Safety and immunogenicity of Pfs25H-EPA/Alhydrogel, a transmission-blocking vaccine against Plasmodium falciparum: a randomised, double-blind, comparator-controlled, dose-escalation study in healthy Malian adults

Sagara, Issaka; Healy, Sara A.; Assadou, Mahamadoun H.; Gabriel, Erin E.; Kone, M.; Sissoko, Kourane; Tembine, Intimbeye; Guindo, Merepen A.; Doucoure, M'Bouye; Niaré, Karamoko; Dolo, Amagana; Rausch, Kelly M.; Narum, David L.; Jones, Davey L.; MacDonald, Nicholas J.; Zhu, Daming; Mohan, Rathy; Muratova, Olga; Baber, Ibrahima; Coulibaly, Mamadou B.; Fay, Michael P.; Anderson, Charles; Wu, Yimin; Traorè, Sékou F.; Doumbo, Ogobara K.; Duffy, Patrick E.

doi:10.1016/s1473-3099(18)30344-x

Cited by 91 publications

(78 citation statements)

References 28 publications

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“…Such a medicine would be viewed as altruistic, and the ethical context would be similar to that previously discussed for transmission-blocking vaccines [ 64 , 65 ]. There are experimental approaches to transmission-blocking vaccines [ 66 , 67 ], with the most advanced candidate being in clinical testing [ 68 ]. The safety and tolerability for a new TCP-6 molecule needs to be at a similar level to that traditionally seen in vaccination programmes.…”

Section: Introductionmentioning

confidence: 99%

A discovery and development roadmap for new endectocidal transmission-blocking agents in malaria

Burrows

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Macintyre

et al. 2018

Malar J

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Reaching the overall goal of eliminating malaria requires halting disease transmission. One approach to blocking transmission is to prevent passage of the parasite to a mosquito, by preventing formation or transmission of gametocytes. An alternative approach, pioneered in the veterinary field, is to use endectocides, which are molecules that render vertebrate blood meals toxic for the mosquito vector, also killing the parasite. Field studies and modelling suggest that reducing the lifespan of the mosquito may significantly reduce transmission, given the lengthy maturation process of the parasite. To guide the development of new endectocides, or the reformulation of existing molecules, it is important to construct a framework of the required attributes, commonly called the target candidate profile. Here, using a combination of insights from current endectocides, mathematical models of the malaria transmission dynamics, and known impacts of vector control, a target candidate profile (TCP-6) and a regulatory strategy are proposed for a transmission reducing agent. The parameters chosen can be used to assess the potential of a new medicine, independent of whether it has classical endectocide activity, reduces the insect and parasite lifespan or any combination of all three, thereby constituting an ‘endectocidal transmission blocking’ paradigm.

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Section: Introductionmentioning

confidence: 99%

A discovery and development roadmap for new endectocidal transmission-blocking agents in malaria

Burrows

Slater

Macintyre

et al. 2018

Malar J

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“…Unfortunately, clinical trial results have not given support to the continued development of a stand-alone Pfs25-EPA TB vaccine. Pfs25-EPA conjugates formulated with Alhydrogel™, an aluminum based adjuvant, in phase 1 trials conducted in the United States 11 and in Mali, West Africa 12 have required four doses to generate antibody titers that significantly reduced parasite transmission as assessed by an ex vivo standard membrane feeding assay (SMFA) 11,12 .…”

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confidence: 99%

Structure and function of a malaria transmission blocking vaccine targeting Pfs230 and Pfs230-Pfs48/45 proteins

et al. 2020

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Proteins Pfs230 and Pfs48/45 are Plasmodium falciparum transmission-blocking (TB) vaccine candidates that form a membrane-bound protein complex on gametes. The biological role of Pfs230 or the Pfs230-Pfs48/45 complex remains poorly understood. Here, we present the crystal structure of recombinant Pfs230 domain 1 (Pfs230D1M), a 6-cysteine domain, in complex with the Fab fragment of a TB monoclonal antibody (mAb) 4F12. We observed the arrangement of Pfs230 on the surface of macrogametes differed from that on microgametes, and that Pfs230, with no known membrane anchor, may exist on the membrane surface in the absence of Pfs48/45. 4F12 appears to sterically interfere with Pfs230 function. Combining mAbs against different epitopes of Pfs230D1 or of Pfs230D1 and Pfs48/45, significantly increased TB activity. These studies elucidate a mechanism of action of the Pfs230D1 vaccine, model the functional activity induced by a polyclonal antibody response and support the development of TB vaccines targeting Pfs230D1 and Pfs230D1-Pfs48/45.

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“…NCT02013687). The initial trials using Alhydrogel formulations of Pfs-EPA or Pfs25-VLP showed that they were safe but did not stimulate robust TBA titers, and these results have led to the testing of alternative adjuvants, including AS01 (113)(114)(115).…”

Section: Gametocyte/gamete Antigens Pfs230 Pfs48/45 Pfs47 and Hap2mentioning

confidence: 99%

Transmission-Blocking Vaccines: Old Friends and New Prospects

et al. 2019

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In the progression of the life cycle of Plasmodium falciparum, a small proportion of asexual parasites differentiate into male or female sexual forms called gametocytes. Just like their asexual counterparts, gametocytes are contained within the infected host's erythrocytes (RBCs). However, unlike their asexual partners, they do not exit the RBC until they are taken up in a blood meal by a mosquito. In the mosquito midgut, they are stimulated to emerge from the RBC, undergo fertilization, and ultimately produce tens of thousands of sporozoites that are infectious to humans. This transmission cycle can be blocked by antibodies targeting proteins exposed on the parasite surface in the mosquito midgut, a process that has led to the development of candidate transmission-blocking vaccines (TBV), including some that are in clinical trials. Here we review the leading TBV antigens and highlight the ongoing search for additional gametocyte/gamete surface antigens, as well as antigens on the surfaces of gametocyte-infected erythrocytes, which can potentially become a new group of TBV candidates.

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Safety and immunogenicity of Pfs25H-EPA/Alhydrogel, a transmission-blocking vaccine against Plasmodium falciparum: a randomised, double-blind, comparator-controlled, dose-escalation study in healthy Malian adults

Abstract: Division of Intramural Research, National Institute of Allergy and Infectious Diseases.

Cited by 91 publications

References 28 publications

A discovery and development roadmap for new endectocidal transmission-blocking agents in malaria

A discovery and development roadmap for new endectocidal transmission-blocking agents in malaria

Structure and function of a malaria transmission blocking vaccine targeting Pfs230 and Pfs230-Pfs48/45 proteins

Transmission-Blocking Vaccines: Old Friends and New Prospects

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