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Influenza viruses grown in eggs for the purposes of vaccine generation often acquire mutations during egg adaptation or possess different glycosylation patterns than viruses circulating among humans. Here, we report that seasonal influenza virus vaccines possess an egg-derived glycan that is an antigenic decoy, with egg-binding MAbs reacting with a sulfated N -acetyllactosamine (LacNAc). Influenza viruses grown in eggs for the purposes of vaccine generation often acquire mutations during egg adaptation or possess different glycosylation patterns than viruses circulating among humans. Here, we report that seasonal influenza virus vaccines possess an egg-derived glycan that is an antigenic decoy, with egg-binding MAbs reacting with a sulfated N -acetyllactosamine (LacNAc). Half of subjects that received an egg-grown vaccine mounted an antibody response against this egg-derived antigen. Egg-binding monoclonal antibodies specifically bind viruses grown in eggs, but not viruses grown in other chicken-derived cells, suggesting that only egg-grown vaccines can induce antiegg antibodies. Notably, antibodies against the egg antigen utilized a restricted antibody repertoire and possessed features of natural antibodies, as most antibodies were IgM and had a simple heavy-chain complementarity-determining region 3. By analyzing a public data set of influenza virus vaccine-induced plasmablasts, we discovered egg-binding public clonotypes that were shared across studies. Together, this study shows that egg-grown vaccines can induce antibodies against an egg-associated glycan, which may divert the host immune response away from protective epitopes.

H5N1 highly pathogenic avian influenza viruses have spread globally and pose a pandemic risk. Prior studies suggest that early life exposures to group 1 influenza viruses (H1N1 and H2N2) prime antibodies that cross-react to the hemagglutinin of H5N1, which is also a group 1 virus. However, less is known about how immune history affects antibody responses against the H5N1 neuraminidase (NA). We measured NA inhibition antibodies against multiple H5N1 viruses using sera from 155 individuals born between 1927 and 2016. Individuals likely primed in childhood with H1N1 viruses possessed higher levels of antibodies that cross-react with the NA of H5N1 viruses compared to those primed with H2N2 or H3N2 viruses. While young children rarely possessed cross-reactive N1 antibodies, childhood infections with contemporary H1N1, but not H3N2, viruses elicited them. We also measured antibodies against an H5N5 virus (A6 genotype) that recently caused a fatal infection in the United States. Consistent with the lack of circulation of N5 viruses in humans, we found low levels of antibodies against the N5 NA. Our data suggest that immune history greatly impacts the generation of cross-reactive NA antibodies, and that reassortment with other NAs may increase the risk of H5 infection of humans. H5N1 avian influenza viruses have pandemic potential, yet antibody responses to their neuraminidase aren’t well studied. Here, the authors demonstrate that childhood exposure to H1N1 viruses enhances cross-reactive antibody levels against H5N1 neuraminidase, highlighting the potential impact of immune priming on future influenza virus risks.

Human land use tends to decrease the diversity of native plant species and facilitate the invasion and establishment of exotic ones. Such changes in land use and plant community composition usually have negative impacts on the assemblages of native herbivorous insects. Highly specialized herbivores are expected to be especially sensitive to land use intensification and the presence of exotic plant species because they are neither capable of consuming alternative plant species of the native flora nor exotic plant species. Therefore, higher levels of land use intensity might reduce the proportion of highly specialized herbivores, which ultimately would lead to changes in the specialization of interactions in plant-herbivore networks. This study investigates the community-wide effects of land use intensity on the degree of specialization of 72 plant-herbivore networks, including effects mediated by the increase in the proportion of exotic plant species. Contrary to our expectation, the net effect of land use intensity on network specialization was positive. However, this positive effect of land use intensity was partially canceled by an opposite effect of the proportion of exotic plant species on network specialization. When we analyzed networks composed exclusively of endophagous herbivores separately from those composed exclusively of exophagous herbivores, we found that only endophages showed a consistent change in network specialization at higher land use levels. Altogether, these results indicate that land use intensity is an important ecological driver of network specialization, by way of reducing the local host range of herbivore guilds with highly specialized feeding habits. However, because the effect of land use intensity is offset by an opposite effect owing to the proportion of exotic host species, the net effect of land use in a given herbivore assemblage will likely depend on the extent of the replacement of native host species with exotic ones.

