Table 3.
A list of TB peptide-based vaccines evaluated for immunogenicity and protection in animal models.
| Reference | Protein and peptide (sequences) | Formulation (likers or adjuvant) | Host organism | Dose/route | Adjuvant | Challenge | Efficacy |
|---|---|---|---|---|---|---|---|
| (234) | Rv3407 64-72 (IPARRPQNL), and Rv3407 68-76 (RPQNLLDVT) | – | Splenocytes from vaccinated BALB/c mice | 105 splenocytes per well were stimulated with 10 μg of peptide | – | - | These peptides stimulated splenocytes collected from vaccine immunized mice secreting significantly higher IFN-γ |
| (197) | 15 peptides† from Rv0203, Rv3106, Rv2223c, Rv3201c, Rv3296, Rv1242, Rv1184c, Rv3207c, Rv1157c, Rv1158c, Rv1291c, Rv1860, Rv2190c, Rv333c, Rv0309 | – | PBMCs | – | – | - | 15 peptides stimulated IFN-γ response, and eight peptides stimulated lymphocyte proliferation in vitro. |
| (235) | pcDNA3-M-38 vaccine, MPT64 190-198 (FAVTNDGVI) and 38 kDa proteins 166-175 (IAALNPGVNL) | pcDNA3 vector + MPT64 190-198 (FAVTNDGVI) + 38 kDa proteins 166-175 (IAALNPGVNL) | C57BL/6 (H-2b) mice | 100µg of DNA per mouse/i.m., 3 times at intervals of 21 days | – | – | DNA immunization with p3-M-38 vaccine could induce epitope-specific CD8+ CTL response but not antibodies |
| (236) | Ag85B 96–111 (QDAYNAAGGHNAVFN) and Ag85B 241–256 (PAFEWYYQSGLSIVMP) | Rv1886c 96-111 or Rv1886c 241-256 + RVG peptide (YTIWMPENPRPGTPCDIFTNSR) | C57BL/6 mice | 10μg of peptides (RVG, Rv1886c 96-111 or Rv1886c 241-256)/s.c. or i.n., 3 times at 14days apart | – | – | Higher levels of IL-12, IFN-γ, IL-2, and TNF-α |
| (237) | Rv0934 169-405 and Rv0934 802-1119 | Rv0934 169-405 + Rv0934 802-1119 + His-tag | BALB/c mice | Triplicate over a 2-week interval/s.c. | DDA/poly (I: C) | – | Elicited higher IgG and IFN-γ, IL-2 |
| (198) | TB 001 DNA multi epitope vaccine, 24 peptides from Antigen 85 complex, MPT 64, MPB/MPT 70, MPT 63, the 38 kDa, 14-kDa, 16-kDa, 19-kDa, and 32-kDa Mtb |
24 peptides linked with GPGPG linker | HLA-DR B*0101 transgenic mice | 100 μg of DNA vaccine/i.m., 3 times at intervals of 14 days | rIL-15 | - | Epitope-specific T cell responses were observed to eight of the 24 epitopes contained in the DNA construct |
| (223) | ESAT-6 (Rv3875) 1–15 (MTEQQWNFAGIEAAA) | ESAT-6 or Δ15ESAT-6 (lack the immunodominant ESAT-6 1–15) + CAF01 adjuvant | CB6F1 mice | 5 μg of ESAT-6 or Δ15-ESAT with a 200μl CAF01/s.c., 3 times, with a 2-week interval | CAF01 | Mtb Erdman strain (20-50 CFUs/aerosol) | Both vaccines reduced CFUs at the early time point, only the Δ15ESAT-6-based vaccine gave significant levels of protection (0.9 log10 reduction of CFU) |
| (222) | ESAT-6 (Rv3875) 51–70 (YQGVQQKWDATATELNNALQ) | DDA/MPLA/IL2 emulsion | B6CBAF1 mice | 10μg peptide with a mixture of 25μg MPLA, and 100 ng recombinant mouse IL-2/i.p. or i.m., 3 times, with a 2-week interval | DDA and TLR4 agonist MPLA | Mtb H37Rv strain (5×104 CFUs/i.v. or 250 CFUs/aerosol) | ESAT-651–70 epitope promoted significant levels of protective immunity (equivalent to BCG and ESAT-6). |
| (238) | ESAT-6 (Rv3875) 4-18 (QQWNFAGIEAAASAI), ESAT-6 22-36 (VTSIHSLLDEGKQSL) and ESAT-6 56-70 (QKWDATATELNNALQ) | pIRES + FL + ESAT-6 4-18 +AAY + ESAT-6 22-36 + AAY + ESAT-6 56-70 + HIS | C57BL/6 mice | 100 µg plasmid DNA per mouse/i.m., two boosters at the interval of 3 weeks | – | Mtb H37Rv strain (5×105 CFUs/intratracheal instillation) | DNA vaccine and boosted with the peptides increased IFN-γ and IL-12, the number of IFN-γ+ T cells and activities of CTL as well as IgG, enhanced protection challenge. |
