About

Dr. Sean Murphy is an Associate Professor at the University of Washington in the Department of Laboratory Medicine. His work focuses on the immune response to complex infectious diseases and on diagnostic test development, with a major emphasis on malaria infection caused by Plasmodium parasites. His laboratory studies the protective immune responses induced by immunizations with attenuated Plasmodium sporozoites, aiming to identify protective antigens and develop multi-component subunit vaccines targeting the pre-erythrocytic stage of malaria infection. These efforts are directed toward accelerating malaria elimination and eradication worldwide. Dr. Murphy collaborates with various institutions, including the Fred Hutch Cancer Research Center and the Seattle Biomed Malaria Clinical Trials Center, where he helps conduct controlled human malaria infection studies to identify effective malaria drug and vaccine candidates. He also develops and supports molecular diagnostic assays for malaria, recognized as some of the most sensitive globally, and promotes quality assurance initiatives among international CHMI centers. His research extends to exploring novel methods for inducing broadly protective immune responses and applying these tools to other infectious and autoimmune diseases, with a focus on improving both human and livestock health.

Research topics

• Biology
• Virology
• Computer Science
• Political Science
• Sociology
• Medicine
• Cell biology
• Immunology
• Philosophy
• Engineering
• Pathology
• Environmental ethics
• Genetics
• Biochemistry
• Engineering ethics
• Molecular biology
• Chemistry

Selected publications

• Sex-based differences in Plasmodium infection in the control groups of controlled human malaria infection trials in malaria-naive populations in the USA and the Netherlands: a pooled analysis

  The Lancet Microbe · 2026-01-13 · 1 citations

  articleOpen accessSenior author

  BACKGROUND: Before infecting red blood cells and causing the clinical manifestations of malaria, the hepatotropic parasite Plasmodium falciparum completes a complex liver stage. Sex-based differences in pathogenesis by hepatotropic micro-organisms are well documented but unstudied for P falciparum in humans. We aimed to evaluate the effect of sex on the time to blood-stage positivity and initial blood-stage parasite densities as indicators of liver-stage dynamics and parasite replication. METHODS: We conducted a pooled analysis of data from malaria-naive participants in control groups from controlled human malaria infection (CHMI) studies conducted between Jan 1, 2010, and Dec 31, 2024, in which samples were tested using Plasmodium 18S ribosomal RNA nucleic acid amplification tests (18S NAATs) at laboratories in Seattle (WA, USA) and Leiden (Netherlands). Participants aged 18-48 years were eligible for inclusion if they were in placebo or infectivity control groups in any CHMI study at the two laboratories and developed parasitaemia following CHMI. Patient demographics and 18S NAAT data were obtained from study leads at each centre and collated, standardised, and reviewed. Information on P falciparum strain, challenge route, and sampling schedule were extracted from study protocols or publications. The main outcome, time to positivity (TTP), was calculated as the study day of the first positive 18S NAAT of any density, measured during a 28-day monitoring period following CHMI. Using an interval-censored generalised gamma accelerated failure time model, we compared time to blood-stage positivity by sex, adjusting for challenge route, P falciparum strain, and study site. Odds of developing detectable infection after 7 days post-challenge was compared between male and female participants using a linear mixed-effects model adjusted for the same terms. FINDINGS: =31% [95% CI 0-57]). There were no notable demographic differences between male and female participants regarding age, challenge route, or strain. The mean time to first detectable parasitaemia was slightly longer in male participants (7·59 days [SD 1·15]) than in female participants (7·17 days [0·91]). Adjusted accelerated failure time analysis suggested that TTP occurred 8% later in male participants than female participants (time ratio 1·08 [1·03-1·16]). Male participants were significantly more likely than female participants to have a detectable infection after day 7 (19 [35%] of 54 male participants vs six [13%] of 48 female participants), with adjusted odds of delayed infection 5·20 times (95% CI 1·52-17·70) higher in male than female participants. INTERPRETATION: Our findings suggest that male individuals are more likely to have a delayed detection of blood-stage parasites following CHMI with P falciparum compared with female individuals. Although the inability to directly measure liver-stage burden is a limitation, CHMI offers a controlled system to infer liver-stage dynamics. Thus, P falciparum infection is likely to involve a sex-specific host-pathogen interaction in the liver, emphasising the importance of considering sex as a biological variable in liver-targeting clinical interventions. FUNDING: The Gates Foundation and the University of Washington.

