Vaccination with prefusion-stabilized respiratory syncytial virus fusion protein induces genetically and antigenically diverse antibody responses.

An effective vaccine for respiratory syncytial virus (RSV) is an unrealized public health goal. A single dose of the prefusion-stabilized fusion (F) glycoprotein subunit vaccine (DS-Cav1) substantially increases serum-neutralizing activity in healthy adults. We sought to determine whether DS-Cav1 vaccination induces a repertoire mirroring the pre-existing diversity from natural infection or whether antibody lineages targeting specific epitopes predominate. We evaluated RSV F-specific B cell responses before and after vaccination in six participants using complementary B cell sequencing methodologies and identified 555 clonal lineages. DS-Cav1-induced lineages recognized the prefusion conformation of F (pre-F) and were genetically diverse. Expressed antibodies recognized all six antigenic sites on the pre-F trimer. We identified 34 public clonotypes, and structural analysis of two antibodies from a predominant clonotype revealed a common mode of recognition. Thus, vaccination with DS-Cav1 generates a diverse polyclonal response targeting the antigenic sites on pre-F, supporting the development and advanced testing of pre-F-based vaccines against RSV.

Highly Dynamic Gene Family Evolution Suggests Changing Roles for PON Genes Within Metazoa.

Change in gene family size has been shown to facilitate adaptation to different selective pressures. This includes gene duplication to increase dosage or diversification of enzymatic substrates and gene deletion due to relaxed selection. We recently found that the PON1 gene, an enzyme with arylesterase and lactonase activity, was lost repeatedly in different aquatic mammalian lineages, suggesting that the PON gene family is responsive to environmental change. We further investigated if these fluctuations in gene family size were restricted to mammals and approximately when this gene family was expanded within mammals. Using 112 metazoan protein models, we explored the evolutionary history of the PON family to characterize the dynamic evolution of this gene family. We found that there have been multiple, independent expansion events in tardigrades, cephalochordates, and echinoderms. In addition, there have been partial gene loss events in monotremes and sea cucumbers and what appears to be complete loss in arthropods, urochordates, platyhelminths, ctenophores, and placozoans. In addition, we show the mammalian expansion to three PON paralogs occurred in the ancestor of all mammals after the divergence of sauropsida but before the divergence of monotremes from therians. We also provide evidence of a novel PON expansion within the brushtail possum. In the face of repeated expansions and deletions in the context of changing environments, we suggest a range of selective pressures, including pathogen infection and mitigation of oxidative damage, are likely influencing the diversification of this dynamic gene family across metazoa.