About

Jesse Bloom is a professor affiliated with the Fred Hutch Cancer Center and the University of Washington. His research focuses on rapid evolution in viral diseases, including influenza. His group employs a combination of experimental and computational techniques to study questions in virology, immunology, and protein biochemistry from an evolutionary perspective. Bloom's work aims to understand the mechanisms and implications of viral evolution, which has significant relevance for public health and the development of medical interventions.

Research topics

• Virology
• Biology
• Medicine
• Genetics
• Internal medicine
• Immunology
• Computer Science
• Computational biology
• Pharmacology
• Chemistry
• Biochemistry
• Cell biology

Selected publications

• Influenza hemagglutinin subtypes have different sequence constraints despite sharing extremely similar structures

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-06

  articleOpen accessSenior authorCorresponding

  Hemagglutinins (HA) from different influenza A virus subtypes share as little as ~40% amino acid identity, yet their protein structure and cell entry function are highly conserved. Here we examine the extent that sequence constraints on HA differ across three subtypes. To do this, we first use pseudovirus deep mutational scanning to measure how all amino-acid mutations to an H7 HA affect its cell entry function. We then compare these new measurements to previously described measurements of how all mutations to H3 and H5 HAs affect cell entry function. We find that ~50% of HA sites display substantially diverged preferences for different amino acids across the HA subtypes. The sites with the most divergent amino-acid preferences tend to be buried and have biochemically distinct wildtype amino acids in the different HA subtypes. We provide an example of how rewiring the interactions among contacting residues has dramatically shifted which amino acids are tolerated at specific sites. Overall, our results show how proteins with the same structure and function can become subject to very different site-specific evolutionary constraints as their sequences diverge.

  PublisherOA PDFDOI

• Spike mutations that affect the function and antigenicity of recent KP.3.1.1-like SARS-CoV-2 variants

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-19

  preprintOpen accessSenior authorCorresponding

  Abstract SARS-CoV-2 is under strong evolutionary selection to acquire mutations in its spike protein that reduce neutralization by human polyclonal antibodies. Here we use pseudovirus-based deep mutational scanning to measure how mutations to the spike from the recent KP.3.1.1 SARS-CoV-2 strain affect cell entry, binding to ACE2 receptor, RBD up/down motion, and neutralization by human sera and clinically relevant antibodies. The spike mutations that most affect serum antibody neutralization sometimes differ between sera collected before versus after recent vaccination or infection, indicating these exposures shift the neutralization immunodominance hierarchy. The sites where mutations cause the greatest reduction in neutralization by post-vaccination or infection sera include receptor-binding domain (RBD) sites 475, 478 and 487, all of which have mutated in recent SARS-CoV-2 variants. Multiple mutations outside the RBD affect sera neutralization as strongly as any RBD mutations by modulating RBD up/down movement. Some sites that affect RBD up/down movement have mutated in recent SARS-CoV-2 variants. Finally, we measure how spike mutations affect neutralization by three clinically relevant SARS-CoV-2 antibodies: VYD222, BD55-1205, and SA55. Overall, these results illuminate the current constraints and pressures shaping SARS-CoV-2 evolution, and can help with efforts to forecast possible future antigenic changes that may impact vaccines or clinical antibodies. Importance This study measures how mutations to the spike of a SARS-CoV-2 variant that circulated in early 2025 affect its function and recognition by both the polyclonal antibodies produced by the human immune system and monoclonal antibodies used as prophylactics. These measurements are made with a pseudovirus system that enables safe study of viral protein mutations using virions that can only infect cells once. The study identifies mutations that decrease recognition by current human antibody immunity; many of these mutations are increasingly being observed in new viral variants. It also shows the importance of mutations that move the spike’s receptor binding domain up or down. Overall, these results are useful for forecasting viral evolution and assessing which newly emerging variants have reduced recognition by immunity and antibody prophylactics.

  PublisherOA PDFDOI

• Combined crystallographic fragment screening and deep mutational scanning enable discovery of Zika virus NS2B-NS3 protease inhibitors

  Nature Communications · 2025-10-08 · 6 citations

  articleOpen access

  The Zika viral protease NS2B-NS3 is essential for the cleavage of viral polyprotein precursor into individual structural and non-structural (NS) proteins and is therefore an attractive drug target. Generation of a robust crystal system of co-expressed NS2B-NS3 protease has enabled us to perform a crystallographic fragment screening campaign with 1076 fragments. 46 fragments with diverse scaffolds are identified to bind in the active site of the protease, with another 6 fragments observed in a potential allosteric site. To identify binding sites that are intolerant to mutation and thus suppress the outgrowth of viruses resistant to inhibitors developed from bound fragments, we perform deep mutational scanning of the NS2B-NS3 protease. Merging fragment hits yields an extensive set of 'mergers', defined as synthetically accessible compounds that recapitulate constellations of observed fragment-protein interactions. In addition, the highly sociable fragment hits enable rapid exploration of chemical space via algorithmic calculation and thus yield diverse possible starting points. In this work, we maximally explore the binding opportunities to NS2B-NS3 protease, facilitating its resistance-resilient antiviral development.

