Recent malaria does not substantially impact COVID-19 antibody response or rates of symptomatic illness in communities with high malaria and COVID-19 transmission in Mali, West Africa.

Malaria has been hypothesized as a factor that may have reduced the severity of the COVID-19 pandemic in sub-Saharan Africa. To evaluate the effect of recent malaria on COVID-19 we assessed a subgroup of individuals participating in a longitudinal cohort COVID-19 serosurvey that were also undergoing intensive malaria monitoring as part of antimalarial vaccine trials during the 2020 transmission season in Mali. These communities experienced a high incidence of primarily asymptomatic or mild COVID-19 during 2020 and 2021. In 1314 individuals, 711 were parasitemic during the 2020 malaria transmission season; 442 were symptomatic with clinical malaria and 269 had asymptomatic infection. Presence of parasitemia was not associated with new COVID-19 seroconversion (29.7% (211/711) vs. 30.0% (181/603), p=0.9038) or with rates of reported symptomatic seroconversion during the malaria transmission season. In the subsequent dry season, prior parasitemia was not associated with new COVID-19 seroconversion (30.2% (133/441) vs. 31.2% (108/346), p=0.7499), with symptomatic seroconversion, or with reversion from seropositive to seronegative (prior parasitemia: 36.2% (64/177) vs. no parasitemia: 30.1% (37/119), p=0.3842). After excluding participants with asymptomatic infection, clinical malaria was also not associated with COVID-19 serostatus or symptomatic seroconversion when compared to participants with no parasitemia during the monitoring period. In communities with intense seasonal malaria and a high incidence of asymptomatic or mild COVID-19, we did not demonstrate a relationship between recent malaria and subsequent response to COVID-19. Lifetime exposure, rather than recent infection, may be responsible for any effect of malaria on COVID-19 severity.

Safety, pharmacokinetics, and antimalarial activity of the novel triaminopyrimidine ZY-19489: a first-in-human, randomised, placebo-controlled, double-blind, single ascending dose study, pilot food-effect study, and volunteer infection study.

BACKGROUND: New antimalarials with novel mechanisms of action are needed to combat the emergence of drug resistance. Triaminopyrimidines comprise a novel antimalarial class identified in a high-throughput screen against asexual blood-stage Plasmodium falciparum. This first-in-human study aimed to characterise the safety, pharmacokinetics, and antimalarial activity of the triaminopyrimidine ZY-19489 in healthy volunteers. METHODS: A three-part clinical trial was conducted in healthy adults (aged 18-55 years) in Brisbane, QLD, Australia. Part one was a double-blind, randomised, placebo-controlled, single ascending dose study in which participants enrolled into one of six dose groups (25, 75, 150, 450, 900, or 1500 mg) were randomly assigned (3:1) to ZY-19489 or placebo. Part two was an open-label, randomised, two-period cross-over, pilot food-effect study in which participants were randomly assigned (1:1) to a fasted-fed or a fed-fasted sequence. Part three was an open-label, randomised, volunteer infection study using the P falciparum induced blood-stage malaria model in which participants were enrolled into one of two cohorts, with participants in cohort one all receiving the same dose of ZY-19489 and participants in cohort two randomly assigned to receive one of two doses. The primary outcome for all three parts was the incidence, severity, and relationship to ZY-19489 of adverse events. Secondary outcomes were estimation of ZY-19489 pharmacokinetic parameters for all parts; how these parameters were affected by the fed state for part two only; and the parasite reduction ratio, parasite clearance half-life, recrudescent parasitaemia, and pharmacokinetic-pharmacodynamic modelling parameters for part three only. This trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12619000127101, ACTRN12619001466134, and ACTRN12619001215112). FINDINGS: 48 participants were enrolled in part one (eight per cohort for 25-1500 mg cohorts), eight in part two (four in each group, all dosed with 300 mg), and 15 in part three (five dosed with 200 mg, eight with 300 mg, and two with 900 mg). In part one, the incidence of drug-related adverse events was higher in the 1500 mg dose group (occurring in all six participants) than in lower-dose groups and the placebo group (occurring in one of six in the 25 mg group, two of six in the 75 mg group, three of six in the 150 mg group, two of six in the 450 mg group, four of six in the 900 mg group, and four of 12 in the placebo group), due to the occurrence of mild gastrointestinal symptoms. Maximum plasma concentrations occurred 5-9 h post-dosing, and the elimination half-life was 50-97 h across the dose range. In part two, three of seven participants had a treatment-related adverse event in the fed state and four of eight in the fasted state. Dosing in the fed state delayed absorption (maximum plasma concentration occurred a median of 12·0 h [range 7·5-16·0] after dosing in the fed state vs 6·0 h [4·5-9·1] in the fasted state) but had no effect on overall exposure (difference in area under the concentration-time curve from time 0 [dosing] extrapolated to infinity between fed and fasted states was -0·013 [90% CI -0·11 to 0·08]). In part three, drug-related adverse events occurred in four of five participants in the 200 mg group, seven of eight in the 300 mg group, and both participants in the 900 mg group. Rapid initial parasite clearance occurred in all participants following dosing (clearance half-life 6·6 h [95% CI 6·2-6·9] for 200 mg, 6·8 h [95% CI 6·5-7·1] for 300 mg, and 7·1 h [95% CI 6·6-7·6] for 900 mg). Recrudescence occurred in four of five participants in the 200 mg group, five of eight in the 300 mg group, and neither of the two participants in the 900 mg group. Simulations done using a pharmacokinetic-pharmacodynamic model predicted that a single dose of 1100 mg would clear baseline parasitaemia by a factor of 109. INTERPRETATION: The safety, pharmacokinetic profile, and antimalarial activity of ZY-19489 in humans support the further development of the compound as a novel antimalarial therapy. FUNDING: Cadila Healthcare and Medicines for Malaria Venture.