Plant-pollinator coextinctions are likely to become more frequent as habitat alteration and climate change continue to threaten pollinators. The consequences of the resulting collapse of plant communities will depend partly on how quickly plant functional and phylogenetic diversity decline following pollinator extinctions. We investigated the functional and phylogenetic consequences of pollinator extinctions by simulating coextinctions in seven plant-pollinator networks coupled with independent data on plant phylogeny and functional traits. Declines in plant functional diversity were slower than expected under a scenario of random extinctions, while phylogenetic diversity often decreased faster than expected by chance. Our results show that plant functional diversity was relatively robust to plant-pollinator coextinctions, despite the underlying rapid loss of evolutionary history. Thus, our study suggests the possibility of uncoupled responses of functional and phylogenetic diversity to species coextinctions, highlighting the importance of considering both dimensions of biodiversity explicitly in ecological studies and when planning for the conservation of species and interactions.

Avian H5N1 influenza viruses are circulating widely in cattle and other mammals and pose a risk for a human pandemic. Previous studies suggest that older humans are more resistant to H5N1 infections due to childhood imprinting with other group 1 viruses (H1N1 and H2N2); however, the immunological basis for this is incompletely understood. Here we measured H5N1 antibody responses in sera from 157 individuals born between 1927 and 2016. We show that antibody titers to historical and recent H5N1 strains are highest in older individuals and correlate more strongly with birth year than with age, consistent with immune imprinting. Young children, who were likely not yet exposed to seasonal influenza viruses, had low levels of H5-specific antibodies. We also measured H5N1 antibody responses in sera from 100 individuals before and after receiving an A/Vietnam/1203/2004 H5N1 vaccine. We found that both younger and older humans produced H5-reactive antibodies to the A/Vietnam/1203/2004 vaccine strain and to a contemporary clade 2.3.4.4b strain, with higher seroconversion rates in young children who had lower levels of antibodies before vaccination. These studies suggest that younger individuals might benefit more from vaccination than older individuals in the event of an H5N1 pandemic. H5N1 strain-specific antibodies are higher in older individuals and correlate more with birth year than with age, suggesting that younger individuals are potentially more likely to benefit from H5N1 vaccination.

The ability of populations to adapt depends on a complex suite of traits including mutation and recombination rates and functional constraints on genes subject to selection. How much selection can act on these traits to promote adaptability remains an open question. This dissertation investigates the ultimate example of evolved adaptability, the adaptive immune system of jawed vertebrates. Adaptive immunity has been selected in jawed vertebrates to recognize pathogens through recombination, mutation and selection in populations of B cells rapidly evolving during the immune response within an individual. This short- term adaptability is enabled by the diversity of immunoglobulin genes that recombine to produce B cell receptors and by the receptors’ mutation rate during the immune response, features that have been shaped by selection in vertebrate populations over hundreds of millions of years. We explore how these features contribute to the adaptability of the immune response through computational and statistical analyses of the response to influenza and HIV. We ask if despite possible epistatic interactions among recombining immunoglobulin genes, specificity for particular pathogens is associated with individual genes. We find that influenza infection in mice selects for B cell receptors using specific immunoglobulin genes during the immune response, suggesting that selection of immunoglobulin genes in the long term could lead to their specialization for particular pathogens. Because the adaptability of B cells depends on mutations that change affinity for the antigen, we also investigate the short-term evolution of mutational hotspots in B cell receptor sequences. While the long-term evolution of immunoglobulin genes led to an abundance of hotspots in the antingen-binding loops of the receptor, we find that selection and neutral mutations disrupt those hotspots over years of coevolution between B cells and HIV, a loss of mutability that might limit the adaptability of B cell responses to chronic or repeated infections. Finally, we investigate how immunity arises from infection history and how the resulting protection shapes the ecology of influenza virus lineages. We conclude by proposing ways to integrate life-history and ecology into the study of the adaptability and specialization of immunity.