  PublisherOA PDFDOI

• SIMPLseq: a high-sensitivity <i>Plasmodium falciparum</i> genotyping and PCR contamination tracking tool

  medRxiv · 2025-11-06

  preprintOpen access

  Abstract Background Pathogen genotyping via polymerase chain reaction (PCR) amplicon sequencing (AmpSeq) is an informative disease surveillance tool. Several large AmpSeq panels containing &gt;100 multiplexed PCR amplicons have been developed as alternatives to whole-genome sequencing (WGS) methods for the Plasmodium spp. parasites that cause malaria, especially for parasite drug resistance tracking and relatedness analysis. However, these large multiplexes often require a costly pre-amplification stage and typically yield sparse data for samples with parasitemia below 10 parasites/μl. Smaller multiplexes optimized for low-parasitemia genotyping have received insufficient methodological work but have the potential to serve multiple important applications. Managing contamination risk during PCR steps represents another key methodological gap that requires attention in the AmpSeq field. Methods Here we describe a new 6-locus Plasmodium falciparum AmpSeq ‘miniplex’ (SIMPLseq) optimized for high-sensitivity analyses that also integrates a contamination detection system based on well-specific inline barcodes applied during first-round PCR (PCR1; in addition to conventional indexing steps in the second-round PCR). We assess panel diversity using publicly available WGS and use mock samples to estimate sensitivity and precision relative to 4CAST, a previously described miniplex. We also create deliberate contamination events to assess sensitivity and estimate unintentional contamination rates during assay application to malaria-infected dried blood spots collected in Mali. Results SIMPLseq shows high haplotypic diversity in silico , distinguishing 96.0% of sample pairs drawn randomly from 12 subnational sample sets. SIMPLseq outperforms 4CAST in sensitivity analyses, achieving 100% average locus detection at ≥0.5 parasites/μl and ≥50% average locus detection at 0.25 and 0.125 parasites/μl, with zero false-positive haplotypes across 25 replicates. Inline barcoding did not significantly affect yield when using a ‘sentinel’ design, whereby one of the six multiplexed PCR1 primer pairs contains the well-specific sequence pair. Sentinel barcoding correctly identified all 24 contaminations introduced deliberately during PCR1 product handling and identified 39 unintentional contaminations in the 1420-sample Malian run. Conclusions SIMPLseq significantly extends the malaria genomic epidemiology toolkit, employing a simple laboratory protocol based on entirely open-source reagents that is significantly more sensitive and also less costly than most other targeted sequencing protocols. Key use cases for SIMPLseq include recurrent infection classification, polyclonality estimation, and genotypic infection endpoints in intervention efficacy trials.

  PublisherOA PDFDOI

• Cytokines Associated With Moderate and Severe Adverse Events During a Sporozoite Malaria Vaccine Trial With Controlled Human Malaria Infection

  The Journal of Infectious Diseases · 2025-08-13

  article

  Ensuring the safety and efficacy of candidate vaccines is critical. Although mechanisms underpinning protective immune responses to malaria vaccines are frequently investigated, immune responses correlating with moderate and severe adverse events (AEs) are rarely examined. Here, we leverage a malaria vaccine trial with a higher-than-expected AE rate and frequent sampling to investigate cytokine profiles associated with AEs. We found that Interleukin-6 was elevated on days in which individuals experienced moderate and severe AEs. More research on immune responses associated with AEs is warranted in order to identify biomarkers associated with systemic reactogenicity and accelerate vaccine development.

