Pathogenesis and Immunity Section
Established in 2009
Patrick E. Duffy, M.D. (He/Him/His)
- Novel malaria vaccine concepts
- Preclinical evaluation of vaccine candidates
- Clinical trials, both U.S. and international
- Immunologic, molecular, and entomologic assay development
The Vaccine Development Unit (VDU) conceives, produces, and tests novel malaria vaccine approaches. Since LMIV was launched in 2009, the team has emphasized malaria eradication as a vaccine goal, using a so-called vaccine to interrupt malaria transmission (VIMT). VIMT can include transmission-blocking, pre-erythrocytic, and potentially other components. In addition, VDU pursues concepts to protect pregnant women and their infants.
Transmission-Blocking Vaccines (TBV)
TBVs are unlike other malaria vaccine candidates: they do not protect recipients from infection or disease, and instead prevent infection of mosquitoes to reduce malaria in a community. LMIV has the world’s leading TBV candidate, named Pfs230D1, which induces antibodies that lyse parasites in the mosquito midgut. Pfs230D1 is currently in phase 2 clinical evaluation of safety and functional activity in Mali. We are also conducting clinical trials of TBVs throughout West Africa, in collaboration with partners from the Netherlands, Denmark, Mali, Burkina Faso, Liberia, and Guinea, to build on our success with Pfs230D1.
Pre-Erythrocytic Vaccines (PEV)
Pre-erythrocytic stage vaccines target sporozoite and liver stages that occur just after mosquitoes inject parasites (and just before disease-causing blood stage parasites develop). The GSK vaccine RTS,S is based on the sporozoite surface protein called CSP, and was approved by WHO in 2021 to reduce clinical malaria in young children. To improve on RTS,S vaccine, LMIV and partners have identified novel pre-erythrocytic antigens that enhance protection conferred by CSP in animal models, and are now producing these antigens suitable for testing in human studies.
LMIV works with local biotech Sanaria, Inc. to develop whole sporozoite vaccines. Sanaria manufactures sporozoites (called PfSPZ) suitable for human injection. LMIV and Mali colleagues conducted the first trials showing that Sanaria PfSPZ Vaccine (comprised of irradiated PfSPZ) protects adults from naturally occurring malaria. LMIV also assessed another approach—called “chemoprophylaxis vaccination”, in which live PfSPZ are inoculated while individuals receive antimalarial drugs. Phase 1 studies of this approach, called PfSPZ-CVac, achieved unprecedented durable sterile immunity in US volunteers. LMIV and partners are now conducting clinical field trials of PfSPZ-CVac, and seeking to understand the immunologic mechanism for PfSPZ-CVac potency.
Placental Malaria Vaccines
Placental malaria kills ~50,000 African mothers each year. Malaria-infected erythrocytes use the VAR2CSA surface antigen to bind chondroitin sulfate A (CSA) and sequester in the placenta, with dire sequelae for mothers and offspring. LMIV scientists have gleaned fundamental insights into VAR2CSA biology in recent years and are now developing novel VAR2CSA vaccine designs. LMIV recently reported a nonhuman primate model that recapitulates the features of malaria in pregnant women and is suitable for preclinical testing of VAR2CSA vaccine candidates.
In collaboration with Sanaria, Inc. and Mali colleagues, LMIV is preparing for the first trials of malaria vaccines in pregnant women. LMIV and Mali scientists have completed a trial of Sanaria’s PfSPZ Vaccine that vaccinated women before conception and examined its protective benefits during subsequent pregnancies. Future trials are under design that will assess PfSPZ Vaccine administered during pregnancy.
M.D., Duke University, Durham, NC
Dr. Duffy completed medical school at Duke University, internal medicine training at Walter Reed Army Medical Center, and postdoctoral research training in molecular vaccine development at NIAID. He now leads research teams that focus on malaria pathogenesis, immunity, and vaccine development. He has extensive experience leading human observational and interventional studies of malaria, as well as mentorship of young scientists in US and Africa. Together with his LMIV colleague Dr. Michal Fried, he conducted seminal studies that revealed the mechanistic basis for placental malaria infection and protective immunity. As the Chief of the Laboratory of Malaria Immunology and Vaccinology (LMIV) at NIH, he is responsible for the intramural NIAID program to develop and test malaria vaccines in clinical trials. Under his leadership, LMIV has developed the first malaria transmission-blocking vaccines to enter field trials, has partnered with the local biotech Sanaria to conduct the first field efficacy trials of whole organism malaria vaccines, and is now pioneering a path in partnership with Mali colleagues to test the most promising malaria vaccines in pregnant women. Before taking the position at LMIV in Nov 2009, he served as Malaria Program Director at Seattle Biomedical Research Institute (now part of Seattle Children’s Research Institute), and as Affiliate Professor of Pathobiology and of Global Health at the University of Washington. In Seattle, at NIH, and in Mali, he and his partners established facilities for controlled human malaria infection (CHMI) studies with P. falciparum or P. vivax, and while at NIH, he has pioneered the use of mosquito feeding studies on human subjects as an endpoint for field trials of vaccines that will be used for malaria elimination.
