The use of transgenic Plasmodium berghei expressing the Plasmodium vivax antigen P25 to determine the transmission-blocking activity of sera from malaria vaccine trials

Ramjanee, Souraya; Robertson, James S.; Franke-Fayard, Blandine; Sinha, Ria; Waters, Andrew P.; Janse, Chris J.; Wu, Yimin; Blagborough, Andrew M.; Saul, Allan; Sinden, Robert E.

doi:10.1016/j.vaccine.2006.09.035

Cited by 48 publications

(43 citation statements)

References 19 publications

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“…We replaced native pb25 and pb28 with pfs25 to construct a transgenic P. berghei parasite. Our findings were consistent with those for Pvs25 transgenic P. berghei parasites (16) and suggest functional conservation of P25 between the human malaria parasites (P. falciparum and P. vivax) and the murine parasite (P. berghei), since Pfs25 and Pvs25 (16) successfully complemented the functions of both Pb25 and Pb28 during mosquito-stage development. At the amino acid level, Pfs25 and Pb25 share 44% sequence identity, including the presence of N-terminal signal peptides, a C-terminal glycosylphosphatidyinositol anchor signal, and four epidermal growth factor-like domains (6,10).…”

Section: Discussionsupporting

confidence: 87%

“…A recently published paper described the generation of transgenic P. berghei parasites expressing Pvs25 that were found to be valuable in assessing P. vivax transmission-blocking antibodies in both membrane feeding assays and in vitro ookinete development assays (16). The availability of an animal model would circumvent the need for an artificial MFA and permit direct evaluation of the potency of malaria transmission-blocking vaccine formulations based on the Pfs25 antigen in preclinical studies and functional assessments of malaria transmission from vaccinated hosts to mosquitoes.…”

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confidence: 99%

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Murine Model for Assessment of Plasmodium falciparum Transmission-Blocking Vaccine Using Transgenic Plasmodium berghei Parasites Expressing the Target Antigen Pfs25

2008

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Currently, there is no animal model for Plasmodium falciparum challenge to evaluate malaria transmissionblocking vaccines based on the well-established Pfs25 target antigen. The biological activity of transmissionblocking antibodies is typically assessed using an assay known as the membrane feeding assay (MFA). It is an in vitro method that involves mixing antibodies with cultured P. falciparum gametocytes and feeding them to mosquitoes through an artificial membrane followed by assessment of infection in the mosquitoes. We genetically modified Plasmodium berghei to express Pfs25 and demonstrated that the transgenic parasites (TrPfs25Pb) are susceptible to anti-Pfs25 antibodies during mosquito-stage development. The asexual growth kinetics and mosquito infectivity of TrPfs25Pb were comparable to those of wild-type parasites, and TrPfs25Pb displayed Pfs25 on the surface of ookinetes. Immune sera from nonhuman primates immunized with a Pfs25-based vaccine when passively transferred to mice blocked transmission of TrPfs25Pb to Anopheles stephensi. Furthermore, mice immunized with Pfs25 DNA vaccine and challenged with TrPfs25Pb displayed reduced malaria transmission compared to mice immunized with wild-type plasmid. These studies describe development of an animal malaria model alternative to the in vitro MFA and show that the model can facilitate P. falciparum transmission-blocking vaccine evaluation based on the target antigen Pfs25. We believe that an animal model to test transmission-blocking vaccines would be superior to the MFA, since there may be additional immune factors that synergize the transmission-blocking activity of antibodies in vivo.Annually, 300 to 500 million people worldwide suffer from clinical malaria, and approximately 1 million people, mainly children under 5 years old, die as a result of the disease (8, 18). Successful transmission of Plasmodium parasites relies on the uptake of sexual stages (gametocytes) of the pathogen by mosquitoes during a blood meal. Subsequent gametogenesis and fertilization of female and male gametes establishes a sexual reproduction phase in the mosquito midgut. Resulting zygotes transform into motile ookinetes, which traverse the peritrophic matrix and midgut epithelium, lodge on the basal lamina of the midgut, and develop into oocysts. Sporozoites produced in the oocysts are released into the hemocoel, then invade salivary glands, and are subsequently introduced to new hosts when the mosquito takes another blood meal. A number of stage-specific proteins have been shown to play important roles during fertilization and ookinete formation, and antibodies recognizing these antigens are potent blockers of parasite development in mosquitoes (12). Among the proteins that are expressed on the surface of zygotes and ookinetes, P25 and P28 have been shown to be crucial for successful transmission of Plasmodium parasites (7, 21). Both P25 and P28 are strong candidates for transmission-blocking vaccines (TBV), and phase I clinical trials for Pfs25 (Plasmodium falciparum) and P...

