Serum antibody assay for determining protection from malaria, and pre-erythrocytic subunit vaccines

a malaria and antibody assay technology, applied in the field of serum antibody assay, can solve the problems of low-level immune response and minimal protection, cumbersome chmi, and high cos

Inactive Publication Date: 2016-11-03
UNITED STATES OF AMERICA +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, mosquito bite is not a useful way to administer sporozoites and as a practical matter, a whole sporozoite vaccine approach would require the capacity to manufacture live, aseptic, radiation-attenuated, purified, preserved PfSPZ as the immunogen of an injectable vaccine that meets regulatory standards (T. C. Luke, et al., J. Exp. Biol. 206, 3803-3808 (2003); S. L. Hoffman, et al., Hum. Vac. 6, 97-106 (2010); J. E. Epstein, et al., Science 334, 475-480 (2011)).
PfSPZ Vaccine proved safe and well-tolerated, but elicited low-level immune response and minimal protection.
It was hypothesized that the limited efficacy was due to the inefficiency of the ID and SC routes of administration (J. E. Epstein, et al.
While effective, CHMI is cumbersome and expensive, requiring participation of several clinicians, experts, and hospital facilities.

Method used

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  • Serum antibody assay for determining protection from malaria, and pre-erythrocytic subunit vaccines
  • Serum antibody assay for determining protection from malaria, and pre-erythrocytic subunit vaccines
  • Serum antibody assay for determining protection from malaria, and pre-erythrocytic subunit vaccines

Examples

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Effect test

example 1

[0142]A clinical trial testing the immunogenicity and efficacy of aseptic, radiation-attenuated, purified, cryopreserved sporozoites used as the immunogen in a vaccine formulation (Sanaria® PfSPZ Vaccine, provided by Sanaria Inc.), and administered by intravenous injection, resulted in 13 individuals that were protected against controlled human malaria infection (CHMI) and 19 that were not protected (Table 4). In the group receiving the highest dosage (675,000 total PfSPZ), 6 out of 6 individuals were protected; and the group receiving the next lower dosage (540,000 total PfSPZ) had 6 out of 9 protected (Seder et al., Science 2013).

TABLE 4Protection efficacyTotalPfSPZ perdosage ofProtection %DoseDosesPfSPZ# volunteers# ProtectedProtection %Combined7500 (low)430000300%0%645000300%3000041200009111%9%(medium)6180000200%135000 (high)45400009667%80%567500066100%

[0143]The 5-dose (675000 SPZ) group in which all subjects were protected differed from other groups, e.g., these subjects receiv...

example 2

P. falciparum Proteome Microarray Chip Fabrication

[0144]P. falciparum (Pf) genes, representing 91% of the Pf proteome, were selected and cloned into the Escherichia coli (E. coli) expression vector pXT7. Included among these genes were those corresponding to SEQ ID NOs:1-10. Custom polymerase chain reaction (PCR) primers comprising 20-bp gene-specific sequences with 33-bp adapter sequences were used to amplify target amplicons from Pf genomic DNA. The adapter sequences, which flank the target amplicons, are homologous to the adapter sequences at the ends of the linearized T7 expression vector pXT7 into which they were cloned. The homology allows the amplified PCR products to be cloned into the expression vector by in vivo homologous recombination in competent DH5a cells. The resulting clone mixtures were then verified by PCR using sequence specific primers and subsequently sequenced. For proteins microarray chip fabrication, Pf proteins were expressed in E. coli-based cell-free in v...

example 3

[0151]Among the 1,567 immunoreactive antigens, a subset of proteins was identified as useful for identifying of protected subjects, or being “Associated with Protection.” In addition to CSP and MSP5, pre-CHMI antibodies against antigens with high AUC were glycogen synthase kinase 3, or GSK3 (gene id: PF3D7_0312400; AUC: 0.94, BH P-value=0.004) and a conserved protein of unknown function (PF3D7_1030200; AUC: 0.88, BH P-value=0.036). These antigens and other top antigen are shown in FIG. 4.

[0152]For antibody Deltas (the difference between pre-immunization and pre-CHMI), we identified a leucine-rich repeat protein, called LRR9 (PF3D7_0906700; AUC: 0.90, BH P-value=0.003), and a protein described as double C2-like domain-containing protein, or DOC2 (PF3D7_1243900; AUC: 0.96, BH P-value=0.0005) with high AUC for protection. These antigens and other top antigens are shown in Table 6 and FIG. 5. As with the down-selected chip, the CSP was a top candidate with a pre-CHMI AUC of 0.93 (BH P-v...

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Abstract

Disclosed herein are diagnostic methods and compositions for identifying individuals that are protected against Plasmodium falciparum caused malaria. Such methods are particularly useful for determining not only the protective efficacy of Pf whole parasite vaccines for individual subjects, but also within populations of vaccinated subjects. Also disclosed herein are subunit vaccines comprising at least one Pf immunologic determinant for protection against Plasmodium-caused malaria.

Description

FIELD OF THE INVENTION[0001]This invention relates generally to the field of malaria immunology and vaccinology.REFERENCE TO A SEQUENCE LISTING SUBMITTED ELECTRONICALLY VIA EFS-WEB[0002]The content of the electronically submitted sequence listing (Name: “2602_0150001_SeqListing_ST25.txt”; Size: 46,696 bytes; and date of creation: Mar. 3, 2016) filed herewith the application is incorporated by reference in its entirety.BACKGROUND OF THE INVENTION[0003]Malaria control interventions, including insecticide-impregnated bed nets, insecticide spraying, and antimalarial drugs, have reduced malaria morbidity and mortality substantially (World Health Organization, World Malaria Report: 2013 (2013; www.who / int / malaria / publications / world_malaria_report_2013 / report / en / ). However, in 2010, despite these measures, there were an estimated 220 million clinical cases and 0.66 to 1.24 million deaths caused by malaria (World Health Organization, World Malaria Report: 2012, C. J. Murray et al., Lancet 3...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): G01N33/68A61K39/015
CPCG01N33/6854A61K39/015G01N2333/445A61K2039/521G01N2469/20A61K2039/54G01N33/56905A61K2039/522Y02A50/30
Inventor FELGNER, PHILIPHOFFMAN, STEPHEN L.SEDER, ROBERTCAMPO, JR., JOSEPH J.
Owner UNITED STATES OF AMERICA
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