Investigation of liposomal self-adjuvanting peptide epitopes derived from conserved blood-stage Plasmodium antigens.

Malaria is a vector born parasitic disease causing millions of deaths every year. Despite the high mortality rate, an effective vaccine against this mosquito-borne infectious disease is yet to be developed. Up to date, RTS,S/AS01 is the only vaccine available for malaria prevention; however, its efficacy is low. Among a variety of malaria antigens, merozoite surface protein-1(MSP-1) and ring-infected erythrocyte surface antigen (RESA) have been proposed as promising candidates for malaria vaccine development. We developed peptide-based Plasmodium falciparum vaccine candidates that incorporated three previously reported conserved epitopes from MSP-1 and RESA into highly effective liposomal polyleucine delivery system. Indeed, MSP-1 and RESA-derived epitopes conjugated to polyleucine and formulated into liposomes induced higher epitope specific antibody titres. However, immunized mice failed to demonstrate protection in a rodent malaria challenge study with Plasmodium yoelii. In addition, we found that the three reported P. falciparum epitopes did not to share conformational properties and high sequence similarity with P. yoelii MSP-1 and RESA proteins, despite the epitopes were reported to protect mice against P. yoelii challenge.

Development and Evaluation of a Cryopreserved Whole-Parasite Vaccine in a Rodent Model of Blood-Stage Malaria.

Infection with malaria parasites continues to be a major global public health issue. While current control measures have enabled a significant decrease in morbidity and mortality over the last 20 years, additional tools will be required if we are to progress toward malaria parasite eradication. Malaria vaccine research has focused on the development of subunit vaccines; however, more recently, interest in whole-parasite vaccines has reignited. Whole-parasite vaccines enable the presentation of a broad repertoire of antigens to the immune system, which limits the impact of antigenic polymorphism and genetic restriction of the immune response. We previously reported that whole-parasite vaccines can be prepared using chemically attenuated parasites within intact red blood cells or using killed parasites in liposomes, although liposomes were less immunogenic than attenuated parasites. If they could be frozen or freeze-dried and be made more immunogenic, liposomal vaccines would be ideal for vaccine deployment in areas where malaria is endemic. Here, we develop and evaluate a Plasmodium yoelii liposomal vaccine with enhanced immunogenicity and efficacy due to incorporation of TLR4 agonist, 3D(6-acyl) PHAD, and mannose to target the liposome to antigen-presenting cells. Following vaccination, mice were protected, and strong cellular immune responses were induced, characterized by parasite-specific splenocyte proliferation and a mixed Th1/Th2/Th17 cytokine response. Parasite-specific antibodies were induced, predominantly of the IgG1 subclass. CD4+ T cells and gamma interferon were critical components of the protective immune response. This study represents an important development toward evaluation of this whole-parasite blood-stage vaccine in a phase I clinical trial. IMPORTANCE Malaria is a mosquito-borne infectious disease that is caused by parasites of the genus, Plasmodium. There are seven different Plasmodium spp. that can cause malaria in humans, with P. falciparum causing the majority of the morbidity and mortality. Malaria parasites are endemic in 87 countries and continue to result in >200 million cases of malaria and >400,000 deaths/year, mostly children <5 years of age. Malaria infection initially presents as a flu-like illness but can rapidly progress to severe disease in nonimmune individuals if treatment is not initiated promptly. Existing control strategies for the mosquito vector (insecticides) and parasite (antimalarial drugs) are becoming increasingly less effective due to the development of resistance. While artemisinin combination therapies are frontline treatment for P. falciparum malaria, resistance has been documented in numerous countries. A highly effective malaria vaccine is urgently required to reduce malaria-attributable clinical disease and death and enable progression toward the ultimate goal of eradication.

Pre-clinical evaluation of a whole-parasite vaccine to control human babesiosis.

Babesia spp. are tick-transmitted intra-erythrocytic protozoan parasites that infect humans and animals, causing a flu-like illness and hemolytic anemia. There is currently no human vaccine available. People most at risk of severe disease are the elderly, immunosuppressed, and asplenic individuals. B. microti and B. divergens are the predominant species affecting humans. Here, we present a whole-parasite Babesia vaccine. To establish proof-of-principle, we employed chemically attenuated B. microti parasitized red blood cells from infected mice. To aid clinical translation, we produced liposomes containing killed parasite material. Vaccination significantly reduces peak parasitemia following challenge. B cells and anti-parasite antibodies do not significantly contribute to vaccine efficacy. Protection is abrogated by the removal of CD4+ T cells or macrophages prior to challenge. Importantly, splenectomized mice are protected by vaccination. To further facilitate translation, we prepared a culture-based liposomal vaccine and demonstrate that this performs as a universal vaccine inducing immunity against different human Babesia species.

Progress in the Development of Subunit Vaccines against Malaria.

Malaria is a life-threatening disease and one of the main causes of morbidity and mortality in the human population. The disease also results in a major socio-economic burden. The rapid spread of malaria epidemics in developing countries is exacerbated by the rise in drug-resistant parasites and insecticide-resistant mosquitoes. At present, malaria research is focused mainly on the development of drugs with increased therapeutic effects against Plasmodium parasites. However, a vaccine against the disease is preferable over treatment to achieve long-term control. Trials to develop a safe and effective immunization protocol for the control of malaria have been occurring for decades, and continue on today; still, no effective vaccines are available on the market. Recently, peptide-based vaccines have become an attractive alternative approach. These vaccines utilize short protein fragments to induce immune responses against malaria parasites. Peptide-based vaccines are safer than traditional vaccines, relatively inexpensive to produce, and can be composed of multiple T- and B-cell epitopes integrated into one antigenic formulation. Various combinations, based on antigen choice, peptide epitope modification and delivery mechanism, have resulted in numerous potential malaria vaccines candidates; these are presently being studied in both preclinical and clinical trials. This review describes the current landscape of peptide-based vaccines, and addresses obstacles and opportunities in the production of malaria vaccines.