Transmission Blocking Vaccines
- Testing Pfs25-EPA/Alhydrogel as a Potential Malaria Transmission Blocking Vaccine
- ClinicalTrials.gov ID NCT01867463
- Key words: Malaria, transmission blocking vaccine
- Study of the Safety and Immunogenicity of Pfs230D1M-EPA/Alhydrogel and Pfs25M-EPA/Alhydrogel , a Transmission Blocking Vaccine Against Plasmodium Falciparum Malaria, in Adults in the U.S. and Mali
- ClinicalTrials.gov ID NCT02334462
- Key words: Malaria, transmission blocking vaccine, Pfs25, Pfs230, Alhydrogel, United States, Mali
- Safety and Immunogenicity of Pfs25M-EPA/AS01 and Pfs230D1M-EPA/AS01 Vaccines, Transmission Blocking Vaccines Against Plasmodium Falciparum, at Full and Fractional Dosing in Adults in Mali
- ClinicalTrials.gov ID NCT02942277
- Pfs230D1M-EPA/AS01 Vaccine, a Transmission Blocking Vaccine Against Plasmodium Falciparum, in an Age De-Escalation Trial of Children and a Family Compound Trial in Mali
- ClinicalTrials.gov ID NCT03917654
- Key words: Malaria, transmission blocking vaccine, Pfs230, AS01, children, Mali o Key words: Malaria, transmission blocking vaccine, Pfs25, Pfs230, Mali
- Study of the Transmission-Blocking Vaccine Pfs230D1-EPA/Matrix-M Against Malaria in Adults in Mali
- ClinicalTrials.gov ID NCT05135273
- Key words: Malaria, transmission blocking vaccine, Pfs230, Matrix-M, Mali
- PfSPZ Vaccine: Dose Optimization With Heterologous Challenge in Healthy Malaria-Naïve Adults
- ClinicalTrials.gov ID NCT02601716
- Key words: PfSPZ Vaccine, Dose optimization, Heterologous challenge
- Safety, Immunogenicity, and Protective Efficacy of Radiation Attenuated Plasmodium Falciparum NF54 Sporozoites in Healthy African Adults in Mali
- ClinicalTrials.gov ID NCT02627456
- Key words: Radiation attenuated sporozoites, Mali
- Safety, Immunogenicity, and Protective Efficacy of Two Regimens of Radiation Attenuated Plasmodium Falciparum NF54 Sporozoites (PfSPZ Vaccine) During Natural Transmission Season in Healthy African Adults in Mali
- ClinicalTrials.gov ID NCT03510481
- Key words: Radiation attenuated sporozoites, PfSPZ Vaccine, Natural Transmission, Mali
- Safety, Immunogenicity, and Protective Efficacy of Radiation Attenuated Plasmodium Falciparum NF54 Sporozoites (PfSPZ Vaccine) During Malaria Transmission Season in Healthy African Adult Women of Childbearing Potential in Mali
- ClinicalTrials.gov ID NCT03989102
- Key words: Radiation attenuated sporozoite, Mali, Women of Childbearing Potential
- PfSPZ Vaccine Trial in Malian Children
- ClinicalTrials.gov ID NCT04940130
- Key words: Malaria, PfSPZ Vaccine, Children, Mali
- Sanaria PfSPZ Challenge With Pyrimethamine Chemoprophylaxis (PfSPZ-CVac Approach): Phase 1 Trial to Determine Safety and Protective Efficacy of Sanaria PfSPZ Challenge With Concurrent Pyrimethamine Treatment That Inhibits Development of Asexual Blood Stages of Plasmodium Falciparum
- ClinicalTrials.gov ID NCT02511054
- Key words: Malaria, chemoprophylaxis vaccination, PfSPZ-CVac, pyrimethamine, United States
- Dose Escalation PfSPZ-CVac
- ClinicalTrials.gov ID NCT03083847
- Key words: Malaria, PfSPZ-CVac, Dose-escalation
- Sanaria PfSPZ Challenge With Pyrimethamine or Chloroquine Chemoprophylaxis Vaccination (PfSPZ-CVac Approach): A Randomized Double Blind Placebo Controlled Phase I/II Trial to Determine Safety and Protective Efficacy Against Natural Plasmodium Falciparum Infection in Bancoumana and Surrounding Areas, Mali
- ClinicalTrials.gov ID NCT03952650
- Key words: Malaria, PfSPZ Challenge, chemoprophylaxis vaccination, pyrimethamine, PfSPZ-CVac, chloroquine, Mali
- Host and Parasite Factors That Influence Susceptibility to Malaria Infection and Disease During Pregnancy and Early Childhood in Ouelessebougou and Bamako, Mali
- ClinicalTrials.gov ID NCT01168271
- Key words: Malaria, Pregnancy, Childhood, Mali
- Impact of Malaria on Pregnant Women in Ouelessebougou, Mali
- ClinicalTrials.gov ID NCT02974608
- Key words: Malaria, pregnant women, Mali
Sissoko MS, Healy SA, Katile A, Zaidi I, Hu Z, Kamate B, Samake Y, Sissoko K, Mwakingwe-Omari A, Lane J, Imeru A, Mohan R, Thera I, Guindo CO, Dolo A, Niare K, Koïta F, Niangaly A, Rausch KM, Zeguime A, Guindo MA, Bah A, Abebe Y, James ER, Manoj A, Murshedkar T, Kc N, Sim BKL, Billingsley PF, Richie TL, Hoffman SL, Doumbo O, Duffy PE. Safety and efficacy of a three-dose regimen of Plasmodium falciparum sporozoite vaccine in adults during an intense malaria transmission season in Mali: a randomised, controlled phase 1 trial. Lancet Infect Dis. 2022 Mar;22(3):377-389.
