Controlled Human Malaria Infection: Applications, Advances, and Challenges

Stanisic, Danielle I.; McCarthy, James S.; Good, Michael F.

doi:10.1128/iai.00479-17

Cited by 114 publications

(108 citation statements)

References 230 publications

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“…However, due to the limited availability of insectaries that can provide infected mosquitoes on a regular basis, and the absence of accepted surrogates of protection, there is a necessity for blood stage challenge in healthy volunteers. Contrary to murine or monkey models where direct challenge with blood stage parasites is common, challenge with blood stage parasites in human has only been performed in limited vaccine studies using naïve volunteers [85,86]. Because of safety reasons, blood parasites used for challenge need to be fully characterized.…”

Section: Anti-parasite Vaccinesmentioning

confidence: 99%

“…However, since most of blood stage candidates are polymorphic, it is of utmost importance to assess the effect of polymorphism to have an idea of potential vaccine coverage. In addition, blood cells used for blood stage parasite propagation need to be pre-screened for the presence of a wide range of potential pathogens [86].…”

Section: Anti-parasite Vaccinesmentioning

confidence: 99%

“…Indeed, this implies an active and close follow-up of the volunteers to obtain multiple time points. One possibility to obtain more homogenous results would be to perform the challenge with defined number of infected red blood cells at a same time of infection across all groups [86,94]. However, this requires overcoming a series of hurdles such as the development of standardized inoculums with known number of parasites at the same stage of development and the availability of donor blood, which have to be heavily tested for the presence of any pathogens.…”

Section: Anti-parasite Vaccinesmentioning

confidence: 99%

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Assessing Malaria Vaccine Efficacy

Rénia¹,

Goh²,

Peng³

et al. 2018

Towards Malaria Elimination - A Leap Forward

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After many years of silence, eradication of malaria is, once again, one of the top priorities on the agenda of many international health and development agencies. To meet this idealistic goal, a combination of control tools is needed. From this armentarium, a malaria vaccine is central to prevent infection and/or disease. However, numerous malaria vaccine candidates have shown limited efficacy in Phase II and III studies. One reason for these failures has been that the assessment of efficacy in the context of malaria has been difficult to standardize. In this article, we have reviewed and discussed the different ways to assess the outcome of a malaria vaccination.

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Section: Anti-parasite Vaccinesmentioning

confidence: 99%

Section: Anti-parasite Vaccinesmentioning

confidence: 99%

Section: Anti-parasite Vaccinesmentioning

confidence: 99%

See 1 more Smart Citation

Assessing Malaria Vaccine Efficacy

Rénia¹,

Goh²,

Peng³

et al. 2018

Towards Malaria Elimination - A Leap Forward

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“…Gametocytes used in a vaccine could be inactivated [31] or killed and presented in liposomes or another suitable formulation [34]. While gametocyte culture is tedious, it is possible to produce populations of pure gametocytes by culture and enrichment [35] which could form the basis for a novel vaccine.Such vaccines would be tested for safety in Phase I trials and could then be tested for efficacy in early stage Phase Ib/II trials using controlled human malaria infections [36] where a reduction in peripheral gametocytaemia and a reduction in the ability of male gametocytes to exflagellate in the presence of T-cells might be expected. These are both mechanisms for which T-cells are thought to play critical roles [19,28,33].…”

mentioning

confidence: 99%

“…Such vaccines would be tested for safety in Phase I trials and could then be tested for efficacy in early stage Phase Ib/II trials using controlled human malaria infections [36] where a reduction in peripheral gametocytaemia and a reduction in the ability of male gametocytes to exflagellate in the presence of T-cells might be expected. These are both mechanisms for which T-cells are thought to play critical roles [19,28,33].…”