Investigation of Intestinal and Blood Parasites in People Returning to Turkey with a History of Traveling Abroad During the Pandemic

Objective: To investigate intestinal and blood parasites in people who have a history of traveling abroad during the Coronavirus disease-2019 pandemic and returning to Turkey. Methods: In this study, 104 patients with gastrointestinal system and/or fever complaints who had traveled abroad during the pandemic period and returned to Turkey were included. Parasitic agents were investigated by taking blood and stool samples from the patients. Additionally, urine samples were obtained from patients with hematuria or dysuria with the suspicion of schistosomiasis. A direct microscopic examination, the Crypto-Giardia immunochromatographic test, and ELISA methods were used in the examination of the stool samples. In order to detect Plasmodium species, blood samples were examined by preparing both the rapid diagnostic test and thick drop and thin smear preparations. Results: One or more parasite species were detected in 38 (38.5%) of 104 patients included in the study. While intestinal parasites were detected in 16 (32%) of 50 patients who traveled to Iran and 16 (33.3%) of 48 patients who traveled to Northern Iraq, blood parasites were not found. Schistosoma mansoni was detected in all 5 of the patients with a history of traveling to Sudan. Plasmodium falciparum was detected in 1 patient who traveled to the African continent. Conclusion: It is vital to take precautions to prevent parasitic diseases, such as malaria and schistosomiasis, during travels to African countries. During travels to neighboring countries of Turkey, such as Northern Iraq and Iran, hygiene should be paid attention to, so as to prevent contracting intestinal parasitic diseases. In addition, it was concluded that people who plan to travel abroad should have information about the endemic parasitic diseases of the country that they are going to.

Impact of a blood-stage vaccine on Plasmodium vivax malaria (preprint)

Background There are no licensed vaccines against Plasmodium vivax , the most common cause of malaria outside of Africa. Methods We conducted two Phase I/IIa clinical trials to assess the safety, immunogenicity and efficacy of two vaccines targeting region II of P. vivax Duffy-binding protein (PvDBPII). Recombinant viral vaccines (using ChAd63 and MVA vectors) were administered at 0, 2 months or in a delayed dosing regimen (0, 17, 19 months), whilst a protein/adjuvant formulation (PvDBPII/Matrix-M™) was administered monthly (0, 1, 2 months) or in a delayed dosing regimen (0, 1, 14 months). Delayed regimens were due to trial halts during the COVID-19 pandemic. Volunteers underwent heterologous controlled human malaria infection (CHMI) with blood-stage P. vivax parasites at 2-4 weeks following their last vaccination, alongside unvaccinated controls. Efficacy was assessed by comparison of parasite multiplication rate (PMR) in blood post-CHMI, modelled from parasitemia measured by quantitative polymerase-chain-reaction (qPCR). Results Thirty-two volunteers were enrolled and vaccinated (n=16 for each vaccine). No safety concerns were identified. PvDBPII/Matrix-M™, given in the delayed dosing regimen, elicited the highest antibody responses and reduced the mean PMR following CHMI by 51% (range 36-66%; n=6) compared to unvaccinated controls (n=13). No other vaccine or regimen impacted parasite growth. In vivo growth inhibition of blood-stage P. vivax correlated with functional antibody readouts of vaccine immunogenicity. Conclusions Vaccination of malaria-naïve adults with a delayed booster regimen of PvDBPII/ Matrix-M™ significantly reduces the growth of blood-stage P. vivax . Funded by the European Commission and Wellcome Trust; VAC069, VAC071 and VAC079 ClinicalTrials.gov numbers NCT03797989 , NCT04009096 and NCT04201431 .

Haematological response in experimental human Plasmodium falciparum and Plasmodium vivax malaria.

