IDCRC Investigator Profile: Sean C. Murphy, MD

Sean C. Murphy, MD, PhD, is an assistant director of clinical microbiology and associate professor of laboratory medicine at the University of Washington (UW) School of Medicine. Dr. Murphy’s work focuses on the immune response to complex infectious diseases and on diagnostic test development. The major focus of the laboratory is malaria infection of humans and animal models by Plasmodium parasites.

Dr. Murphy currently serves as the protocol co-chair for the Phase 1 Clinical Trial for Experimental Malaria Vaccine (LARC2 Study). Read more about this study here.

How long have you worked with a VTEU?

I have been involved with the UW and Kaiser VTEUs since 2015 and have been a member of the Malaria Expert Working Group throughout this current funding cycle.

Can you share more about a current IDCRC study you're working on?

At the UW VTEU, we are running the VTEU 23-0010 Sanaria PfSPZ-LARC2 Vaccine study, a double-blind, placebo-controlled trial of a late-attenuated sporozoite vaccine using the controlled human malaria infection, or Controlled Human Malaria Infection Experience (CHMI) model. This plasmodium falciparum vaccine candidate is hypothesized to be more immunogenic and protective than early-arresting irradiated sporozoite vaccines because it fully develops in hepatocytes, thereby expressing thousands of unique antigens that can be the targets of humoral and, importantly, cellular immune responses that contribute to complete protection against liver-stage Plasmodium infection.

The CHMI model is an incredibly valuable clinical trial approach that allows us to rapidly evaluate protection against challenge here in non-endemic Seattle, thereby giving us an early indicator of vaccine protective efficacy. In addition to being one of the protocol chairs, my molecular diagnostic laboratory at the University of Washington (Malaria Molecular Diagnostic Laboratory, MMDL) performs all of the efficacy endpoints using our highly sensitive reverse transcription PCR (RT-PCR) for Plasmodium 18S rRNA that we have used for over a decade to support CHMI studies in Seattle, as well as thick blood smears that were required by regulators for this particular study. Read about IDCRC Studies 

Briefly describe the IDCRC-supported trials you’ve supported.

Of these trials, what has been the most impactful or a highlight of the work?

The three studies noted above all utilized sporozoite-based vaccines. These vaccines are very different from subunit vaccines consisting of just a few proteins or nucleic acids encoding proteins. In my pre-clinical research laboratory at UW, we are working very hard to make an elegant subunit vaccine by trying to identify key protective immunogens, develop novel adjuvants, and select the best vaccine modality to achieve protection with just a handful of antigens. In contrast, sporozoites (even early arresting sporozoites) express >1000 unique antigens and leverage the biology of the parasite to target the liver and induce liver-specific immunity. While sporozoites require unique manufacturing and administration, the VTEU studies that I have been involved in definitely highlight the high rates of protection that can be achieved with sporozoite vaccines and set the bar very high for subunit vaccines.

Through studies within and beyond the VTEU, our MMDL team has also been able to advance Plasmodium 18S rRNA molecular diagnostic testing as a gold standard for malaria clinical trials. Although the regulatory pathway has at times been problematic, we conducted CHMI studies for a decade using molecular diagnostic testing without blood smears and leveraged our testing not just for CHMI studies but also for field studies in malaria-endemic areas that have revealed the natural history of prevalent asymptomatic infections. More sensitive molecular testing allows us to see infections that would otherwise be completely invisible by less sensitive tests, resulting in better and more accurate endpoints and a better ability to judge the protective effect of candidate drugs, vaccines, and therapeutics. 

What is a strength or example of the importance of the IDCRC during the pandemic and beyond?

Because of the collaboration across IDCRC, NIH, and the VTEUs, we are able to continue to advance malaria vaccines critical to maintain support and focus in our collective fight against this hugely important parasite. Malaria is mostly thought of as a tropical disease, but it is important to remember that 100 years ago there were over one million cases annually in the U.S. (i.e., the conditions can exist for transmission here) and even this year and in the past few years there have been cases of malaria transmitted by local mosquitoes in the U.S. to Americans who had not traveled outside of the U.S.   

What do you like to do outside of the VTEU?

I lead a research group that studies malaria vaccines and diagnostics, and I serve as a clinical pathologist and medical director at UW and Seattle Children's. My clinical pathology area of interest is (not surprisingly) microbiology, and especially parasitology. Outside of these academic and clinical pursuits, I love to spend time with my two boys, my wife, and our dog kayaking, hiking, boating, cooking, and enjoying the Pacific Northwest and beyond.