We estimate that the global burden of malaria due to Plasmodium vivax is approximately 70-80 million cases annually. Probably approximately 10-20% of the world's cases of P. vivax infection occur in Africa, south of the Sahara. In eastern and southern Africa, P. vivax represents around 10% of malaria cases but 50% of all malaria cases. About 80-90% of P. vivax outside of Africa occurs in the Middle East, Asia, and the Western Pacific, mainly in the most tropical regions, and 10-15% in Central and South America. Because malaria transmission rates are low in most regions where P. vivax is prevalent, the human populations affected achieve little immunity to this parasite; as a result, in these regions, P. vivax infections affect people of all ages. Although the effects of repeated attacks of P. vivax through childhood and adult life are only rarely directly lethal, they can have major deleterious effects on personal well-being, growth, and development, and on the economic performance at the individual, family, community, and national levels. Features of the transmission biology of P. vivax give this species greater resilience than the less robust Plasmodiumfalciparum in the face of conditions adverse to the transmission of the parasites. Therefore, as control measures become more effective, the residual malaria burden is likely increasingly to become that of P. vivax.

The neglected burden of Plasmodium vivax malaria

Malaria remains a major cause of morbidity and mortality in the tropics, with Plasmodium falciparum responsible for the majority of the disease burden and P. vivax being the geographically most widely distributed cause of malaria. Gametocytes are the sexual-stage parasites that infect Anopheles mosquitoes and mediate the onward transmission of the disease. Gametocytes are poorly studied despite this crucial role, but with a recent resurgence of interest in malaria elimination, the study of gametocytes is in vogue. This review highlights the current state of knowledge with regard to the development and longevity of P. falciparum and P. vivax gametocytes in the human host and the factors influencing their distribution within endemic populations. The evidence for immune responses, antimalarial drugs, and drug resistance influencing infectiousness to mosquitoes is reviewed. We discuss how the application of molecular techniques has led to the identification of submicroscopic gametocyte carriage and to a reassessment of the human infectious reservoir. These components are drawn together to show how control measures that aim to reduce malaria transmission, such as mass drug administration and a transmission-blocking vaccine, might better be deployed.

Epidemiology and Infectivity of Plasmodium falciparum and Plasmodium vivax Gametocytes in Relation to Malaria Control and Elimination

Mosquitoes of the genus Anopheles transmit malaria parasites to humans. Anopheles mosquito species vary in their vector potential because of environmental conditions and factors affecting their abundance, blood-feeding behavior, survival, and ability to support malaria parasite development. In the complex life cycle of the parasite in female mosquitoes, a process termed sporogony, mosquitoes acquire gametocyte-stage parasites from blood-feeding on an infected host. The parasites carry out fertilization in the midgut, transform to ookinetes, then oocysts, which produce sporozoites. Sporozoites invade the salivary glands and are transmitted when the mosquito feeds on another host. Most individual mosquitoes that ingest gametocytes do not support development to the sporozoite stage. Bottle-necks occur at every stage of the cycle in the mosquito. Powerful new techniques and approaches exist for evaluating malaria parasite development and for identifying mechanisms regulating malaria parasite-vector interactions. This review focuses on those interactions that are important for the development of new approaches for evaluating and blocking transmission in nature.

Malaria parasite development in mosquitoes

Malaria remains one of the most important vector-borne human diseases. Control of malaria caused by Plasmodium falciparum is a major goal, particularly for populations in sub-Saharan Africa. An effective vaccine against malaria that would protect nonimmune individuals from the disease has long been a dream. But will it be a reality? The concept that vaccination may be a useful tool to control the disease is based on a number of observations. Individuals continually exposed to infection by the parasitic protozoan responsible do eventually develop immunity to the disease, and passive immunization with antibody from immune donors can have a dramatic effect on blood stage parasitemia (1). Furthermore, inoculation of live attenuated parasites can protect naive volunteers against infection (2), and immunization with whole killed organisms can protect in animal models (3). Intensive studies of the immune response to the malaria parasite in humans and in models, particularly rodent malaria parasites in laboratory mice, have provided a wealth of information on potential protective mechanisms. Twenty years of antigen identification and gene cloning and expression, have produced many candidates for subunit vaccines (for a comprehensive recent review see ref. 4). Single proteins or peptides have been shown to be at least partially protective when used in vaccination studies in humans or in animal models (see, for example ref. 5). Within these antigens important epitopes have been identified, such as those recognized by neutralizing antibodies (6). All of these findings may suggest that an effective vaccine is “just around the corner,” but what is reality, and what are the scientific obstacles?

By its very nature malaria vaccine research is a mix of empirical and rational approaches. It is hampered by the complexity of the parasite life cycle, imperfect tools to assess the efficacy of immune responses, and limited knowledge and understanding of the …

https://www.pnas.org/content/pnas/96/4/1167.full.pdf

Malaria vaccines

Ty virus-like particles consist of a single protein species that can be produced in yeast. Recombinant Ty-VLPs carrying a string of up to 15 defined cytotoxic T lymphocyte (CTL) epitopes from Plasmodium species prime protective CTL responses in mice following a single administration without adjuvant. Effective processing of epitopes from the string was demonstrated in vitro and in vivo and was not affected by flanking sequences.

