Development of Malaria Transmission-Blocking Vaccines: From Concept to Product

Wu, Yimin; Sinden, Robert E.; Churcher, Thomas S.; Tsuboi, Takafumi; Yusibov, Vidadi

doi:10.1016/bs.apar.2015.04.001

Cited by 85 publications

(83 citation statements)

References 201 publications

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“…However, it is estimated that 438,000 malaria related deaths, mostly due to Plasmodium falciparum , occurred in 2015 [1]. Multiple novel tools are likely to be required to achieve the ultimate goal of malaria eradication, and a transmission-blocking vaccine (TBV) is considered to be one of them [2-4]. TBVs are designed to induce antibodies in human hosts against sexual stage malaria antigens or to antigens found in the mosquito vector, and these antibodies should inhibit parasite development in the mosquito when they are ingested with gametocyte-stage parasites.…”

Section: Introductionmentioning

confidence: 99%

Transmission-blocking activity is determined by transmission-reducing activity and number of control oocysts in Plasmodium falciparum standard membrane-feeding assay

Miura

Swihart

Deng

et al. 2016

Vaccine

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Malaria transmission-blocking vaccines (TBVs) are potentially helpful tools for malaria eradication. The standard membrane-feeding assay (SMFA) is considered one of the “gold standard” assays for TBV development. However, lack of consensus in reporting results from SMFA has made it very challenging to compare results from different studies. Two main readouts, % inhibition in mean oocyst count per mosquito (TRA) and % inhibition in prevalence of infected mosquitoes (TBA), have been used widely. In this study, we statistically modeled the oocyst data in SMFA using data from 105 independent feeding experiments including 9,804 mosquitoes. The model was validated using an independent data set that included 10,790 mosquitoes from 110 feeding studies. The model delineates a relationship between TRA, the mean oocyst count in the control mosquitoes (mo-contl), and TBA. While TRA was independent from mo-contl, TBA values changed depending on mo-contl. Regardless of monoclonal or polyclonal antibodies tested, there were strong concordances between observed TBA and predicted TBA based on the model using mo-contl and observed TRA. Simulations showed that SMFA with lower true control means had increased uncertainty in TRA estimates. The strong linkage between TBA, TRA and mo-contl inspired creation of a standardized TBA, a model-based TBA standardized to a target control mean, which allows comparison across multiple feeds regardless of mo-contl. This is the first study showing that the observed TBA can be reasonably predicted by mo-contl and the TRA of the test antibody using independent experimental data. This study indicates that TRA should be used to compare results from multiple feeds with different levels of mo-contl. If a measure of TBA is desired, it is better to report standardized TBA rather than observed TBA. These recommendations support rational comparisons of results from different studies, thus benefiting future TBV development.

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Section: Introductionmentioning

confidence: 99%

Transmission-blocking activity is determined by transmission-reducing activity and number of control oocysts in Plasmodium falciparum standard membrane-feeding assay

Miura

Swihart

Deng

et al. 2016

Vaccine

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“…The primary mode of action of TBVs is via induction of antibodies that target surface antigens expressed in the sexual stages of the parasite. P. falciparum TBV candidates include prefertilization antigens Pfs230 and Pfs48/45 and postfertilization antigens Pfs25 and Pfs28 (6,7). So far, vaccine approaches based on recombinant protein-adjuvant formulations have met with limited success due to the complex conformational nature of these antigens, often resulting in improperly folded, unstable, and aggregated proteins (6).…”

mentioning

confidence: 99%

“…P. falciparum TBV candidates include prefertilization antigens Pfs230 and Pfs48/45 and postfertilization antigens Pfs25 and Pfs28 (6,7). So far, vaccine approaches based on recombinant protein-adjuvant formulations have met with limited success due to the complex conformational nature of these antigens, often resulting in improperly folded, unstable, and aggregated proteins (6). DNA vaccines encoding specific P. falciparum TBV target antigens offer alternatives to traditional platforms as seen in murine (8) and nonhuman primate (9) models.…”

mentioning

confidence: 99%

Evaluation of the Impact of Codon Optimization and N-Linked Glycosylation on Functional Immunogenicity of Pfs25 DNA Vaccines Delivered by In Vivo Electroporation in Preclinical Studies in Mice