  PublisherOA PDFDOI

• Replaying germinal center evolution on a quantified affinity landscape

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-05 · 23 citations

  preprintOpen access

  Darwinian evolution of immunoglobulin genes within germinal centers (GC) underlies the progressive increase in antibody affinity following antigen exposure. Whereas the mechanics of how competition between GC B cells drives increased affinity are well established, the dynamical evolutionary features of this process remain poorly characterized. We devised an experimental evolution model in which we "replay" over one hundred instances of a clonally homogenous GC reaction and follow the selective process by assigning affinities to all cells using deep mutational scanning. Our data reveal how GCs achieve predictable evolutionary outcomes through the cumulative effects of many rounds of imperfect selection, acting on a landscape shaped heavily by somatic hypermutation (SHM) targeting biases. Using time-calibrated models, we show that apparent features of GC evolution such as permissiveness to low-affinity lineages and early plateauing of affinity are best explained by survivorship biases that distort our view of how affinity progresses over time.

  PublisherOA PDFDOI

• Author response: High-throughput neutralization measurements correlate strongly with evolutionary success of human influenza strains

  2025-11-27

  peer-reviewOpen accessSenior author

  Human influenza viruses rapidly acquire mutations in their hemagglutinin (HA) protein that erode neutralization by antibodies from prior exposures. Here, we use a sequencing-based assay to measure neutralization titers for 78 recent H3N2 HA strains against a large set of children and adult sera, measuring ∼10,000 total titers. There is substantial person-to-person heterogeneity in the titers against different viral strains, both within and across age cohorts. The growth rates of H3N2 strains in the human population in 2023 are highly correlated with the fraction of sera with low titers against each strain. Notably, strain growth rates are less correlated with neutralization titers against pools of human sera, demonstrating the importance of population heterogeneity in shaping viral evolution. Overall, these results suggest that high-throughput neutralization measurements of human sera against many different viral strains can help explain the evolution of human influenza.

  PublisherDOI

• RSV F evolution escapes some monoclonal antibodies but does not strongly erode neutralization by human polyclonal sera

  Journal of Virology · 2025-07-03 · 7 citations

  articleOpen accessSenior author

  Vaccines and monoclonal antibodies targeting the respiratory syncytial virus (RSV) fusion protein (F) have recently begun to be widely used to protect infants and high-risk adults. Some other viral proteins evolve to erode polyclonal antibody neutralization and escape individual monoclonal antibodies. However, the impact of RSV F evolution on antibody neutralization is not yet thoroughly understood. Here, we develop an experimental system for measuring neutralization titers against RSV F using pseudotyped lentiviral particles. This system is easily adaptable to evaluate neutralization of relevant clinical strains. We apply this system to demonstrate that the natural evolution of RSV F leads to escape from some monoclonal antibodies, but at most modestly affects neutralization by polyclonal serum antibodies. Overall, our work sheds light on RSV antigenic evolution and describes a tool to measure the ability of antibodies and sera to neutralize contemporary RSV strains.IMPORTANCEWe describe an efficient approach to measure how antibodies inhibit infection by historical and recent human strains of respiratory syncytial virus (RSV). This approach is useful for understanding how viral evolution affects antibody immunity. We apply this approach to demonstrate that RSV evolution can escape some monoclonal antibodies, but polyclonal serum antibodies are less impacted by viral evolution. This information is relevant given the recent development of RSV preventative measures, including monoclonal antibodies and vaccines.

  PublisherDOI

• High-throughput neutralization measurements correlate strongly with evolutionary success of human influenza strains

  eLife · 2025-06-03 · 4 citations

  preprintOpen accessSenior author

  Abstract Human influenza viruses rapidly acquire mutations in their hemagglutinin (HA) protein that erode neutralization by antibodies from prior exposures. Here, we use a sequencing-based assay to measure neutralization titers for 78 recent H3N2 HA strains against a large set of children and adult sera, measuring ∼10,000 total titers. There is substantial person-to-person heterogeneity in the titers against different viral strains, both within and across age cohorts. The growth rates of H3N2 strains in the human population in 2023 are highly correlated with the fraction of sera with low titers against each strain. Notably, strain growth rates are less correlated with neutralization titers against pools of human sera, demonstrating the importance of population heterogeneity in shaping viral evolution. Overall, these results suggest that high-throughput neutralization measurements of human sera against many different viral strains can help explain the evolution of human influenza.