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Section: Discussionsupporting

confidence: 87%

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confidence: 99%

Murine Model for Assessment of Plasmodium falciparum Transmission-Blocking Vaccine Using Transgenic Plasmodium berghei Parasites Expressing the Target Antigen Pfs25

2008

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“…Human studies are expensive, and therefore, this is not a practical first step to evaluate vaccine candidates. Over the last decade or so, transfection of Plasmodium has revolutionized the ways in which protective immune responses can be evaluated using transgenic rodent parasites that have been transfected with the gene encoding a specific human malaria antigen (14,(26)(27)(28)(29). Active-and passive-immunization studies directed toward these antigens are more indicative of a biologically relevant immune response than the evaluation of immunogenicity alone.…”

Section: Discussionmentioning

confidence: 99%

“…Active-and passive-immunization studies directed toward these antigens are more indicative of a biologically relevant immune response than the evaluation of immunogenicity alone. Transgenic parasites carrying the CSP, MSP, and P25 genes of P. falciparum have been developed and are being used to evaluate vaccine candidates and/or platforms (14,(26)(27)(28)(29). To date, only one transgenic P. berghei sporozoite expressing P25 from P. vivax has been developed as a tool for evaluating the efficacy of vaccine candidates (29).…”

Section: Discussionmentioning

confidence: 99%

Development of a Chimeric Plasmodium berghei Strain Expressing the Repeat Region of the P. vivax Circumsporozoite Protein forIn VivoEvaluation of Vaccine Efficacy

et al. 2013

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The development of vaccine candidates against Plasmodium vivax-the most geographically widespread human malaria species-is challenged by technical difficulties, such as the lack of in vitro culture systems and availability of animal models. Chimeric rodent Plasmodium parasites are safe and useful tools for the preclinical evaluation of new vaccine formulations. We report the successful development and characterization of chimeric Plasmodium berghei parasites bearing the type I repeat region of P. vivax circumsporozoite protein (CSP). The P. berghei-P. vivax chimeric strain develops normally in mosquitoes and produces highly infectious sporozoites that produce patent infection in mice that are exposed to the bites of as few as 3 P. berghei-P. vivax-infected mosquitoes. Using this transgenic parasite, we demonstrate that monoclonal and polyclonal antibodies against P. vivax CSP strongly inhibit parasite infection and thus support the notion that these antibodies play an important role in protective immunity. The chimeric parasites we developed represent a robust model for evaluating protective immune responses against P. vivax vaccines based on CSP.T he global burden of malaria due to Plasmodium vivax is approximately 70 to 390 million cases annually (1), with around 2.5 billion people living at risk of infection (2). Even though Plasmodium falciparum remains the leading cause of malaria in Africa, P. vivax malaria is the most geographically widespread of the human malarias (2, 3). It is extensively distributed throughout the tropics, in the Middle East, Asia, the western Pacific, and Latin America (1-4).P. vivax malaria was long considered a benign and non-lifethreatening disease; however, recent publications report an increasing number of severe, complicated cases due to P. vivax infections (5, 6). Efforts toward the development of antimalaria vaccines are still mainly focused on P. falciparum, although P. vivax malaria is "harder to prevent, diagnose, and treat, and both species are coendemic" (7). While the importance of a vaccine targeting P. vivax is recognized, the development of P. vivax malaria vaccines is hampered by insufficient funding and technical difficulties (2,8,9). The lack of in vitro culture systems and suitable animal models, for example, imposes a significant limitation on testing novel vaccine candidates (7, 10).The circumsporozoite protein (CSP) is the most abundant protein on the surfaces of sporozoites and is responsible for eliciting both T-cell and antibody responses. The plasmodial CSP is one of the best studied antigens and is considered to be a major malaria vaccine candidate. RTS,S, the most effective malaria vaccine candidate to date, is based on P. falciparum CSP, thus underscoring CSP's immunogenic properties. CSP is comprised of an immunodominant central repeat region, diverse among Plasmodium species, flanked by two conserved domains: region I at the N terminus of the repeats and a type I thrombospondin repeat (TSR) motif C terminal to the repeat region. Early studies in animal...

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“…Full-length P. vivax P25 (Pvs25) and truncated Pvs25 (in which the glycosylphosphatidylinositol [GPI] sequence was replaced with the GPI sequence of P. berghei P25 [Pb25]; the GPI moiety is important in anchoring P25 on the surfaces of zygotes and ookinetes) were used to replace endogenous Pb25 and Pb28, generating Pv25DR and Pv25DR3 transgenic parasites, respectively (29). These P. berghei transgenic parasites expressed Pvs25 in the zygote and ookinete stages.…”

Section: Transgenic Parasites Based On Sexual-stage Antigens Pfs25 Anmentioning

confidence: 99%

Transgenic Rodent Plasmodium berghei Parasites as Tools for Assessment of Functional Immunogenicity and Optimization of Human Malaria Vaccines

Mlambo

Kumar

2008

Eukaryot Cell

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The use of transgenic Plasmodium berghei expressing the Plasmodium vivax antigen P25 to determine the transmission-blocking activity of sera from malaria vaccine trials

Cited by 48 publications

References 19 publications

Murine Model for Assessment of Plasmodium falciparum Transmission-Blocking Vaccine Using Transgenic Plasmodium berghei Parasites Expressing the Target Antigen Pfs25

Murine Model for Assessment of Plasmodium falciparum Transmission-Blocking Vaccine Using Transgenic Plasmodium berghei Parasites Expressing the Target Antigen Pfs25

Development of a Chimeric Plasmodium berghei Strain Expressing the Repeat Region of the P. vivax Circumsporozoite Protein forIn VivoEvaluation of Vaccine Efficacy

Transgenic Rodent Plasmodium berghei Parasites as Tools for Assessment of Functional Immunogenicity and Optimization of Human Malaria Vaccines

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