A highly protective malaria vaccine would greatly facilitate the prevention and elimination of malaria and containment of drug-resistant parasites. A high level (more than 90%) of protection against malaria in humans has previously been achieved only by immunization with radiation-attenuated Plasmodium falciparum (Pf) sporozoites (PfSPZ) inoculated by mosquitoes; by intravenous injection of aseptic, purified, radiation-attenuated, cryopreserved PfSPZ ('PfSPZ Vaccine'); or by infectious PfSPZ inoculated by mosquitoes to volunteers taking chloroquine or mefloquine (chemoprophylaxis with sporozoites). We assessed immunization by direct venous inoculation of aseptic, purified, cryopreserved, non-irradiated PfSPZ ('PfSPZ Challenge') to malaria-naive, healthy adult volunteers taking chloroquine for antimalarial chemoprophylaxis (vaccine approach denoted as PfSPZ-CVac). Three doses of 5.12 × 10 PfSPZ of PfSPZ Challenge at 28-day intervals were well tolerated and safe, and prevented infection in 9 out of 9 (100%) volunteers who underwent controlled human malaria infection ten weeks after the last dose (group III). Protective efficacy was dependent on dose and regimen. Immunization with 3.2 × 10 (group I) or 1.28 × 10 (group II) PfSPZ protected 3 out of 9 (33%) or 6 out of 9 (67%) volunteers, respectively. Three doses of 5.12 × 10 PfSPZ at five-day intervals protected 5 out of 8 (63%) volunteers. The frequency of Pf-specific polyfunctional CD4 memory T cells was associated with protection. On a 7,455 peptide Pf proteome array, immune sera from at least 5 out of 9 group III vaccinees recognized each of 22 proteins. PfSPZ-CVac is a highly efficacious vaccine candidate; when we are able to optimize the immunization regimen (dose, interval between doses, and drug partner), this vaccine could be used for combination mass drug administration and a mass vaccination program approach to eliminate malaria from geographically defined areas.
Murine models of Plasmodium falciparum malaria may become crucial tools in drug discovery. Here we show that non-myelodepleted NOD-scid IL2R␥ null mice engrafted with human erythrocytes support an infectious burden up to tenfold higher than that supported by engrafted NOD-scid 2microglobulin null mice. The new model was validated for drug discovery and was used to assess the therapeutic efficacy of 4-pyridones, selective inhibitors of P. falciparum cytochrome bc 1 .Malaria is caused by the erythrocytic stages of protozoan parasites of the genus Plasmodium. Among the species pathogenic for humans, Plasmodium falciparum is responsible for 300 to 500 million cases of malaria and over a million deaths annually, particularly in developing countries. The development of new antimalarial medicines and vaccines is a key part of the global strategy for malaria eradication (6).P. falciparum almost exclusively infects human erythrocytes (hE). As a result, candidate drugs and vaccines in early stages of preclinical development are usually tested in vivo by measuring their therapeutic efficacy against rodent-adapted plasmodial species and by assessing the antiparasitic response of non-human immune systems, respectively (11). To overcome the host specificity issue, two conceptually different murine models of erythrocytic stages of P. falciparum malaria have been developed. The first one requires chemical in vivo depletion of phagocytic cells from immunodeficient mice engrafted with hE in order to allow the growth of P. falciparum after intraperitoneal (i.p.) infection (2, 8). However, its variable kinetics of parasitemia and, particularly, the use of toxic reagents, which might affect the efficacy of antimalarials or effector cells, have limited its use in drug discovery (5). Recently, a new P. falciparum murine model that does not require in vivo myeloablative treatment of mice and is suitable for drug discovery was described (1). In this new model, NOD-scid mice genetically deficient in beta-2 microglobulin (2 m tm1Unc , abbreviated as 2 m null ) engrafted with hE (HM-2 m null ) are infected intravenously with P. falciparum strains selected in vivo for their competence to grow reproducibly in hE-engrafted immunodeficient mice (1).The NOD-scid 2 m null mouse strain retains residual NK cell activity as well as other innate immune functions and shows a high incidence of early thymic lymphomas, which dramatically diminish their life span (4). These characteristics may be a serious problem for addressing long-term pharmacokinetic/ pharmacodynamic (PK/PD) studies because of the relatively low total parasite burden per mouse achievable (1) and the short life span of NOD-scid 2 m null mice (4). Interestingly, NOD-scid strains carrying a null mutation of the interleukin 2 (IL-2) receptor ␥ chain (IL2R␥ tm1Wjll , abbreviated as IL2R␥ null ) have been developed (10). These murine strains lack fully mature NK cells and show additional defects in their innate immune system that explain their greater ability to support the engraftme...
Background Malaria in pregnancy has major impacts on mother and child health. To complement existing interventions, such as intermittent preventive treatment and use of impregnated bed nets, we developed a malaria vaccine candidate with the aim of reducing sequestration of asexual “blood-stage” parasites in the placenta, the major virulence mechanism. Methods The vaccine candidate PAMVAC is based on a recombinant fragment of VAR2CSA, the Plasmodium falciparum protein responsible for binding to the placenta via chondroitin sulfate A (CSA). Healthy, adult malaria-naive volunteers were immunized with 3 intramuscular injections of 20 μg (n = 9) or 50 μg (n = 27) PAMVAC, adjuvanted with Alhydrogel or glucopyranosyl lipid adjuvant in stable emulsion (GLA-SE) or in a liposomal formulation with QS21 (GLA-LSQ). Allocation was random and double blind. The vaccine was given every 4 weeks. Volunteers were observed for 6 months following last immunization. Results All PAMVAC formulations were safe and well tolerated. A total of 262 adverse events (AEs) occurred, 94 (10 grade 2 and 2 grade 3) at least possibly related to the vaccine. No serious AEs occurred. Distribution and severity of AEs were similar in all arms. PAMVAC was immunogenic in all participants. PAMVAC-specific antibody levels were highest with PAMVAC-GLA-SE. The antibodies inhibited binding of VAR2CSA expressing P. falciparum-infected erythrocytes to CSA in a standardized functional assay. Conclusions PAMVAC formulated with Alhydrogel or GLA-based adjuvants was safe, well tolerated, and induced functionally active antibodies. Next, PAMVAC will be assessed in women before first pregnancies in an endemic area. Clinical Trials Registration EudraCT 2015-001827-21; ClinicalTrials.gov NCT02647489.
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