  PublisherDOI

• Pleiotropic mutational effects on function and stability constrain the antigenic evolution of influenza haemagglutinin

  Nature Ecology & Evolution · 2025-12-01 · 5 citations

  articleOpen accessSenior author

  The evolution of human influenza virus haemagglutinin (HA) involves simultaneous selection to acquire antigenic mutations that escape population immunity while preserving protein function and stability. Epistasis shapes this evolution, as an antigenic mutation that is deleterious in one genetic background may become tolerated in another. However, the extent to which epistasis can alleviate pleiotropic conflicts between immune escape and protein function/stability is unclear. Here we measure how all amino acid mutations in the HA of a recent human H3N2 influenza strain affect its cell entry function, acid stability and neutralization by human serum antibodies. We find that epistasis has entrenched certain mutations so that reverting to the ancestral amino acid identity in earlier strains is no longer tolerated. Epistasis has also enabled the emergence of antigenic mutations that were detrimental to the cell entry function of HA in earlier strains. However, epistasis appears insufficient to overcome the pleiotropic costs of antigenic mutations that impair the stability of HA, explaining why some mutations that strongly escape human antibodies never fix in nature. Our results refine our understanding of the mutational constraints that shape recent H3N2 influenza evolution: epistasis can enable antigenic change, but pleiotropic effects can restrict its trajectory.

  PublisherDOI

• Fostemsavir analog BMS-818251 has enhanced viral neutralization potency and similar escape mutation profile

  Antimicrobial Agents and Chemotherapy · 2025-08-27

  articleOpen access

  ABSTRACT BMS-818251, a fostemsavir analog, is a next-generation HIV-1 attachment inhibitor with enhanced potency and a similar resistance profile. By using ex vivo viral outgrowth assays with HIV+ donor samples, we demonstrate here that BMS-818251 exhibits superior viral suppression compared to temsavir, the active form of fostemsavir. To map potential resistance pathways, we employed deep mutational scanning and pseudotyped virus neutralization assays to identify escape mutations within the HIV-1 envelope glycoprotein (Env). These mutations were largely clustered around the BMS-818251 binding site, with key resistance mutations reducing drug-binding affinity. Several of the enriched mutations, such as S375I/N, M426L, and M475I, have been previously observed in fostemsavir-treated patients, highlighting their clinical relevance. Isothermal titration calorimetry revealed reduced binding affinity as the primary mechanism of resistance, though with notable exceptions, such as R429G, suggesting additional factors to influence viral escape. Ex vivo Env sequencing confirmed selection of resistance mutations under BMS-818251 pressure, reinforcing the predictive value of deep mutational scanning for in vivo resistance monitoring. Compared to fostemsavir, BMS-818251 achieved more effective viral suppression at lower concentrations, even in donor samples harboring preexisting resistance mutations. These findings support the continued development of BMS-818251 as a promising alternative to fostemsavir, with potential benefits for patients with multidrug-resistant HIV-1.

  PublisherDOI

• The mutation rate of SARS-CoV-2 is highly variable between sites and is influenced by sequence context, genomic region, and RNA structure

  Nucleic Acids Research · 2025-05-29 · 11 citations

  articleOpen access

  RNA viruses like SARS-CoV-2 have high mutation rates, which contribute to their rapid evolution. Mutation rates depend on mutation type and can vary between sites in a virus's genome. Understanding this variation can shed light on the mutational processes at play, and is crucial for quantitative modeling of viral evolution. Using millions of SARS-CoV-2 full-genome sequences, we estimate rates of synonymous mutations for each mutation type and examine how much these rates vary between sites. We find a surprisingly high level of variability. A substantial fraction of this variability can be explained by local sequence context, genomic region, and RNA secondary structure. We estimate fitness effects of each mutation based on the number of times it actually occurs versus the number of times it is expected to occur based on a model of the above features. We identify small regions of the genome where synonymous or noncoding mutations occur much less often than expected, indicative of strong purifying selection on the RNA sequence independent of protein sequence. Overall, this work expands our basic understanding of SARS-CoV-2's evolution by characterizing the virus's mutation process at the level of individual sites and uncovering several striking mutational patterns that arise from unknown mechanisms.

  PublisherOA PDFDOI

Recent grants

• Viral Pathogenesis and Evolution Training Program (VPETP)

  NIH · $2.7M · 2009–2024

• Complete mapping of immune selection from antibodies to HIV

  NIH · $2.4M · 2018–2025

• High-throughput experiments to guide influenza vaccine strain selection

  NIH · $2.1M · 2016–2022

• NIH Grant K22AI093789

  NIH · $268k · 2014

• Prospectively characterizing the functional and antigenic effects of mutations to viral entry proteins

  NIH · $2.1M · 2018–2025

Frequent coauthors

• Allison J. Greaney

  Fred Hutch Cancer Center

  352 shared

• Tyler N. Starr

  University of Utah

  272 shared

• Katharine H. D. Crawford

  University of Washington

  252 shared

• Adam S. Dingens

  Fred Hutch Cancer Center

  193 shared

• Andrea N. Loes

  Howard Hughes Medical Institute

  192 shared

• Rachel Eguia

  Fred Hutch Cancer Center

  154 shared

• David Veesler

  University of Washington

  118 shared

• Sarah K. Hilton

  University of Wisconsin–Madison

  100 shared

Labs

• UW Biological Physics, Structure and DesignPI

Education

• Ph.D., Virology

  University of California, San Francisco

  2001

• M.S., Virology

  University of California, San Francisco

  1997

• B.A., Molecular and Cell Biology

  University of California, Berkeley

  1994