Haematological response in experimental human Plasmodium falciparum and Plasmodium vivax malaria

Abstract

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.

Sterile protection againstPlasmodium vivaxmalaria by repeated blood stage infection in a non-human primate model

“…Next, we investigated the longitudinal dynamics of hematological parameters and selected blood chemistry during the repeated P. vivax infections (Figure 2 and Table S1). During the first inoculation we observed a temporary but significant reduction of both hematocrit and platelet counts that coincided with peak parasitemia, as has been previously observed in Aotus [37] and humans experimentally infected with P. vivax [38] (Figure 2A, Binoculation level I). During the second homologous infection, and with partial immunity ensuing, all the animals had hematological values within the normal range at peak parasitemia on day 20 PI, when they were treated with CQ for three days (Figure 2A, Binoculation level II).…”

Characterizing the blood stage antimalarial activity of tafenoquine in healthy volunteers experimentally infected withPlasmodium falciparum

“…As expected, no significant safety signals were associated with tafenoquine dosing of volunteers with normal G6PD levels in the current study. A mild transient decrease in hemoglobin occurred in a few participants, although this did not appear to be dose related and has been observed previously with blood stage malaria challenge of healthy volunteers [28].…”

Transmission blocking activity of low dose tafenoquine in healthy volunteers experimentally infected with Plasmodium falciparum

“…Interestingly, this participant had an elevated CRP (46 mg/L at day 25) compared to the other participants (all ≤16 mg/L). An inhibitory effect of inflammatory cytokines on gametocyte transmissibility has been demonstrated in vitro and in an animal model (28, 29), and it is therefore possible that this may have contributed to lower transmission in this participant.The generally high transmission rates achieved at baseline (with relatively low gametocyte densities) were likely facilitated by the Percoll enrichment step prior to mosquito feeding, as well as optimization of the timing of feeding assays relative to the entry of mature gametocytes into the circulation.…”