A protein particle vaccine containing multiple malaria epitopes.

Immunity to malarial infections in human populations is known to affect the development of the asexual blood stages of the parasites in the human host and to be capable of conferring significant protection against morbidity and mortality due to the disease. In this study we show that during acute infection with Plasmodium vivax malaria, one of the two main malarial pathogens of humans, most individuals also develop immunity that suppresses the infectivity of the sexual stages of the parasite to mosquitoes. The immunity is antibody mediated and is directed against the parasites in the mosquito midgut shortly after ingestion of blood by a mosquito. This immunity could be expected to have significant effects on the natural transmission of P. vivax malaria.

https://iai.asm.org/content/iai/55/2/369.full.pdf

Malaria transmission-blocking immunity induced by natural infections of Plasmodium vivax in humans.

The infectivity to mosquitoes of 31 acute Plasmodium vivax patients was measured by permitting mosquitoes to feed directly on the patients. The infectivity of these patients correlated closely with titers of antibodies in their serum as measured by indirect immunofluorescence against air-dried female gametes of P. vivax. Infectivity by direct feeding was also closely parallel to the transmission-blocking activity of the sera of patients as measured by the suppression of infectivity of parasitized blood by autologous serum relative to normal (nonmalarial) human serum when fed to mosquitoes through a membrane. These results are consistent with serum antibodies in human P. vivax infections as major factors determining the infectivity of an infected individual to mosquitoes. It was further noted that individuals having a second attack of P. vivax within less than 4 months were considerably less infectious to mosquitoes than first-attack patients were. This "boosting" of transmission-blocking immunity was much less if longer intervals intervened between attacks. We discuss the immunological implications and possible epidemiological significance of this short-term boosting of transmission-blocking immunity by successive P. vivax infections.

Boosting of transmission-blocking immunity during natural Plasmodium vivax infections in humans depends upon frequent reinfection

Summary Antibodies were raised in rabbits by immunizing against fresh unfixed or cryopreserved female gametes of the human malaria pathogen Plasmodium vivax. The antibodies were shown to react with the surface of gametes by the indirect immunofluorescent test. When parasite isolates from P. vivax infected individuals were fed through a membrane to Anopheles tessellatus mosquitoes in the presence of immune rabbit sera, they completely blocked the infectivity of the parasite isolates to the vector. Immunoglobulins separated from these sera also blocked infectivity to the same extent as did the immune sera indicating that antibodies were responsible for the transmission blocking effect of the sera. This study indicated that P. vivax like other malaria parasites is highly susceptible to anti gamete transmission blocking immunity.

Anti-gamete antibodies block transmission of human vivax malaria to mosquitoes.

The design of a malarial vaccine based on the circumsporozoite (CS) protein, a major surface antigen of the sporozoite stage of the malaria parasite, requires the identification of T and B cell epitopes for inclusion in recombinant or synthetic vaccine candidates We have investigated the specificity and function of a series of T cell clones, derived from volunteers immunized with Plasmodium falciparum sporozoites, in an effort to identify relevant epitopes in the immune response to the pre-erythrocytic stages of the parasite CD4+ T cell clones were obtained which specifically recognized a repetitive epitope located in the 5' repeat region of the CS protein This epitope, when conjugated to the 3' repeat region in a synthetic MAPs construct, induced high titers of antisporozoite antibodies in C57BL mice A second T cell epitope, which mapped to aa 326-345 of the carboxy terminal, was recognized by lytic, as well as non-lytic, CD4+ T cells derived from the sporozoite-immunized volunteers The demonstration of CD4+ CTL in the human volunteers, and the recent studies in the rodent model (Renia et al, 1991; Tsuji et al, 1990), suggest that CS-specific CD4+ T cells, in addition to their indirect role as helper cells in the induction of antibody and CD8+ effector cells, may also play a direct role in protection against sporozoite challenge by targeting EEF within the liver

/pdf/t-cell-responses-to-repeat-and-non-repeat-regions-of-the-4qjb8lfzov.pdf

T cell responses to repeat and non-repeat regions of the circumsporozoite protein detected in volunteers immunized with Plasmodium falciparum sporozoites

Y. D. Munesinghe

Papers

Malaria transmission-blocking immunity induced by natural infections of Plasmodium vivax in humans.

Boosting of transmission-blocking immunity during natural Plasmodium vivax infections in humans depends upon frequent reinfection

Anti-gamete antibodies block transmission of human vivax malaria to mosquitoes.

T cell responses to repeat and non-repeat regions of the circumsporozoite protein detected in volunteers immunized with Plasmodium falciparum sporozoites