Biology subjects

Cobey, S.

Publications and source records attributed to Cobey, S..

14 recordsLinked to original sources

bioRxiv2026

Strain-specific differences in the response to egg-derived versus recombinant protein influenza vaccines

The 2023/2024 influenza vaccine included an updated H1N1 component designed to better match a new clade of H1N1 that had multiple mutations in antigenic epitopes of hemagglutinin. Despite this update, the vaccine trended towards being less effective against the vaccine-matched H1N1 clade than the parental H1N1 clade lacking the new antigenic mutations. Here we measure neutralization titers of serum antibodies from individuals who had received either a recombinant protein or an egg-derived vaccine against a set of viruses with hemagglutinins from 58 H1N1 strains representative of the diversity during the 2023/2024 season. We find that egg-derived vaccine recipients, but not recombinant protein vaccine recipients, had a relatively lower boost in neutralizing titers to the new clade that the updated vaccine was designed to target. We suggest that the difference in the extent that the egg-derived versus recombinant protein vaccines boosted neutralizing titers to the new H1N1 clade is because the seed strain for the egg-derived vaccine strain had acquired a reversion of a key antigenic mutation (K142R) present in that clade. Our results show how egg-derived versus recombinant protein vaccines can elicit different relative titer boosts against different subsets of viral strains, a phenomenon that could impact vaccine effectiveness. ImportanceInfluenza vaccines can be produced from virus grown in eggs, or grown in cells or made with recombinant protein. Egg-derived influenza vaccines often contain egg-adaptive mutations in the viral antigen hemagglutinin (HA) which can impact the antigenicity or immunogenicity of the HA. In this study, we compare neutralization titers from egg-derived and recombinant protein vaccine recipients against recently circulating influenza A(H1N1) strains. We find that the egg-derived vaccine induces less of a boost in titers than the recombinant protein vaccine to the new clade of viral strains that the vaccine was designed to target.

immunology↗

bioRxiv2025

Susceptible host dynamics explain pathogen resilience to perturbations

Interventions to slow the spread of SARS-CoV-2 significantly disrupted the transmission of other pathogens. As interventions lifted, whether and when human pathogens would eventually return to their pre-pandemic dynamics remains to be answered. Here, we present a framework for estimating pathogen resilience based on how fast epidemic patterns return to their pre-pandemic dynamics. By analyzing time series data from Hong Kong, Canada, Korea, and the US, we quantify the resilience of common respiratory pathogens and further predict when each pathogen will eventually return to its pre-pandemic dynamics. Our predictions are able to distinguish which pathogens should have returned already, and deviations from these predictions reveal long-term impacts of pandemic perturbations. We find a faster rate of susceptible replenishment underlies pathogen resilience and sensitivity to both large and small perturbations. Overall, our analysis highlights the persistent nature of common respiratory pathogens compared to vaccine-preventable infections, such as measles. Significance StatementCOVID-19 interventions slowed the transmission of many respiratory pathogens in different ways, raising questions about the mechanisms driving the variation in responses to interventions. To address this gap, we characterized the sensitivity of pathogen transmission to perturbations by quantifying how fast each pathogen returned to its pre-pandemic circulation patterns. We analyzed data from Hong Kong, Canada, Korea, and the US, and showed that common respiratory pathogens are far less sensitive to perturbations than measles, a vaccine-preventable infection. Finally, we showed that the speed of replenishment of the susceptible population--for example, through waning immunity--largely determines this sensitivity, suggesting that the persistence of common respiratory pathogens is likely driven by rapid susceptible replenishment.

ecology↗

bioRxiv2024

A unified theory for predicting pathogen mutual invasibility and co-circulation

A key aim in the dynamics and control of infectious diseases is predicting competitive outcomes of pathogen interactions. Observed pathogen community structure indicates both considerable coexistence of related variants and spectacular instances of replacement, notably in seasonal influenza and SARS-CoV-2. However, an overall comparative quantitative framework for invasion and coexistence remains elusive. Inspired by modern ecological coexistence theory, we address this gap by developing pathogen invasion theory (PIT) and test the resulting framework against empirical systems. PIT predicts near-universal mutual invasibility across major pathogen systems, including seasonal influenza strains and SARS-CoV-2 variants. Predicting co-circulation from mutual invasibility further depends on the extent of overcompensatory susceptible depletion dynamics. Our analyses highlight the central role of immuno-epidemiological factors in determining pathogen coexistence and community structure.

ecology↗

bioRxiv2024

High-throughput sequencing-based neutralization assay reveals how repeated vaccinations impact titers to recent human H1N1 influenza strains

