About

Scott Hensley, PhD, is a Professor of Microbiology at the University of Pennsylvania's Perelman School of Medicine. His research focuses on influenza viruses, including H5N1 and seasonal influenza, as well as SARS-CoV-2. He investigates mechanisms that promote antigenic drift in influenza viruses, assesses population immunity against new strains with pandemic potential, and studies how childhood influenza exposures influence immune responses to seasonal and pandemic strains. His work aims to understand viral evolution, immune response heterogeneity, and vaccine development to improve viral vaccines and therapeutics. Hensley's laboratory conducts experiments to better understand influenza virus immune evasion, monitor the spread of influenza with pandemic potential, and develop new vaccine platforms. His research also explores how SARS-CoV-2 evolves in populations with heterogeneous immunity. He has contributed to understanding antibody responses, viral pathogenesis, and vaccine efficacy, with a particular interest in antigenic drift, viral receptors, and antibody specificity. His work is characterized by applying basic immunological and virological approaches to address pressing issues in infectious disease control.

Research topics

• Immunology
• Medicine
• Biology
• Virology
• Computer Science
• Internal medicine
• Pathology
• Genetics
• Molecular biology
• Computational biology

Selected publications

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

  2026-01-28

  peer-reviewOpen access

  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

• Reviewer #2 (Public review): High-throughput neutralization measurements correlate strongly with evolutionary success of human influenza strains

  2026-01-28

  peer-reviewOpen access

  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.

  PublisherOA PDFDOI

• Reviewer #1 (Public review): High-throughput neutralization measurements correlate strongly with evolutionary success of human influenza strains

  2026-01-28

  peer-reviewOpen access

  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

• Paternal immune activation protects offspring from severe disease during viral infection 3329

  The Journal of Immunology · 2025-11-01

  articleOpen access

  Abstract Description Maternal immune activation during gestation can influence offspring behavior and immunity. However, the influence of paternal immune activation (PIA) on progeny is understudied. Limited evidence indicates that PIA influences offspring behavior via alterations in epigenetic information carried within sperm. Yet, explorations into the impacts of PIA on offspring immunity are minimal. I have shown that PIA with or without viral replication remodels the epigenetic information within sperm by altering the small RNA profile. Moreover, we have demonstrated that PIA alters transcription in the early embryo, downregulating immune regulatory genes. To further explore the impacts of PIA, juvenile offspring from PIA or control males were infected with an adult lethal dose of Influenza A Virus. Offspring sired by PIA males had improved survival and less severe clinical outcomes during infection. Protection did not correlate with lower viral burden in the lungs, leading us to explore differences in immune mediated pathology. Altogether, inflammation in the father alters offspring immunity, providing protection during viral infection. We believe PIA mediated alterations to sperm small RNAs spark differential immune regulation as early as the preimplantation embryo, leading to protection from severe infection within offspring. This paradigm-altering finding uncovers a new mechanism in the evolutionary arms race between host and pathogen wherein immunity can be acquired within one generation. Funding Sources NSF GRFP The PEW Charitable Trust The David and Lucille Packard Foundation Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)

  PublisherOA PDFDOI

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

  eLife · 2025-06-03 · 4 citations

  preprintOpen access

  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

• Antigenic Characterization of H1N1 Influenza Viruses That Circulated During the 2019–2020 Season in Philadelphia, Pennsylvania

  Influenza and Other Respiratory Viruses · 2025-06-01

  articleOpen accessSenior authorCorresponding

  BACKGROUND: Multiple clades of H1N1 influenza A viruses (IAVs) circulated during the 2019-2020 season. Here, we completed serological assays to determine the specificities of serum antibodies from humans infected with viruses from different H1N1 clades during the 2019-2020 season. METHODS: We collected nasopharyngeal (NP) swabs and serum from influenza-infected individuals who received care within the University of Pennsylvania Health System (UPHS). We sequenced H1N1 viruses from NP swabs and completed hemagglutination inhibition assays using serum and viruses from different H1N1 clades that we identified from NP swabs. We also collected serum samples from influenza B virus (IBV)-infected patients at UPHS, allowing us to examine antibody titers associated with H1N1 versus IBV infection. RESULTS: Sequence analyses revealed that most IAV-infected individuals were infected with clade 6B.1A.5a.1 and 6B.1A.5a.2 H1N1 viruses that possessed substitutions at major antigenic sites of hemagglutinin. We found that antibodies from both H1N1- and IBV-infected individuals recognized the 6B.1A.1 H1N1 vaccine component of the 2019-2020 vaccine more efficiently compared to the circulating 6B.1A.5a.1 and 6B.1A.5a.2 H1N1 viruses. Patients infected with 6B.1A.5a.2 clade H1N1 viruses had significantly higher titers against the vaccine strain virus, suggesting that the 6B.1A.5a.2 virus evaded antibodies elicited from previous vaccinations or infections. CONCLUSIONS: These studies suggest that most individuals, irrespective of whether they were infected with H1N1 virus or IBV during the 2019-2020 season, possessed antibodies that poorly reacted to circulating H1N1 strains.