High-affinity antibodies arise within weeks of infection from the evolution of B cell receptors under selection to improve antigen recognition. This rapid adaptation is enabled by the frequency and distribution of highly mutable \"hotspot\" motifs in B cell receptor genes. High mutability in antigen binding regions (CDRs) creates variation in binding affinity, whereas low mutability in structurally important regions (FRs) may reduce the frequency of destabilizing mutations. During the response, the loss of mutational hotspots and changes in their distribution across CDRs and FRs are predicted to compromise the adaptability of B cell receptors, yet the contributions of different mechanisms to gains and losses of hotspots remain unclear. We reconstructed changes in anti-HIV B cell receptor sequences and show that mutability losses were about 60% more frequent than gains in both CDRs and FRs, with the higher relative mutability of CDRs maintained throughout the response. At least 34% of the mutability losses were caused by synonymous mutations. However, non-synonymous substitutions caused most of the mutability loss in CDRs. Because CDRs also show strong positive selection, this result suggests positive selection contributed to as much as 66\\% of the mutability loss in those regions. Although recurrent adaptation to the evolving virus could indirectly select for high mutation rates, we found no evidence of indirect selection to increase or retain hotspots. Our results suggest mutability losses are intrinsic to the neutral and adaptive evolution of B cell populations and might constrain their adaptation to rapidly evolving pathogens such as HIV and influenza.

Abstract Influenza viruses grown in eggs for the purposes of vaccine generation often acquire mutations during egg adaptation or possess differential glycosylation patterns than viruses circulating amongst humans. Here, we report that seasonal influenza virus vaccines possess an egg-derived sulfated N-acetyllactosamine (LacNAc) that is an antigenic decoy. Half of subjects that received an egg-grown vaccine mounted an antibody response against this egg-derived antigen. Egg-binding monoclonal antibodies specifically bind viruses grown in eggs, but not viruses grown in other chicken derived cells, suggesting only egg-grown vaccines can induce anti-LacNAc antibodies. Notably, antibodies against the sulfated LacNAc utilized a restricted antibody repertoire and possessed features of natural antibodies, as most antibodies were IgM and have simple heavy chain complementarity determining region 3. By analyzing a public dataset of influenza virus vaccine induced plasmablasts, we discovered egg-binding public clonotypes that were shared across studies. Together, this study shows that egg-grown vaccines can induce antibodies against an egg-associated glycan, which may divert the host immune response away from protective epitopes. Competing Interest Statement The authors have declared no competing interest.

Plant-pollinator coextinctions are likely to become more frequent as habitat alteration and climate change continue to threaten pollinators. The consequences of the resulting collapse of plant communities will depend partly on how quickly plant functional and phylogenetic diversity decline following pollinator extinctions. We investigated the functional and phylogenetic consequences of pollinator extinctions by simulating coextinctions in seven plant-pollinator networks coupled with independent data on plant phylogeny and functional traits. Declines in plant functional diversity were slower than expected under a scenario of random extinctions, while phylogenetic diversity often decreased faster than expected by chance. Our results show that plant functional diversity was relatively robust to plant-pollinator coextinctions, despite the underlying rapid loss of evolutionary history. Thus, our study suggests the possibility of uncoupled responses of functional and phylogenetic diversity to species coextinctions, highlighting the importance of considering both dimensions of biodiversity explicitly in ecological studies and when planning for the conservation of species and interactions.

Human land use tends to decrease the diversity of native plant species and facilitate the invasion and establishment of exotic ones. Such changes in land use and plant community composition usually have negative impacts on the assemblages of native herbivorous insects. Highly specialized herbivores are expected to be especially sensitive to land use intensification and the presence of exotic plant species because they are neither capable of consuming alternative plant species of the native flora nor exotic plant species. Therefore, higher levels of land use intensity might reduce the proportion of highly specialized herbivores, which ultimately would lead to changes in the specialization of interactions in plant-herbivore networks. This study investigates the community-wide effects of land use intensity on the degree of specialization of 72 plant-herbivore networks, including effects mediated by the increase in the proportion of exotic plant species. Contrary to our expectation, the net effect of land use intensity on network specialization was positive. However, this positive effect of land use intensity was partially canceled by an opposite effect of the proportion of exotic plant species on network specialization. When we analyzed networks composed exclusively of endophagous herbivores separately from those composed exclusively of exophagous herbivores, we found that only endophages showed a consistent change in network specialization at higher land use levels. Altogether, these results indicate that land use intensity is an important ecological driver of network specialization, by way of reducing the local host range of herbivore guilds with highly specialized feeding habits. However, because the effect of land use intensity is offset by an opposite effect owing to the proportion of exotic host species, the net effect of land use in a given herbivore assemblage will likely depend on the extent of the replacement of native host species with exotic ones.