The high genetic diversity of influenza viruses means that traditional serological assays have too low throughput to measure serum antibody neutralization titers against all relevant strains. To overcome this challenge, we have developed a sequencing-based neutralization assay that simultaneously measures titers against many viral strains using small serum volumes via a workflow similar to traditional neutralization assays. The key innovation is to incorporate unique nucleotide barcodes into the hemagglutinin (HA) genomic segment, and then pool viruses with numerous different barcoded HA variants and quantify infectivity of all of them simultaneously using next-generation sequencing. With this approach, a single researcher performed the equivalent of 2,880 traditional neutralization assays (80 serum samples against 36 viral strains) in approximately one month. We applied the sequencing-based assay to quantify the impact of influenza vaccination on neutralization titers against recent human H1N1 strains for individuals who had or had not also received a vaccine in the previous year. We found that the viral strain specificities of the neutralizing antibodies elicited by vaccination vary among individuals, and that vaccination induced a smaller increase in titers for individuals who had also received a vaccine the previous year--although the titers six months after vaccination were similar in individuals with and without the previous-year vaccination. We also identified a subset of individuals with low titers to a subclade of recent H1N1 even after vaccination. This study demonstrates the utility of high-throughput sequencing-based neutralization assays that enable titers to be simultaneously measured against many different viral strains. We provide a detailed experimental protocol (DOI: https://dx.doi.org/10.17504/protocols.io.kqdg3xdmpg25/v1) and a computational pipeline (https://github.com/jbloomlab/seqneut-pipeline) for the sequencing-based neutralization assays to facilitate the use of this method by others.

microbiology↗

bioRxiv2024

A speed limit on serial strain replacement from original antigenic sin

Many pathogens evolve to escape immunity, yet it remains difficult to predict whether immune pressure will lead to diversification, serial replacement of one variant by another, or more complex patterns. Pathogen strain dynamics are mediated by cross-protective immunity, whereby exposure to one strain partially protects against infection by antigenically diverged strains. There is growing evidence that this protection is influenced by early exposures, a phenomenon referred to as original antigenic sin (OAS) or imprinting. In this paper, we derive new constraints on the emergence of the pattern of successive strain replacements demonstrated by influenza, SARS-CoV-2, seasonal coronaviruses, and other pathogens. We find that OAS implies that the limited diversity found with successive strain replacement can only be maintained if R0 is less than a threshold set by the characteristic antigenic distances for cross-protection and for the creation of new immune memory. This bound implies a "speed limit" on the evolution of new strains and a minimum variance of the distribution of infecting strains in antigenic space at any time. To carry out this analysis, we develop a theoretical model of pathogen evolution in antigenic space that implements OAS by decoupling the antigenic distances required for protection from infection and strain-specific memory creation. Our results demonstrate that OAS can play an integral role in the emergence of strain structure from host immune dynamics, preventing highly transmissible pathogens from maintaining serial strain replacement without diversification.

evolutionary biology↗

bioRxiv2022

Chance and contingency in B cell evolution limit the similarity of antibody responses to infection across individuals

Antibodies result from the competition of B cell lineages evolving under selection for improved antigen recognition, a process known as affinity maturation. High-affinity antibodies to pathogens such as HIV, influenza, and SARS-CoV-2 are frequently reported to arise from B cells whose receptors, the precursors to antibodies, are encoded by particular immunoglobulin alleles. This raises the possibility that the presence of particular germline alleles in the B cell repertoire is a major determinant of the quality of the antibody response. Alternatively, initial differences in germline alleles propensities to form high-affinity receptors might be overcome by chance events during affinity maturation. We first investigate these scenarios in simulations: when germline-encoded fitness differences are large relative to the rate and effect size variation of somatic mutations, the same germline alleles persistently dominate the response of different individuals. In contrast, if germline-encoded advantages can be easily overcome by subsequent mutations, allele usage becomes increasingly divergent over time, a pattern we then observe in mice experimentally infected with influenza virus. We investigated whether affinity maturation might nonetheless strongly select for particular amino acid motifs across diverse genetic backgrounds, but we found no evidence of convergence to similar CDR3 sequences or amino acid substitutions. These results suggest that although germline-encoded specificities can lead to similar immune responses between individuals, diverse evolutionary routes to high affinity limit the genetic predictability of responses to infection and vaccination. Author SummaryAntibodies arise as B cell receptors encoded by the stochastic recombination of immunoglobulin genes. While those genes evolve over millions of years, the receptors themselves evolve within weeks as B cells compete under selection for improved antigen recognition. This competition shapes the response to infection and vaccination; how much the outcome depends on the initial choice of immunoglobulin genes versus subsequent receptor evolution is an open question that informs the predictability of the immune response and the long-term evolution of immunoglobulins. In simulations, we show that immunoglobulin genes with hardcoded specificity for the antigen can lead to either transient or persistent similarity in the response of different individuals. When the initial advantage is large relative to the effects of mutation, B cells using the same genes consistently dominate the response across individuals. Weaker initial advantages lead to similar responses early on but are later overcome by B cell evolution playing out differently in each individual due to chance events. We observe such increasingly divergent responses in mice infected with influenza virus. While long-term selection might hardcode specificities for particular pathogens on immunoglobulin genes, our results suggest diverse paths to potent antibodies can nonetheless limit the predictability of the response.

