Naturally acquired immunity to
malaria is robust and protective against all strains of the same species of Plasmodium This develops as a result of repeated natural
infection, taking several years to develop. Evidence suggests that apoptosis of immune lymphocytes due to uncontrolled parasite growth contributes to the slow acquisition of immunity. To hasten and augment the development of natural immunity, we studied controlled
infection immunization (CII) using low-dose exposure to different parasite species (Plasmodium chabaudi, P. yoelii, or P. falciparum) in two rodent systems (BALB/c and C57BL/6 mice) and in human volunteers, with
drug therapy commencing at the time of initiation of
infection. CIIs with infected erythrocytes and in conjunction with
doxycycline or
azithromycin, which are delayed death drugs targeting the parasite's apicoplast, allowed extended exposure to parasites at low levels. In turn, this induced strong protection against homologous challenge in all immunized mice. We show that P. chabaudi/P. yoelii
infection initiated at the commencement of
doxycycline therapy leads to cellular or antibody-mediated protective immune responses in mice, with a broad Th1
cytokine response providing the best correlate of protection against homologous and heterologous species of PlasmodiumP. falciparum CII with
doxycycline was additionally tested in a pilot clinical study (n = 4) and was found to be well tolerated and immunogenic, with immunological studies primarily detecting increased cell-associated immune responses. Furthermore, we report that a single dose of the longer-acting drug,
azithromycin, given to mice (n = 5) as a single subcutaneous treatment at the initiation of
infection controlled P. yoelii
infection and protected all mice against subsequent challenge.