  PublisherDOI

• WHO malaria nucleic acid amplification test external quality assessment scheme: results of eleven distributions over 6 years

  Malaria Journal · 2025-03-23

  articleOpen access

  BACKGROUND: The World Health Organization (WHO) recommends parasite-based diagnosis of malaria before treatment. The use of nucleic-acid amplification (NAAT) for detection of Plasmodium spp. has expanded rapidly in recent years, for epidemiological research globally and clinical care in high-resource settings. Data from NAATs are frequently used to inform policy decisions, so quality control is essential to ensure results are reliable and comparable. Therefore, robust quality control, including an external quality assessment (EQA) scheme targeting malaria NAATs, is essential. The WHO Global Malaria Programme and the UK National External Quality Assessment Service (UK NEQAS) have collaborated since 2017 to implement a global malaria NAAT EQA scheme. METHODS: Panels of specimens containing five major species of human-infecting Plasmodium at various parasite concentrations and negative samples were created in lyophilized blood (LB) and dried blood spot (DBS) formats. Two distributions per year were sent, containing five LB and five DBS specimens. Samples were validated by expert referee laboratories prior to distribution. Between 37 and 51 laboratories participated in each distribution and submitted results online. Participants were scored based on their laboratory's stated capacity to identify Plasmodium species, and individual laboratory reports were sent which included performance comparison with anonymized peers. Change in performance over time was calculated using a generalized mixed model with a logit link function. RESULTS: Participating laboratories were located in 42 countries. Sample format (DBS or LB) and parasite density were found to significantly affect performance, while referee labs performed better at identifying P. falciparum samples than non-referee labs. Performance of laboratories improved significantly over time, especially for lower density and P. falciparum samples. CONCLUSIONS: Results from the first eleven distributions indicate that the EQA scheme has facilitated improved performance of laboratories over time, highlighting the value of implementing such programmes. EQA schemes are critical to safeguarding the reliability of data and diagnoses, especially in situations where NAAT methodologies and protocols are used. In future, funders should make participation in an EQA scheme a requirement for laboratories, and countries can take initiatives to embed such schemes into their own national assessment programmes.

  PublisherOA PDFDOI

• Androgens inhibit protective CD8+ T cell responses against pre-erythrocytic malaria parasites in mice

  Nature Communications · 2025-06-04 · 3 citations

  articleOpen accessSenior author

  Attenuated whole organism vaccines targeting the malaria liver stage reliably confer sterile immunity. These vaccines completely protect female mice from infection, but protection in male mice remains unproven. We discover that male mice vaccinated with prime-and-trap, a whole organism-based vaccine strategy, exhibit poorer protection against Plasmodium sporozoite challenge than females. We investigate this sex difference, and identify vaccinated males have fewer hepatic memory CD8+ T cells than females when scaling for liver biomass, and reduced inflammatory responses post-vaccination. Surgical hormone manipulation clarifies that the presence of testicular hormones hinders protection in male mice. The presence of androgens does not affect memory CD8+ T cell quantity nor quality, but reduces recruitment of CD8+ T cells in male liver tissues via a restricted inflammatory response. Here, we show both males and females form functional memory responses following prime-and-trap vaccination, but the presence of androgens during sporozoite challenge impair protection in male mice. In vaccination there may be differences between the sexes in terms of protection. Here the authors show that male mice are less well protected by Plasmodium liver stage vaccines compared to female mice and this is due to lower hepatic memory CD8+ T cell density and reduced recruitment of these memory T cells, which are affected by the presence of testicular hormones.

  PublisherOA PDFDOI

• Distinguishing new from persistent infections at the strain level using longitudinal genotyping data

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-08

  preprintOpen access

  Motivation: Longitudinal pathogen genotyping data from individual hosts can uncover strain-specific infection dynamics and their relationships to disease and intervention, especially in the malaria field. An important use case involves distinguishing newly incident from pre-existing (persistent) strains, but implementation faces statistical challenges relating to individual samples containing multiple strains, strains sharing alleles, and markers dropping out stochastically during the genotyping process. Current approaches to distinguish new versus persistent strains therefore rely primarily on simple rules that consider only the time since alleles were last observed. Results: eries), a set of statistical methods to estimate, from longitudinal genotyping data, the probability each sequenced allele represents a new infection harboring that allele, the total molecular force of infection (molFOI, the cumulative number of newly acquired strains over time) for each individual, and the total number of new infection events for each individual. DINEMITES can handle time points with missing sequencing data, incorporate treatment history and covariates affecting the rate of new or persistent infections, and can scale to studies with thousands of samples sequenced across multiple loci containing hundreds of possible alleles. In synthetic evaluations, the DINEMITES Bayesian model, which generally outperformed an alternative clustering-based model also developed in this work, accurately estimated key clinical parameters such as molFOI (bias 2.5, compared to -12.2 for a typical simple rule). When applied to three real longitudinal genotyping datasets, the model detected 33%, 112%, and 359% more average infections per participant than would have been detected by applying a typical simple rule to the equivalent datasets without sequencing.