Mwakingwe-Omari A, Healy SA, Lane J, Cook DM, Kalhori S, Wyatt C, Kolluri A, Marte-Salcedo O, Imeru A, Nason M, Ding LK, Decederfelt H, Duan J, Neal J, Raiten J, Lee G, Hume JCC, Jeon JE, Ikpeama I, Kc N, Chakravarty S, Murshedkar T, Church LWP, Manoj A, Gunasekera A, Anderson C, Murphy SC, March S, Bhatia SN, James ER, Billingsley PF, Sim BKL, Richie TL, Zaidi I, Hoffman SL, Duffy PE. Two chemoattenuated PfSPZ malaria vaccines induce sterile hepatic immunity. Nature. 2021 Jul;595(7866):289-294.
Healy SA, Anderson C, Swihart BJ, Mwakingwe A, Gabriel EE, Decederfelt H, Hobbs CV, Rausch KM, Zhu D, Muratova O, Herrera R, Scaria PV, MacDonald NJ, Lambert LE, Zaidi I, Coelho CH, Renn JP, Wu Y, Narum DL, Duffy PE. Pfs230 yields higher malaria transmission-blocking vaccine activity than Pfs25 in humans but not mice. J Clin Invest. 2021 Apr 1;131(7):e146221.
Sagara I, Healy SA, Assadou MH, Gabriel EE, Kone M, Sissoko K, Tembine I, Guindo MA, Doucoure M, Niaré K, Dolo A, Rausch KM, Narum DL, Jones DL, MacDonald NJ, Zhu D, Mohan R, Muratova O, Baber I, Coulibaly MB, Fay MP, Anderson C, Wu Y, Traore SF, Doumbo OK, Duffy PE. Safety and immunogenicity of Pfs25H-EPA/Alhydrogel, a transmission-blocking vaccine against Plasmodium falciparum: a randomised, double-blind, comparator-controlled, dose-escalation study in healthy Malian adults. Lancet Infect Dis. 2018 Sep;18(9):969-982.
Zaidi I, Diallo H, Conteh S, Robbins Y, Kolasny J, Orr-Gonzalez S, Carter D, Butler B, Lambert L, Brickley E, Morrison R, Sissoko M, Healy SA, Sim BKL, Doumbo OK, Hoffman SL, Duffy PE. γδ T Cells Are Required for the Induction of Sterile Immunity during Irradiated Sporozoite Vaccinations. J Immunol. 2017 Dec 1;199(11):3781-3788.
Sissoko MS, Healy SA, Katile A, Omaswa F, Zaidi I, Gabriel EE, Kamate B, Samake Y, Guindo MA, Dolo A, Niangaly A, Niaré K, Zeguime A, Sissoko K, Diallo H, Thera I, Ding K, Fay MP, O'Connell EM, Nutman TB, Wong-Madden S, Murshedkar T, Ruben AJ, Li M, Abebe Y, Manoj A, Gunasekera A, Chakravarty S, Sim BKL, Billingsley PF, James ER, Walther M, Richie TL, Hoffman SL, Doumbo O, Duffy PE. Safety and efficacy of PfSPZ Vaccine against Plasmodium falciparum via direct venous inoculation in healthy malaria-exposed adults in Mali: a randomised, double-blind phase 1 trial. Lancet Infect Dis. 2017 May;17(5):498-509.
APTI: African Postdoctoral Training Initiative
The Pathogenesis and Immunity Section conducts human and animal studies of malaria pathogenesis and host immunity, including population-based studies in communities exposed to Plasmodium falciparum. Our research emphasizes pregnant women and children, the populations most susceptible to malaria morbidity and mortality, with collaborative cohort studies ongoing in Mali, Liberia and Guinea.