Datta

Bansal

Kumar

et al. 2015

Clin Vaccine Immunol

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bPlasmodium falciparum sexual stage surface antigen Pfs25 is a well-established candidate for malaria transmission-blocking vaccine development. Immunization with DNA vaccines encoding Pfs25 has been shown to elicit potent antibody responses in mice and nonhuman primates. Studies aimed at further optimization have revealed improved immunogenicity through the application of in vivo electroporation and by using a heterologous prime-boost approach. The goal of the studies reported here was to systematically evaluate the impact of codon optimization, in vivo electroporation, and N-linked glycosylation on the immunogenicity of Pfs25 encoded by DNA vaccines. The results from this study demonstrate that while codon optimization and in vivo electroporation greatly improved functional immunogenicity of Pfs25 DNA vaccines, the presence or absence of N-linked glycosylation did not significantly impact vaccine efficacy. These findings suggest that N-glycosylation of Pfs25 encoded by DNA vaccines is not detrimental to overall transmission-blocking efficacy. Malaria caused by Plasmodium species is still endemic in 97 countries, and WHO estimated that 3.3 billion people are at risk of disease, with ϳ584,000 deaths reported in 2013 (1). Plasmodium falciparum is responsible for the most morbidity and mortality and is thus the major focus of current vaccine development efforts (2). The malaria eradication research agenda (malERA) initiative of 2011 underscored the need for a multipronged approach for malaria control and elimination that includes vaccines targeting infection (3) and transmission along with various control measures currently in use such as indoor residual spraying and insecticide-treated mosquito nets (4).Malaria transmission-blocking vaccines (TBVs) target the sexual life cycle stages of the parasite that develop in the mosquito vector with the goal of interrupting transmission and further spread of the infection (5). The primary mode of action of TBVs is via induction of antibodies that target surface antigens expressed in the sexual stages of the parasite. P. falciparum TBV candidates include prefertilization antigens Pfs230 and Pfs48/45 and postfertilization antigens Pfs25 and Pfs28 (6, 7). So far, vaccine approaches based on recombinant protein-adjuvant formulations have met with limited success due to the complex conformational nature of these antigens, often resulting in improperly folded, unstable, and aggregated proteins (6). DNA vaccines encoding specific P. falciparum TBV target antigens offer alternatives to traditional platforms as seen in murine (8) and nonhuman primate (9) models. Additional benefits for use of DNA vaccines include ease of design and sequence modification, stability, and transportability (10). Studies in mice with Pfs25 DNA plasmids showed high TBV activity with Ͼ95% oocyst reduction in the mosquitoes (8). Similar studies in rhesus macaques, however, revealed only modest immunogenicity even after four immunization doses and required heterologous boosting with recombinant protein for ...

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“…Development of vaccines for malaria has focused on antigens expressed during various stages of the parasite, and malaria transmission blocking vaccines (TBVs) target antigens in sexual and mosquito midgut stage parasites. In Plasmodium falciparum these TBV target antigens include Pfs230 and Pfs48/45 expressed on circulating intra-erythrocytic male and female gametocytes and gametes, as well as Pfs25 expressed during mosquito midgut stage development (zygote to ookinete) [1]. Pfs25 has undergone extensive pre-clinical evaluation and a few phase I clinical trials as adjuvant formulated recombinant protein with mixed and varying outcomes [2–5].…”

Section: Introductionmentioning

confidence: 99%

Comparative functional potency of DNA vaccines encoding Plasmodium falciparum transmission blocking target antigens Pfs48/45 and Pfs25 administered alone or in combination by in vivo electroporation in rhesus macaques

Datta

Bansal

Grasperge

et al. 2017

Vaccine

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Antibodies recognizing conformational epitopes in Pfs48/45, an antigen expressed on the surface of Plasmodium falciparum gametes and zygotes, have firmly established Pfs48/45 as a promising transmission blocking vaccine (TBV) candidate. However, it has been difficult to reproducibly express Pfs48/45 in a variety of recombinant expression systems. The goal of our studies was to evaluate functional immunogenicity of Pfs48/45 using DNA vaccine format in rhesus macaques. An additional goal was to ensure that when used in combination with another malarial antigen, specific immunity to both antigens was not compromised. For testing combination vaccines, we employed Pfs25 DNA plasmids that have previously undergone evaluations in rodents and nonhuman primates. Pfs25 is expressed on the surface of parasites after fertilization and is also a lead TBV candidate. DNA plasmids based on codon-optimized sequences of Pfs48/45 and Pfs25 were administered by in vivo electroporation, followed by a final recombinant protein boost. Our studies demonstrate that Pfs48/45 encoded by DNA plasmids is capable of inducing potent transmission blocking antibody responses, and such transmission blocking immune potency of Pfs48/45 was not compromised when tested in combination with Pfs25, These findings provide the evidence in favor of further studies on Pfs48/45 and Pfs25, either alone or in combination with other known malaria vaccine candidates for developing effective vaccines capable of interrupting malaria transmission.

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Development of Malaria Transmission-Blocking Vaccines: From Concept to Product

Cited by 85 publications

References 201 publications

Transmission-blocking activity is determined by transmission-reducing activity and number of control oocysts in Plasmodium falciparum standard membrane-feeding assay

Transmission-blocking activity is determined by transmission-reducing activity and number of control oocysts in Plasmodium falciparum standard membrane-feeding assay

Evaluation of the Impact of Codon Optimization and N-Linked Glycosylation on Functional Immunogenicity of Pfs25 DNA Vaccines Delivered by In Vivo Electroporation in Preclinical Studies in Mice

Comparative functional potency of DNA vaccines encoding Plasmodium falciparum transmission blocking target antigens Pfs48/45 and Pfs25 administered alone or in combination by in vivo electroporation in rhesus macaques

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