  PublisherDOI

• Anti-sporozoite monoclonal antibody for malaria prevention: secondary efficacy outcome of a phase 2 randomized trial

  Nature Medicine · 2025-06-03 · 7 citations

  articleOpen access

  Abstract CIS43LS is a long-acting monoclonal antibody specific for the Plasmodium falciparum circumsporozoite protein expressed on sporozoites. We previously reported that CIS43LS is protective against P. falciparum infection as detected by thick blood smear (TBS; primary endpoint) in a phase 2 double-blind randomized trial involving 330 healthy Malian adults receiving placebo or a single intravenous infusion of 10 mg kg −1 or 40 mg kg −1 of CIS43LS (1:1:1). At enrollment, all participants received artemether–lumefantrine to clear possible P. falciparum infection. Although TBS examination is the standard assay to assess efficacy in malaria vaccines trials in endemic areas, it has poor analytical sensitivity; therefore, it remained unknown whether CIS43LS had achieved sterile protection against infection. Here we report the prespecified secondary efficacy endpoint that used a Plasmodium 18S rRNA quantitative reverse transcription–PCR (qRT–PCR) assay that is ~2,000-fold more sensitive than TBS. We analyzed 5,015 dried blood spots collected before CIS43LS or placebo administration and biweekly thereafter over a 6-month malaria season. At 6 months, efficacy of CIS43LS against qRT–PCR-detected infection assessed in a time-to-event analysis was 87.4% for 40 mg kg −1 (adjusted 95% confidence interval (CI), 79.5–92.3; P &lt; 0.001) and 77.0% for 10 mg kg −1 (adjusted 95% CI, 65.0–84.0; P &lt; 0.001) versus placebo. A post hoc analysis with a gametocyte mRNA-specific qRT–PCR assay showed 6-month efficacy against gametocytemia of 87.7% for 40 mg kg −1 (adjusted 95% CI, 75.6–93.8; P &lt; 0.001) and 73.0% for 10 mg kg −1 (adjusted 95% CI, 54.0–84.0; P &lt; 0.001), versus placebo. These data indicate that a single dose of anti-sporozoite monoclonal antibodies can achieve durable, sterile protection against P. falciparum infection, underscoring their potential to reduce malaria disease burden and transmission. ClinicalTrials.gov identifier: NCT04329104 .

  PublisherOA PDFDOI

• Sex-Based Differences to Plasmodium Infection in the Placebo Arms of Controlled&amp;nbsp;Human Malaria Infection (CHMI) Trials in Malaria-Naïve Populations: A Pooled Analysis

  SSRN Electronic Journal · 2025-01-01 · 1 citations

  preprintOpen accessSenior author
  PublisherDOI

• Systemic trafficking of mRNA lipid nanoparticle vaccine following intramuscular injection generates potent tissue-specific T cell response

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-24

  preprintOpen access

  Abstract The mRNA lipid nanoparticles (LNPs) represent a new generation of vaccine carriers designed to elicit potent immune responses against infectious diseases and cancer. Despite the clinical success and rapid advancements in mRNA LNP technologies, the trafficking patterns of LNPs after intramuscular (i.m.) administration and the subsequent tissue-specific immunological effects have not been systematically characterized. Here, we report that trafficking of mRNA LNPs to different organs following i.m. injection is crucial for the induction of tissue-specific immunity beyond systemic immune response, particularly in tissue-resident CD8 + T cell generation, which is important for localized defense. By fine-tuning the composition of mRNA LNPs, trafficking patterns to systemic organs can be modulated, which can alter the resulting tissue-specific immune response. Formulations with a greater ability to enter the bloodstream can preferentially localize and transfect cells in specific organs like the liver, elicit stronger tissue-specific CD8 + T cell immune responses, and achieve enhanced efficacy in a liver tumor model. These findings highlight the potential to tailor mRNA LNP compositions to modulate trafficking following i.m. injection, thereby providing novel strategies for designing tissue-specific vaccines. Such strategies are particularly valuable for organ-specific diseases like cancer and infectious diseases, where tissue targeting and long-lasting immunity are essential for therapeutic success.

