Methods and compositions for treating and preventing malaria using an invasion ligand directed to a protease-resistant receptor
View Patent ↗This invention relates to an immunogenic molecule comprising a contiguous amino acid sequence of an invasion ligand of a strain of Plasmodium falciparum , the invasion ligand capable of binding to an erythrocyte receptor, the receptor function being resistant to trypsin and neuraminidase and chymotrypsin, wherein when administered to a subject the molecule is capable of inducing an immune response to the strain. The invention further relates to compositions and methods for the treatment of diseases such as malaria.
1. A composition comprising a combination of:
(a) an isolated immunogenic molecule consisting of a sequence selected from the group consisting of SEQ ID NOS: 2, 4, 5, 6, 7, 8, 9, 10, 11 and 12, or an isolated immunogenic molecule consisting of a sequence selected from the group consisting of the amino acid sequence set forth in SEQ ID NOS: 2, 4, 5, 6, 7, 8, 9, 10, 11 and 12 except for the amino acid substitution in a corresponding residue where applicable in any of SEQ ID NOS: 2, 4, 5, 6, 7, 8, 9, 10, 11 and 12 selected from:
E at amino acid 25 in SEQ ID NO: 2 is replaced with K, Y at amino acid 124 in SEQ ID NO: 2 is replaced with H, H at amino acid 125 in SEQ ID NO: 2 is replaced with N, S at amino acid 174 in SEQ ID NO: 2 is replaced with Y, C at amino acid 180 in SEQ ID NO: 2 is replaced with Y, I at amino acid 181 in SEQ ID NO: 2 is replaced with K or R, N at amino acid 324 is replaced with Y or D, Y at amino acid 335 in SEQ ID NO: 2 is replaced with F, E at amino acid 339 in SEQ ID NO: 2 is replaced with D, V at amino acid 348 in SEQ ID NO: 2 is replaced with I, I at amino acid 384 in SEQ ID NO: 2 is replaced with V, I at amino acid 387 in SEQ ID NO: 2 is replaced with M, and K at amino acid 406 in SEQ ID NO: 2 is replaced with N;
(b) an isolated immunogenic molecule consisting of amino acids 761-1271 of the erythrocyte binding antigen (EBA) protein EBA175 of SEQ ID NO: 17 or an isolated immunogenic molecule consisting of amino acids 761-1271 of the erythrocyte binding antigen (EBA) protein EBA175 of SEQ ID NO: 17 except for the amino acid substitution selected from: S at amino acid 768 in SEQ ID NO: 17 replaced with N, E at amino acid 923 of SEQ ID NO: 17 replaced with K, K at amino acid 932 in SEQ ID NO: 17 replaced with E, E at amino acid 1058 in SEQ ID NO: 17 replaced with V, and G at amino acid 1100 in SEQ ID NO: 17 replaced with D; and
(c) an effective amount of a vaccine adjuvant;
wherein the composition induces an immune response to a strain of Plasmodium falciparum when administered to a subject.
2. The composition according to claim 1 , wherein the immune response is an invasion-inhibitory immune response.
3. The composition according to claim 1 wherein the strain of Plasmodium falciparum is a wild type strain.
4. The composition according to claim 1 further comprising a pharmaceutically acceptable excipient.
5. A method of treating a condition caused by or associated with infection by Plasmodium falciparum comprising administering to a subject in need thereof an effective amount of the composition according to claim 1 .
6. A composition comprising a combination of:
(a) an isolated immunogenic molecule consisting of a sequence selected from the group consisting of SEQ ID NOS: 2, 4, 5, 6, 7, 8, 9, 10, 11 and 12, or an isolated immunogenic molecule consisting of a sequence selected from the group consisting of the amino acid sequence set forth in SEQ ID NOS: 2, 4, 5, 6, 7, 8, 9, 10, 11 and 12except for the amino acid substitution in a corresponding residue where applicable in any of SEQ ID NOS: 2, 4, 5, 6, 7, 8, 9, 10, 11 and 12 selected from:
E at amino acid 25 in SEQ ID NO: 2 is replaced with K, Y at amino acid 124 in SEQ ID NO: 2 is replaced with H, H at amino acid 125 in SEQ ID NO: 2 is replaced with N, S at amino acid 174in SEQ ID NO: 2 is replaced with Y, C at amino acid 180 in SEQ ID NO: 2 is replaced with Y, I at amino acid 181 in SEQ ID NO: 2 is replaced with K or R, N at amino acid 324 is replaced with Y or D, Y at amino acid 335 in SEQ ID NO: 2 is replaced with F, E at amino acid 339 in SEQ ID NO: 2 is replaced with D, V at amino acid 348 in SEQ ID NO: 2 is replaced with I, I at amino acid 384 in SEQ ID NO: 2 is replaced with V, I at amino acid 387 in SEQ ID NO: 2 is replaced with M, and K at amino acid 406 in SEQ ID NO: 2 is replaced with N;
(b) an isolated immunogenic molecule consisting of amino acids 761-1271 of the erythrocyte binding antigen (EBA) protein EBA175 of SEQ ID NO: 17 or an isolated immunogenic molecule consisting of amino acids 761-1271 of the erythrocyte binding antigen (EBA) protein EBA175 of SEQ ID NO: 17 except for the amino acid substitution selected from: S at amino acid 768 in SEQ ID NO: 17 replaced with N, E at amino acid 923 of SEQ ID NO: 17 replaced with K, K at amino acid 932 in SEQ ID NO: 17 replaced with E, E at amino acid 1058 in SEQ ID NO: 17 replaced with V, and G at amino acid 1100 in SEQ ID NO: 17 replaced with D; and
(c) an effective amount of a vaccine adjuvant;
wherein at least one immunogenic molecule is fused to Glutathione S-transferase (GST) or histidine (HIS) tag or is conjugated to a carrier protein and wherein the composition induces an immune response to Plasmodium falciparum when administered to a subject.
7. The composition of claim 6 wherein the immunogenic molecule of subpart (b) is fused to Glutathione S-transferase (GST) or histidine (HIS) tag or is conjugated to a carrier protein.
8. The composition of claim 6 wherein the immunogenic molecule of subpart (b) is a Fusion protein or is conjugated to a carrier protein.