mentioning

confidence: 99%

A whole parasite transmission-blocking vaccine for malaria: an ignored strategy

Good

Yanow

2017

Emerging Topics in Life Sciences

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Malaria vaccine approaches can be divided into 'subunit' and 'whole parasite', and these can be directed at the sporozoite, liver stage, asexual or sexual stages. All combinations of approach and stage are under development with the exception of a whole parasite sexual stage (gametocyte) vaccine. A gametocyte vaccine would aim primarily to block transmission of malaria from the human host to the mosquito vector and as such is referred to as a 'transmission-blocking vaccine'. An immunological feature of whole parasite vaccines for the sporozoite/liver stage and for the asexual blood stage is the reliance on cellular immunity involving T-cells to control parasite growth. T-cells can also respond vigorously to gametocytes and kill them in the vertebrate host and/or arrest their development. To date, cellular immunity has not been exploited in transmission-blocking vaccine development. Here, the data supporting a gametocyte whole parasite vaccine are reviewed and a strategy for vaccine development and testing is outlined.Malaria continues to exact a huge global toll on human life with up to 300 million new cases and over 400 000 deaths each year [1]. While the number of deaths has reduced significantly over the last decade, further reductions will depend on the availability of effective drugs to combat emerging drug resistance and the development of an effective vaccine.A malaria vaccine aims to block parasite growth and development at one or more stages in the life cycle. The life cycle in the vertebrate host commences with the bite of an infected Anopheles mosquito which injects tens to hundreds of sporozoites (Figure 1). Those reaching the liver within ∼30 min develop into exoerythrocytic schizonts within hepatocytes. After a further 8 days of growth, 30 000-40 000 merozoites emerge from each infected liver cell, with each one capable of entering a new red blood cell to continue the life cycle in the blood. For the dominant species of human malaria parasites (Plasmodium falciparum and P. vivax), there is a 48 h life cycle in the red cell with the asexual forms progressing from 'rings' to trophozoites and then segmented schizonts which burst to liberate new merozoites that invade fresh red cells. For P. falciparum, there is an approximate 10-fold increase in parasite numbers over the 48 h period. The exponential growth in parasite biomass leads directly and indirectly to the ensuing symptoms and pathology of malaria.The sexual parasite forms in the vertebrate host are the gametocytes. These are believed to develop continuously during the asexual life cycle with ∼10% of merozoites committed to sexual stage development during each round of asexual stage growth [2]. All merozoites from a particular schizont are committed to gametocytogenesis with all those from a given schizont becoming either male or female gametocytes [3]. The immature gametocytes, which remain within red cells, protect themselves from the innate immune defences of the host by sequestering in bone marrow in the extravascular spaces, only to reappea...

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2010 to 2020: Ten Years of Malaria Drug Discovery

Yeung

Calderón

2021

Burger's Medicinal Chemistry and Drug Discovery

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The seventh edition of Burger's Medicinal Chemistry, Drug Discovery and Development included an extensive review of antimalarial drugs and drug targets. Since it was published nearly 10 years ago, the annual number of deaths due to malaria in endemic countries have steadily declined. However, over the past two years, a stabilization in number of malaria deaths hints to a reversal of this trend. This may be in part due to parasite evolution to overcome efficacy of antimalarial therapies, including the now well‐established spread of resistance to artemisinin‐combination therapies in Southeast Asia. Fortunately, the last decade also witnessed a renewed effort by academic researchers, product development partnerships, and pharmaceutical companies to restart malaria drug discovery. Innovations in high‐throughput screening, assay development, access to large chemical libraries, advancements in parasite biology, and whole‐genome sequencing have resulted in the discovery of new antimalarial drugs as well as novel targets. These new drug candidates, which kill the parasite through new mechanisms of action have bolstered the malaria drug development pipeline since the last edition. This article summarizes the new drug discovery approaches and achievements over the past decade.

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Controlled Human Malaria Infection: Applications, Advances, and Challenges

Cited by 114 publications

References 230 publications

Assessing Malaria Vaccine Efficacy

Assessing Malaria Vaccine Efficacy

A whole parasite transmission-blocking vaccine for malaria: an ignored strategy

2010 to 2020: Ten Years of Malaria Drug Discovery

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