BACKGROUND: Malaria-associated anaemia, arising from symptomatic, asymptomatic and submicroscopic infections, is a significant cause of morbidity worldwide. Induced blood stage malaria volunteer infection studies (IBSM-VIS) provide a unique opportunity to evaluate the haematological response to early Plasmodium falciparum and Plasmodium vivax infection. METHODS: This study was an analysis of the haemoglobin, red cell counts, and parasitaemia data from 315 participants enrolled in IBSM-VIS between 2012 and 2019, including 269 participants inoculated with the 3D7 strain of P. falciparum (Pf3D7), 15 with an artemisinin-resistant P. falciparum strain (PfK13) and 46 with P. vivax. Factors associated with the fractional fall in haemoglobin (Hb-FF) were evaluated, and the malaria-attributable erythrocyte loss after accounting for phlebotomy-related losses was estimated. The relative contribution of parasitized erythrocytes to the malaria-attributable erythrocyte loss was also estimated. RESULTS: The median peak parasitaemia prior to treatment was 10,277 parasites/ml (IQR 3566-27,815), 71,427 parasites/ml [IQR 33,236-180,213], and 34,840 parasites/ml (IQR 13,302-77,064) in participants inoculated with Pf3D7, PfK13, and P. vivax, respectively. The median Hb-FF was 10.3% (IQR 7.8-13.3), 14.8% (IQR 11.8-15.9) and 11.7% (IQR 8.9-14.5) in those inoculated with Pf3D7, PfK13 and P. vivax, respectively, with the haemoglobin nadir occurring a median 12 (IQR 5-21), 15 (IQR 7-22), and 8 (IQR 7-15) days following inoculation. In participants inoculated with P. falciparum, recrudescence was associated with a greater Hb-FF, while in those with P. vivax, the Hb-FF was associated with a higher pre-treatment parasitaemia and later day of anti-malarial treatment. After accounting for phlebotomy-related blood losses, the estimated Hb-FF was 4.1% (IQR 3.1-5.3), 7.2% (IQR 5.8-7.8), and 4.9% (IQR 3.7-6.1) in participants inoculated with Pf3D7, PfK13, and P. vivax, respectively. Parasitized erythrocytes were estimated to account for 0.015% (IQR 0.006-0.06), 0.128% (IQR 0.068-0.616) and 0.022% (IQR 0.008-0.082) of the malaria-attributable erythrocyte loss in participants inoculated with Pf3D7, PfK13, and P. vivax, respectively. CONCLUSION: Early experimental P. falciparum and P. vivax infection resulted in a small but significant fall in haemoglobin despite parasitaemia only just at the level of microscopic detection. Loss of parasitized erythrocytes accounted for < 0.2% of the total malaria-attributable haemoglobin loss.

Babesiosis as a Cause of Atraumatic Splenic Injury: Two Case Reports and a Review of Literature.

We present two cases of Babesia-induced splenic injury at a single institution. In the late summer, two patients presented with left-sided abdominal pain radiating to the shoulder. They were both found to have hemolytic anemia, thrombocytopenia, and acute splenic infarction on imaging. Blood smears showed intracellular ring forms consistent with Babesia spp. and low parasitemia (<1%). Diagnosis was confirmed by PCR for Babesia microti. Both patients improved with azithromycin and atovaquone, without blood products or surgical intervention. Several weeks following treatment, repeat blood smears revealed no parasites. Splenic infarct and hemorrhage have been previously reported as rare complications of babesiosis. However, given the steady rise in Babesia microti cases in the USA, even these rare complications will become more prevalent. We review both the diagnosis and management of Babesia-induced splenic complications, which can be challenging in patients with low-level parasitemia. Clinicians should consider babesiosis as a cause of atraumatic splenic injury.

Prevalence and characteristics of malaria among COVID-19 individuals: A systematic review, meta-analysis, and analysis of case reports.

