Pre- and post-exposure prophylaxis of tick-transmitted babesiosis by the antimalarial drug tafenoquine

About This Grant

PROJECT SUMMARY/ABSTRACT Human babesiosis caused by Babesia microti is an emerging infectious disease in the United States. The primary vector is the nymph of the deer tick, Ixodes scapularis. If infected, nymphs release B. microti sporozoites from their salivary glands as they feed on humans. Sporozoites invade red blood cells where they undergo asexual replication to yield merozoites. Merozoites egress their host cells, causing their lysis, only to invade other red blood cells. Symptoms appear 1 to 4 weeks after the nymph has fed to repletion and typically consist of fever, chills, sweats, headache, myalgia and anorexia. Severe disease requires hospital admission and often occurs in patients with high parasitemia due to splenectomy or severe immune suppression. Despite antimicrobial therapy, complications such as severe anemia, adult respiratory distress syndrome and renal insufficiency or failure can develop. Death occurs in 2-3% of hospitalized cases. Preventive measures, which are limited to endemic area avoidance and tick exposure reduction, have failed to contain the emergence of babesiosis. No prophylaxis is available. Tafenoquine is approved for pre-exposure prophylaxis of malaria. The regimen consists of a loading dose taken for three consecutive days prior to travel and a weekly maintenance dose thereafter. In preliminary studies, we established that a three-day regimen of tafenoquine is sufficient for post-exposure prophylaxis of mice infected with blood-stage B. microti (merozoites). In a mouse model of malaria, tafenoquine prevents liver stage infection when given prior to intravenous delivery of sporozoites. Proceeding by analogy and aware that tafenoquine acts via reactive oxygen species, i.e., in a non-specific manner, we postulate that tafenoquine is effective against B. microti sporozoites. Accordingly, we hypothesize that tafenoquine can be used for pre-exposure and post-exposure prophylaxis of tick-transmitted babesiosis. In Aim #1, we will initiate three-day regimens of tafenoquine on day 1 or day 3 after nymph repletion. Daily doses will be those identified in our preliminary studies. We will monitor parasitemia on day 2 post-repletion and every 2-4 days until day 60. We will obtain plasma every 4 days and monitor antibody titers, thereby testing whether prophylaxis is uncoupled from humoral immunity. On day 60, to confirm eradication of infection, we will perform an adoptive transfer of blood cells to rag-deficient mice. We will seek to identify a regimen of tafenoquine that confers post-exposure prophylaxis to rag-deficient mice, which experience severe, persistent infection, and to splenectomized mice, which experience severe, life-threatening infection. In Aim #2, we will initiate three-day regimens of tafenoquine on the day of, but prior to nymph exposure. We will identify the daily dose that protects rag-deficient mice and splenectomized mice. If successful, our work will serve as foundation for a trial of tafenoquine for post-exposure prophylaxis of tick-transmitted babesiosis. Our work may also support off- label use of tafenoquine for prophylaxis of babesiosis, particularly to individuals at risk of severe disease.