  PublisherOA PDFDOI

• Assessing the daily natural history of asymptomatic Plasmodium infections in adults and older children in Katakwi, Uganda: a longitudinal cohort study

  The Lancet Microbe · 2024-01-01 · 12 citations

  articleOpen accessSenior authorCorresponding

  BACKGROUND: Low-density asymptomatic Plasmodium infections are prevalent in endemic areas, but little is known about their natural history. The trajectories of these infections and their propensity to fluctuate to undetectable densities can affect detection in clinical trials and field studies. We aimed to classify the natural history of these infections in a high transmission area over 29 days. METHODS: In this longitudinal cohort study, we enrolled healthy, malaria-asymptomatic, afebrile, adults (age 18-59 years) and older children (age 8-17 years) in Katakwi District, Uganda, who were negative for Plasmodium infection on rapid diagnostic tests. Participants were instructed to self-collect one dried blood spot (DBS) per day for a maximum of 29 days. We excluded people if they were pregnant or taking antimalarials. During weekly clinic visits, staff collected a DBS and a 4 mL sample of venous blood. We analysed DBSs by Plasmodium 18S rRNA quantitative RT-PCR (qRT-PCR). We classified DBS by infection type as negative, P falciparum, non-P falciparum, or mixed. We plotted infection type over time for each participant and categorised trajectories as negative, new, cleared, chronic, or indeterminate infections. To estimate the effect of single timepoint sampling, we calculated the daily prevalence for each study day and estimated the number of infections that would have been detected in our population if sampling frequency was reduced. FINDINGS: Between April 9 and May 20, 2021, 3577 DBSs were collected by 128 (40 male adults, 60 female adults, 12 male children, and 16 female children) study participants. 2287 (64%) DBSs were categorised as negative, 751 (21%) as positive for P falciparum, 507 (14%) as positive for non-P falciparum, and 32 (1%) as mixed infections. Daily Plasmodium prevalence in the population ranged from 45·3% (95% CI 36·6-54·1) at baseline to 30·3% (21·9-38·6) on day 24. 37 (95%) of 39 P falciparum and 35 (85%) of 41 non-P falciparum infections would have been detected with every other day sampling, whereas, with weekly sampling, 35 (90%) P falciparum infections and 31 (76%) non-P falciparum infections would have been detected. INTERPRETATION: Parasite dynamics and species are highly variable among low-density asymptomatic Plasmodium infections. Sampling every other day or every 3 days detected a similar proportion of infections as daily sampling, whereas testing once per week or even less frequently could misclassify up to a third of the infections. Even using highly sensitive diagnostics, single timepoint testing might misclassify the true infection status of an individual. FUNDING: US National Institutes of Health and Bill and Melinda Gates Foundation.

  PublisherOA PDFDOI

Recent grants

• A Pilot Study to Evaluate Plasmodium falciparum Liver-Stage Challenge in Prime-and-Trap Vaccinated Rhesus Monkeys

  NIH · $88k · 2019–2020

• Development of an oral liver-targeted prime-and-trap malaria vaccine

  NIH · $4.1M · 2020–2026

• Liver resident memory for malaria

  NIH · $3.9M · 2018–2024

• Liver-stage Plasmodium protein export to the host cell to inform vaccine design.

  NIH · $485k · 2019–2022

• NIH Grant K08AI097238

  NIH · $633k · 2016

Frequent coauthors

• Stefan H. I. Kappe

  University of Washington

  75 shared

• James G. Kublin

  Fred Hutch Cancer Center

  66 shared

• Sara A. Healy

  National Institute of Allergy and Infectious Diseases

  58 shared

• Annette M. Seilie

  University of Washington

  57 shared

• Kasturi Haldar

  University of Notre Dame

  55 shared

• Travis Harrison

  Precision for Medicine (United States)

  53 shared

• Narla Mohandas

  53 shared

• David W. Speicher

  49 shared

Education

• Clinical Pathology residency, Laboratory Medicine

  University of Washington

  2011

• MD/PhD (PhD in Microbiology/Immunology)

  Northwestern University

  2008

• Post-graduate degree in African Studies, Centre for African Studies

  University of Cape Town

  2000

• B.S. - Microbiology

  Iowa State University

  1999