immunology↗

bioRxiv2021

An egg-derived sulfated N-Acetyllactosamine glycan is an antigenic decoy of influenza virus vaccines

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.

immunology↗

bioRxiv2018

Age-specific differences in the dynamics of protective immunity to influenza

Influenza A viruses evolve rapidly to escape host immunity, such that individuals can be infected multiple times with the same subtype. The form and duration of protective immunity after each influenza infection are poorly understood. Here, we quantify the dynamics of protective immunity against influenza A virus infections by fitting individual-level mechanistic models to longitudinal serology from children and adults in a household cohort study. We find that most protection in children is explained by antibody titers measured by the hemagglutination inhibition (HI) assay. In contrast, in adults, HI antibody titers explain a smaller fraction of protection. Protection against circulating strains wanes to approximately 50% of peak levels 3.5-7 years after infection in both age groups, and wanes faster against influenza A(H3N2) than A(H1N1)pdm09. Protection against H3N2 lasts longer in adults than in children. Our results suggest that the focus of influenza antibody responses changes over time from the highly mutable hemagglutinin head to other epitopes, consistent with the immunological theory of original antigenic sin, and that this change of focus might affect protection. Additionally, we estimate that imprinting, or primary infection with a subtype of one phylogenetic group, has little to no effect on the risk of non-medically attended influenza infections in adults. We also find no evidence of long-term cross-protection between subtypes. This work underscores the need for longitudinal data on multiple components of the immune response to better understand the development of immunity and differences in susceptibility within populations.

epidemiology↗

bioRxiv2017

Recurring infection with ecologically distinct human papillomavirus (HPV) types explains high prevalence and diversity

The high prevalence of human papillomavirus (HPV), the most common sexually transmitted infection, arises from the coexistence of over 200 genetically distinct types. Accurately predicting the impact of vaccines that target multiple types requires understanding the factors that determine HPV diversity. The diversity of many pathogens is driven by type-specific or \"homologous\" immunity, which promotes the spread of variants to which hosts have little immunity. To test for homologous immunity and to identify mechanisms determining HPV transmission, we fitted nonlinear mechanistic models to longitudinal data on genital infections in unvaccinated men. Our results provide no evidence for homologous immunity, instead showing that infection with one HPV type strongly increases the risk of infection with that type for years afterwards. For HPV16, the type responsible for most HPV-related cancers, an initial infection increases the one-year probability of reinfection by 20-fold, and the probability of reinfection remains 14-fold higher two years later. This increased risk occurs in both sexually active and celibate men, suggesting that it arises from auto-inoculation, episodic reactivation of latent virus, or both. Overall our results show that high HPV prevalence and diversity can be explained by a combination of a lack of homologous immunity, frequent reinfections, weak competition between types, and variation in type fitness between host subpopulations. Due to the high risk of reinfection, vaccinating boys that have not yet been exposed may be crucial to reduce prevalence, but our results suggest that there may also be large benefits from vaccinating previously infected individuals.

epidemiology↗

bioRxiv2017

Selection and neutral mutations drive pervasive mutability losses in long-lived B cell lineages

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 \"hotspotx\" 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.

evolutionary biology↗

bioRxiv2017

Vaccination and the evolution of seasonal influenza

1Although vaccines against seasonal influenza are designed to protect against circulating strains, by affecting the emergence and transmission of antigenically divergent strains, they might also change the rate of antigenic evolution. Vaccination might slow antigenic evolution by increasing immunity, reducing the chance that even antigenically diverged strains can survive. Vaccination also reduces prevalence, decreasing the supply of potentially beneficial mutations and increasing the probability of stochastic extinction. But vaccination might accelerate antigenic evolution by increasing the transmission advantage of more antigenically diverged strains relative to less diverged strains (i.e., by positive selection). Such evolutionary effects could affect vaccinations direct benefits to individuals and indirect benefits to the host population (i.e., the private and social benefits). To investigate these potential impacts, we simulated the dynamics of an influenza-like pathogen with seasonal vaccination. On average, more vaccination decreased the rate of viral antigenic evolution and the incidence of disease. Notably, this decrease was driven partly by a vaccine-induced decline in the rate of antigenic evolution. To understand how the evolutionary effects of vaccines might affect their social and private benefits, we fitted linear panel models to simulated data. By slowing evolution, vaccination increased the social benefit and decreased the private benefit. Thus, in the long term, vaccinations potential social and private benefits may differ from current theory, which omits evolutionary effects. These results suggest that conventional seasonal vaccines against influenza, if protective against transmission and given to the appropriate populations, could further reduce disease burden by slowing antigenic evolution.