  PublisherOA PDFDOI

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

  2025-11-27

  peer-reviewOpen access

  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

• Author response for "Antigenic Characterization of H1N1 Influenza Viruses That Circulated During the 2019–2020 Season in Philadelphia, Pennsylvania"

  2025-03-15

  peer-reviewSenior author
  PublisherDOI

• An <i>Il12</i> mRNA-LNP adjuvant enhances mRNA vaccine–induced CD8 T cell responses

  Science Immunology · 2025-06-06 · 32 citations

  articleOpen access

  Optimizing vaccine design to induce CD8 T cell responses has been challenging, but lipid nanoparticle (LNP)–encapsulated mRNA vaccines effectively generate CD8 T cell memory. Interleukin-12 (IL-12) supports CD8 T cell expansion and acquisition of effector function, but the role of IL-12 in the generation of CD8 T responses to mRNA vaccination is unclear. Here, we determine that endogenous IL-12 is not required for CD8 T cell responses to mRNA-LNP vaccination. We assessed the adjuvant activity of an mRNA-LNP encapsulating a codon-optimized mRNA that encodes both subunits of IL-12 (LNP–IL-12). Coadministration of LNP–IL-12 with ovalbumin (OVA) mRNA-LNPs enhanced CD8 T cell expansion and effector function and expanded circulating, effector, and tissue-resident memory CD8 T cells. LNP–IL-12 increased CD8 T cell responses against SARS-CoV-2 and influenza virus antigens and improved protection against Listeria monocytogenes –OVA and B16F0-OVA melanoma. Thus, modification of mRNA-LNP formulations to include a cytokine mRNA provides a strategy to enhance CD8 T cell–mediated protection.

  PublisherOA PDFDOI

• H5 influenza virus mRNA-lipid nanoparticle (LNP) vaccination elicits adaptive immune responses in Holstein calves

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-05-01 · 8 citations

  preprint

  Abstract Highly pathogenic avian influenza (HPAI) clade 2.3.4.4b H5N1 is circulating widely in lactating cows in the United States. Due to the critical need for intervention strategies for this outbreak, we evaluated antibody and cellular immune responses of a clade 2.3.4.4b H5 mRNA-LNP vaccine in calves. We found that the H5 mRNA-LNP vaccine induced a robust antibody and CD8 + T cellular-mediated immune response and conferred protection against clade 2.3.4.4b H5N1 infection.

  PublisherDOI

Recent grants

• Training in Emerging Infectious Diseases

  NIH · $4.4M · 2003–2024

• NIH Grant R01AI113047

  NIH · $2.5M · 2020

• Impact of prior influenza exposures on antibody repertoires to new viral strains

  NIH · $3.7M · 2014–2024

• NIH Grant K22AI091651

  NIH · $270k · 2013

• Project 2: Durable impact of HCV on innate and adaptive immunity

  NIH · $75.5M · 2009–2029

Frequent coauthors

• E. John Wherry

  University of Pennsylvania

  143 shared

• Sigrid Gouma

  111 shared

• Laura A. Vella

  Children's Hospital of Philadelphia

  68 shared

• Allison R. Greenplate

  Translational Therapeutics (United States)

  65 shared

• Divij Mathew

  University of Pennsylvania

  65 shared

• Amy E. Baxter

  California University of Pennsylvania

  64 shared

• Josephine R. Giles

  University of Pennsylvania

  62 shared

• Madison E. Weirick

  University of Minnesota

  59 shared

Labs

• Hensley LaboratoryPI

Education

• B.A., Biology

  University of Delaware

  2000

• Ph.D., Cell and Molecular Biology

  University of Pennsylvania

  2006