Plasmodium sporozoite NPDP peptides as vaccine and target novel malaria vaccines and antibodies binding to

A Plasmodium and circumsporozoite protein technology, applied in the direction of antibodies, fusion polypeptides, antibody medical components, etc., can solve the problems of not providing significant protection against severe malaria, complicating vaccine development, and reducing efficacy.

Pending Publication Date: 2020-03-31
INSTITUTE FOR RESEARCH IN BIOMEDECINE +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Lack of booster dose reduces efficacy against severe malaria to negligible effect
Vaccines shown to be less effective in babies
Three doses of vaccine plus booster reduce risk of clinical episodes by 26% over three years, but provide no significant protection against severe malaria
[0009] Furthermore, another factor that has complicated the development of such vaccines is the difficulty in identifying strong correlates of protection
Antibody has been shown to inhibit sporozoite invasion of hepatocytes in in vitro functional tests, but its role in protecting malaria-vaccinated individuals is unknown

Method used

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  • Plasmodium sporozoite NPDP peptides as vaccine and target novel malaria vaccines and antibodies binding to
  • Plasmodium sporozoite NPDP peptides as vaccine and target novel malaria vaccines and antibodies binding to
  • Plasmodium sporozoite NPDP peptides as vaccine and target novel malaria vaccines and antibodies binding to

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0605] Example 1: Isolation of human monoclonal antibodies that bind to Plasmodium falciparum sporozoites

[0606] Four malaria-free Tanzanian donors (identified as donors G, H, U and V) were selected for isolation of human monoclonal antibodies. For this purpose, peripheral blood mononuclear cells (PBMC) were isolated from blood samples of four donors. IgG memory B cells were isolated from frozen peripheral mononuclear cells (PBMCs) by magnetic cell sorting. B cells were incubated with 0.5 μg / mL anti-CD19-PECy7 antibody for 20 min on ice, and then with mouse anti-PE microbeads for 30 min on ice. Cells were then stained with 3.75 μg / mL goat Alexa Fluor 647-conjugated anti-human IgG for 20 min on ice and sorted by FACS. Sorted B cells were immortalized with Epstein-Barr (EBV) virus and plated in the presence of CpG and irradiated PBMC feeder cells as previously described in Traggiai et al. (2004) Nat Med. 10, 871-875. Plate in single cell culture. After 14 days, the cultu...

Embodiment 2

[0612] Example 2: Several monoclonal antibodies show potent anti-sporozoite function in vitro and in vivo

[0613] During the liver stage of the Plasmodium life cycle, sporozoites typically traverse hepatocytes before productively invading target hepatocytes. Exemplary monoclonal antibodies MGG1, MGG2, MGG3, MGG4, MGG8, MGH1, MGH2 and MGH3 (see Tables 1 and 2 for SEQ ID NOs) were tested in vitro for their ability to inhibit sporozoite traversal and invasion of hepatocytes. For this, a quantitative flow cytometry-based assay was used, which is described in Kaushansky A, Rezakhani N, Mann H, Kappe SH, 2012: Development of a quantitative flowcytometry-based assay to assess infection by Plasmodium falciparum sporozoites. Mol Biochem Parasitol.183 (1): 100-3 in. Figure 2A A schematic of this assay is shown. Briefly, in this assay, the hepatocyte HC04 cell line is infected with P. falciparum sporozoites in the presence of FITC-dextran. Sporozoite traversal was measured by upta...

Embodiment 3

[0617] Example 3: Effective monoclonal antibodies display a unique pattern of binding to CSP and use VH3-30

[0618] Plasmodium circumsporozoite protein (CSP) is an immunodominant protein that coats the entire sporozoite surface and plays an important role in sporozoite function. Such as Figure 4A As shown, this protein contains an N-terminal segment beginning with a signal peptide (SP) and ending with region I (RI). Region I is a pentapeptide (KLKQP; SEQ ID NO:25) involved in binding hepatocytes and mosquito salivary glands. In CSP, region I is followed by the NANP repeat region, the immunodominant site of the antibody and the C-terminal thrombospondin-like domain containing the T cell epitope ( Figure 4A ). Figure 4B An exemplary sequence of the circumsporozoite protein of P. falciparum isolate NF54 is shown (SEQ ID NO: 24).

[0619] An antigen-agnostic approach as described in Example 1 was used to identify any antibodies that could bind to the sporozoite surface. ...

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Abstract

The present invention provides a fragment of piasmodium circumsporozoite protein according to SEQ ID NO: 1, for example for use in a malaria vaccine. The present invention also provides nucleic acidsencoding a fragment of piasmodium circumsporozoite protein according to SEQ ID NO: 1, compositions comprising a fragment of piasmodium circumsporozoite protein according to SEQ ID NO: 1 and antibodiesbinding to a fragment of piasmodium circumsporozoite protein according to SEQ ID NO: 1. The antibodies according to the present invention bind specifically to P. falciparum sporozoites and may be used in the treatment and / or prevention of malaria.

Description

technical field [0001] The present invention relates to the field of malaria medicine, in particular to malaria vaccination and antibodies that bind to Plasmodium sporozoites, specifically Plasmodium circumsporozoite protein. [0002] Background of the invention [0003] Malaria is a mosquito-borne infectious disease affecting humans and other animals caused by parasitic protozoa of the genus Plasmodium. The Plasmodium genus includes about 200 species, five of which routinely infect humans, while others infect birds, reptiles, rodents and various primates. P. falciparum (P. falciparum), P. vivax (P. vivax), P. ovale (P. ovale), and P. malariae (P. malariae) together cause infection of nearly all Plasmodium species, Plasmodium falciparum is responsible for the vast majority of malaria deaths. Symptoms of malaria typically include fever, feeling tired, vomiting and headache. In severe cases, it can cause yellowing of the skin, seizures, coma or death. [0004] Malaria is mo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/20A61K38/03A61K39/015A61P33/06
CPCA61K38/03A61K39/015A61K2039/505A61P33/06C07K16/205C07K2317/21C07K2317/34C07K2317/76C07K2319/40Y02A50/30C07K5/10C07K14/445A61K38/07C07K2317/24C07K2317/565C07K2317/92
Inventor A·兰扎韦基亚J·H·Y·谭C·达本伯格B·萨克
Owner INSTITUTE FOR RESEARCH IN BIOMEDECINE
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