Background: Chimeric mice with humanized livers represent a promising tool for infections with Pl... more Background: Chimeric mice with humanized livers represent a promising tool for infections with Plasmodium falciparum to evaluate novel methods for prevention and treatment of pre-erythrocytic stages. Adequate assessment of hepatic infections is generally compromised by the limited number of human hepatocytes infected by developing parasites. Methods: A qPCR-based method has been developed that sensitively and reliably detects P. falciparum liver stage infection of humanized mice and quantitatively expresses the results as the number of parasites per human hepatocyte. Results: This assay allows for detection of liver stage parasites after challenging humanized mice with infected mosquito bites or after intravenous injection with sporozoites. The sensitivity of the protocol, which comprises approximately 25% of the total chimeric liver, allows for the detection of a single infected hepatocyte in the analysed tissue.
Malaria, which is the result of Plasmodium falciparum infection, is a global health threat that r... more Malaria, which is the result of Plasmodium falciparum infection, is a global health threat that resulted in 655,000 deaths and 216 million clinical cases in 2010 alone. Recent phase 3 trials with malaria vaccine candidate RTS,S/AS01 (RTS,S) in children has demonstrated modest efficacy against clinical and severe malaria. RTS,S targets the pre-erythrocytic phase of the disease and induces high antibody titers against the P. falciparum circumsporozoite protein (CSP) and a moderate CD4 + T cell response. The individual contribution of these adaptive immune responses to protection from infection remains unknown. Here, we found that prophylactic administration of anti-CSP mAbs derived from an RTS,S-vaccinated recipient fully protected mice with humanized livers from i.v.-and mosquito bite-delivered P. falciparum sporozoite challenge. Titers of anti-CSP that conveyed full protection were within the range observed in human RTS,S vaccine recipients. Increasing anti-CSP titers resulted in a dose-dependent reduction of the liver parasite burden. These data indicate that RTS,S-induced antibodies are protective and provide sterilizing immunity against P. falciparum infection when reaching or exceeding a critical plasma concentration.
Background: Chimeric mice with humanized livers represent a promising tool for infections with Pl... more Background: Chimeric mice with humanized livers represent a promising tool for infections with Plasmodium falciparum to evaluate novel methods for prevention and treatment of pre-erythrocytic stages. Adequate assessment of hepatic infections is generally compromised by the limited number of human hepatocytes infected by developing parasites. Methods: A qPCR-based method has been developed that sensitively and reliably detects P. falciparum liver stage infection of humanized mice and quantitatively expresses the results as the number of parasites per human hepatocyte. Results: This assay allows for detection of liver stage parasites after challenging humanized mice with infected mosquito bites or after intravenous injection with sporozoites. The sensitivity of the protocol, which comprises approximately 25% of the total chimeric liver, allows for the detection of a single infected hepatocyte in the analysed tissue.
Malaria, which is the result of Plasmodium falciparum infection, is a global health threat that r... more Malaria, which is the result of Plasmodium falciparum infection, is a global health threat that resulted in 655,000 deaths and 216 million clinical cases in 2010 alone. Recent phase 3 trials with malaria vaccine candidate RTS,S/AS01 (RTS,S) in children has demonstrated modest efficacy against clinical and severe malaria. RTS,S targets the pre-erythrocytic phase of the disease and induces high antibody titers against the P. falciparum circumsporozoite protein (CSP) and a moderate CD4 + T cell response. The individual contribution of these adaptive immune responses to protection from infection remains unknown. Here, we found that prophylactic administration of anti-CSP mAbs derived from an RTS,S-vaccinated recipient fully protected mice with humanized livers from i.v.-and mosquito bite-delivered P. falciparum sporozoite challenge. Titers of anti-CSP that conveyed full protection were within the range observed in human RTS,S vaccine recipients. Increasing anti-CSP titers resulted in a dose-dependent reduction of the liver parasite burden. These data indicate that RTS,S-induced antibodies are protective and provide sterilizing immunity against P. falciparum infection when reaching or exceeding a critical plasma concentration.
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