evolutionary biology↗

bioRxiv2017

Despite egg-adaptive mutations, the 2012-13 H3N2 influenza vaccine induced comparable antibody titers to the intended strain

BackgroundInfluenza vaccination aims to prevent infection by influenza virus and reduce associated morbidity and mortality; however, vaccine effectiveness (VE) can be modest, especially for subtype A/H3N2. Failure to achieve consistently high VE has been attributed both to mismatches between the vaccine and circulating influenza strains and to the vaccine's elicitation of protective immunity in only a subset of the population. The low H3N2 VE in 2012-13 was attributed to egg-adaptive mutations that created antigenic mismatch between the intended (A/Victoria/361/2011) and actual vaccine strain (IVR-165).\n\nMethodsWe investigate the basis of the low VE in 2012-2013 by evaluating whether vaccinated and unvaccinated individuals were infected by different viral strains and assessing the serologic responses to A/Victoria/361/2011 and the IVR-165 vaccine strain in an adult cohort before and after vaccination.\n\nResultsWe found no significant genetic differences between the strains that infected vaccinated and unvaccinated individuals. Vaccination increased titers to A/Victoria/361/2011 as much as to IVR-165. These results are consistent with the hypothesis that vaccination served merely to boost preexisting cross-reactive immune responses, which provided limited protection against infection with the circulating influenza strains.\n\nConclusionsIn contrast to suggestive analyses based on ferret antisera, low H3N2 VE in 2012-13 does not appear to be due to the failure of the egg-adapted strain to induce a response to the intended vaccine strain. Instead, low VE might have been caused by the emergence of anti-genically novel influenza strains and low vaccine immunogenicity in a subset of the population.

epidemiology↗

bioRxiv2017

Host population structure and treatment frequency maintain balancing selection on drug resistance

It is a truism that antimicrobial drugs select for resistance, but explaining pathogen- and population-specific variation in patterns of resistance remains an open problem. Like other common commensals, Streptococcus pneumoniae has demonstrated persistent coexistence of drug-sensitive and drug-resistant strains. Theoretically, this outcome is unlikely. We modeled the dynamics of competing strains of S. pneumoniae to investigate the impact of transmission dynamics and treatment-induced selective pressures on the probability of stable coexistence. We find that the outcome of competition is extremely sensitive to structure in the host population, although coexistence can arise from age-assortative transmission models with age-varying rates of antibiotic use. Moreover, we find that the selective pressure from antibiotics arises not so much from the rate of antibiotic use per se but from the frequency of treatment: frequent antibiotic therapy disproportionately impacts the fitness of sensitive strains. This same phenomenon explains why serotypes with longer durations of carriage tend to be more resistant. These dynamics may apply to other potentially pathogenic, microbial commensals and highlight how population structure, which is often omitted from models, can have a large impact.

evolutionary biology↗

bioRxiv2016

Fitness landscapes reveal simple strategies for steering evolution to minimize antibiotic resistance

The evolution of antibiotic resistance presents a practical and theoretical challenge: the design of strategies that limit the risk of evolved resistance while effectively treating current patients. Sequentially cycling antibiotics has been proposed as a way to slow the evolution of resistance by reducing the extent of adaptation to a given drug, and clinical trials have demonstrated its effectiveness in some settings. Empirical fitness landscapes in theory allow the sequence of drugs to be refined to maximize tradeoffs between drugs and thereby slow adaptation even further. Using the measured growth rates of 16 genotypes of Escherichia coli in the presence of {beta}-lactam antibiotics, we test an adaptive strategy, based on a Markov chain transition matrix, to select drug sequences that continuously minimize resistance. Cycling is never selected over the long term. Instead, monotherapy with the antibiotic that permits the least growth in its landscapes absorbing state is rapidly selected from different starting conditions. Analysis of a synthetic fitness landscape shows that cycling drugs that induce sensitivity to one other could, in theory, outperform monotherapy. These results underscore the importance of considering the specific topologies of fitness landscape in determining whether to cycle drugs and suggest a general computational approach to identify high performing, practical strategies to manage resistance.

evolutionary biology↗