers against the homologous strain was found in both previously vaccinated (with a seasonal influenza vaccine) or unvaccinated individuals (average fold increase of 32 and 250, respectively).…”

Inactivated influenza virus vaccines: the future of TIV and QIV

“…Bystander help from T cells can not only lead to higher antibody titers and antibody avidities, but it is also needed for efficient isotype class switching. This is indeed observed for oil in water adjuvants that were tested with IIV in humans [40]. Antibody isotype class switching can be crucial for (universal) influenza vaccine types that rely on antibodies that require Fc receptor mediated mechanisms in order to provide protection, since different antibody subtypes can engage different Fc receptors on effector cells with different efficiencies [19–21].…”

Observed Antibody Space: A Resource for Data Mining Next-Generation Sequencing of Antibody Repertoires

“…Numerous analyses have focused on the frequencies of V(D)J gene usages, which can offer insights into creating biased therapeutic Ab libraries (14)(15)(16). Another therapeutic application of Ab repertoire analysis is advancing vaccine design by comparative longitudinal studies of pre-and postantigen challenge experiments (10,11,(17)(18)(19)(20)(21)(22). Such comparative studies have shown that different individuals can converge on the same Ab sequence against a given vaccine (11,19).…”