BACKGROUND: The world population is currently at a very high risk of Coronavirus disease-2019 (COVID-19), caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). People who live in malaria-endemic areas and get infected by SARS-CoV-2 may be at increased risk of severe COVID-19 or unfavorable disease outcomes if they ignore their malaria status. Therefore, the present study aimed to synthesize, qualitatively and quantitatively, information on the prevalence and characteristics of malaria infection among COVID-19-infected individuals. The findings will help us better understand this particular comorbidity during the COVID-19 pandemic. METHODS: The systematic review protocol was registered at the International Prospective Register of Systematic Reviews (PROSPERO) with the identification number: CRD42021247521. We searched for studies reporting on the coinfection of COVID-19 and malaria in PubMed, Web of Science, and Scopus from inception to March 27, 2021 using Medical Subject Headings (MeSH) terms. The study's methodological quality in the search output was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Tools for cross-sectional study. The pooled prevalence of Plasmodium spp. infection among patients infected with COVID-19 was estimated using the random effect model and then graphically presented as forest plots. The heterogeneity among the included studies was assessed using Cochrane Q and I2 statistics. The characteristics of patients co-infected with COVID-19 and malaria were derived from case reports and series and were formally analyzed using simple statistics. RESULTS: Twelve of 1,207 studies reporting the coinfection of COVID-19 and malaria were selected for further analysis. Results of quantitative synthesis show that the pooled prevalence of Plasmodium spp. infection (364 cases) among COVID-19 individuals (1,126 cases) is 11%, with a high degree of heterogeneity (95% CI: 4%-18%, I2: 97.07%, 5 studies). Most of the coinfections were reported in Nigeria (336 cases), India (27 cases), and the Democratic Republic of Congo (1 case). Results of qualitative synthesis indicate that patients with coinfection are typically symptomatic at presentation with mild or moderate parasitemia. An analysis of case reports and series indicates that co-infected individuals often display thrombocytopenia, lymphopenia, and elevated bilirubin levels. Among four patients (30%) who required treatment with intravenous artesunate, one experienced worsened clinical status after administering the drug. One serious outcome of coinfection involved a pregnant woman who experienced fetal abortion due to the initial misdiagnosis of malaria. CONCLUSIONS: All individuals in malaria-endemic regions who are febrile or display symptoms of COVID-19 should be evaluated for malaria to avoid serious complications. Further prospective studies are required to investigate the burden and outcomes of COVID-19 in malaria-endemic regions. Prompt management is required to prevent serious outcomes in individuals co-infected with COVID-19 and malaria.

Safety, Pharmacokinetics, and Activity of High-Dose Ivermectin and Chloroquine against the Liver Stage of Plasmodium cynomolgi Infection in Rhesus Macaques.

Previously, ivermectin (1 to 10 mg/kg of body weight) was shown to inhibit the liver-stage development of Plasmodium berghei in orally dosed mice. Here, ivermectin showed inhibition of the in vitro development of Plasmodium cynomolgi schizonts (50% inhibitory concentration [IC50], 10.42 µM) and hypnozoites (IC50, 29.24 µM) in primary macaque hepatocytes when administered as a high dose prophylactically but not when administered in radical cure mode. The safety, pharmacokinetics, and efficacy of oral ivermectin (0.3, 0.6, and 1.2 mg/kg) with and without chloroquine (10 mg/kg) administered for 7 consecutive days were evaluated for prophylaxis or radical cure of P. cynomolgi liver stages in rhesus macaques. No inhibition or delay to blood-stage P. cynomolgi parasitemia was observed at any ivermectin dose (0.3, 0.6, and 1.2 mg/kg). Ivermectin (0.6 and 1.2 mg/kg) and chloroquine (10 mg/kg) in combination were well-tolerated with no adverse events and no significant pharmacokinetic drug-drug interactions observed. Repeated daily ivermectin administration for 7 days did not inhibit ivermectin bioavailability. It was recently demonstrated that both ivermectin and chloroquine inhibit replication of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro Further ivermectin and chloroquine trials in humans are warranted to evaluate their role in Plasmodium vivax control and as adjunctive therapies against COVID-19 infections.

Safety, pharmacokinetics, and liver-stage Plasmodium cynomolgi effect of high-dose ivermectin and chloroquine in Rhesus Macaques (preprint)

Previously, ivermectin (1–10 mg/kg) was shown to inhibit liver-stage development of Plasmodium berghei in orally dosed mice. Here, ivermectin showed inhibition of the in vitro development of Plasmodium cynomolgi schizonts (IC 50 = 10.42 μM) and hypnozoites (IC 50 = 29.24 μM) in primary macaque hepatocytes when administered in high-dose prophylactically but not when administered in radical cure mode. The safety, pharmacokinetics, and efficacy of oral ivermectin (0.3, 0.6, and 1.2 mg/kg) with and without chloroquine (10 mg/kg) administered for seven consecutive days was evaluated for prophylaxis or radical cure of Plasmodium cynomolgi liver-stages in Rhesus macaques. No inhibition or delay to blood-stage P. cynomolgi parasitemia was observed at any ivermectin dose (0.3, 0.6, and 1.2 mg/kg). Ivermectin (0.6 and 1.2 mg/kg) and chloroquine (10 mg/kg) in combination were well-tolerated with no adverse events and no significant pharmacokinetic drug-drug interactions observed. Repeated daily ivermectin administration for seven days did not inhibit ivermectin bioavailability. It was recently demonstrated that both ivermectin and chloroquine inhibit replication of the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in vitro . Further ivermectin and chloroquine trials in humans are warranted to evaluate their role in Plasmodium vivax control and as adjunctive therapies against COVID-19 infections.