| (239) | Ag85B (Rv1886c) 10-27 (AWGRRLMIGTAAAVVLPG), Ag85B 19-36 (TAAAVVLPGLVGLAGGAA), Ag85B 91-108 (WDINTPAFEWYYQSGLSI), ESAT6 (Rv3875) 33-47 (KQSLTKLAAAWGGSG), ESAT6 37-51 (TKLAAAWGGSGSEAY), ESAT6 29-43 (LDEGKQSLTKLAAAW), ESAT6 72-95 (LARTISEAGQAMASTEGNVTGMEA) | 1 mL of vaccine mixture contains 10 μg of each peptide, 100 μg of Pam3Cys-SK-4, and 10 μg of CpG ODN | C57BL/6 mice | 50 μl per mouse per dose | TLR9 agonist CpG ODN | Mtb H37Rv strain (150 CFUs/aerosol) | Enhanced BCG protective efficacy, induced Th1 and Th17 responses |
| (116) | Ag85B (Rv1886c) 239-247 (KLVANNTRL), IniB (Rv0341) 33-45 (GLIDIAPHQISSV) and PPE68 (Rv3873) 127-136 (FFGINTIPIA) | Branched chain palmitoyl-peptide conjugate on Tuftsin (TKPKG) carrier, A/P/I mix, A(P)I, and Pal-A(P)I. | CB6F1 mice | 50 μg vaccine in 100 μl PBS were injected s.c. three times, two weeks apart. | – | Mtb H37Rv strain (2×105 CFUs/i.p.) | Significantly lower number of bacteria in the spleen after i.p. challenge with Mtb. |
| (240) | TB10.4 (Rv0288) 4–11 (IMYNYPAM) and Ag85B (Rv1886c) 280–294 (FQDAYNAAGGHNAVF) | TB10.4-KFE8 nanofibers or TB85B-KFE8 nanofibers with KFE8 (FKFEFKFE) + Pam2Cys adjuvant | C57BL6 mice | 1 × 106 CFU of BCG/s.c. prime followed by 25 μl of nanofiber formulations and boosted with 15 μl 30 or 90 days later | Pam2Cys | Mtb H37Rv strain (100 CFUs/aerosol) | Induced a 8-fold expansion in multifunctional CD8+ T cell populations and 1.3 log10 CFU reduction in lung bacterial burden. |
| (241) | Ag85A (Rv3804c) 141-160 | Recombinant (Ag85A) BCG Tokyo or Ag85A DNA vaccine with Ag85A peptide boosting | Guinea pigs | 1. Recombinant (Ag85A) BCG: 5×106 CFUs/s.c. boosted by 500 mg of Ag85A (141–160)/s.c. at 3 weeks later. 2. Ag85A DNA: 50 mg/i.m., 2 times at intervals of 3 weeks, boosted by 500 mg of Ag85A (141–160)/s.c. in IFA. |
– | Mtb Kurono strain (150 CFUs/aerosol) | Peptide boosting is important for the induction of higher protective efficacy by recombinant BCG Tokyo or a tuberculosis DNA vaccine |
| (242) | Acr (Hsp16.3, Rv2031c) 91–104 (SEFAYGSFVRTVSL) | Hsp16.3 91–104 peptide mixed with DDA-MPLA (TLR4 agonist) or IFA | BALB/c mice | 25μg synthetic peptide with DDA-MPLA/mouse/s.c., 3 times, with a 2-week interval | 250μg DDA + 25μg MPLA, or 100μl IFA | Mtb H37Rv strain (1×105 CFUs/i.v.) | Induced significantly stronger specific antibodies but lower IFN-γ than BCG, the protection was equivalent to BCG |
| (210) | Acr (Rv2031c) 91–110 (SEFAYGSFVRTVSLPVGADE) | Peptide + Pam2Cys | BALB/c mice or Duncan-Hartley guinea pigs |
20 nmol per mouse or 100 nmol per guinea pig/i.p., 21 days later a booster (10 nmol per mouse and 50 nmol per guinea pig) | – | Mtb H37Rv strain (100 CFUs per mouse or 30 CFUs per guinea pigs, aerosol) | Enhanced activation of DCs, rousted Th1 immune response, and harbored significantly lower CFUs in the lungs |
| (146) | Acr (Rv2031c) 91–110 (SEFAYGSFVRTVSLPVGADE) | L91 vaccine, 1 HTL (SEFAYGSFVRTVSLPVGADE) + TLR-2 agonist (Pam2Cys) | BALB/c mice | Danish strain of BCG (106 CFU/animal), 21 days later, two boosters with L91 (20 nmol) at the interval of 2 weeks | – | Mtb H37Rv strain (100 CFUs/aerosol) | L91 booster significantly enhanced Th1 cells and Th17 cells and reduced the mycobacterial burden |
| (115) | Acr (Rv2031c) 91–110 (SEFAYGSFVRTVSLPVGADE), TB10.4 (Rv0288) 20-28 (GYAGTLQSL) | L4.8 vaccine, 1 HTL (SEFAYGSFVRTVSLPVGADE) + 1 CTL (GYAGTLQSL) + TLR-2 agonist (Pam2Cys) | BALB/c mice | Danish strain of BCG (106 CFU/animal), 21 days later, two boosters with L4.8 (20 nmol) at the interval of 2 weeks | – | Mtb H37Rv strain (100 CFUs/aerosol) | Significantly elicited both CD8 T cells and CD4 T cells immunity, and the BCG-L4.8 prime boost strategy imparts a better protection against TB than the BCG alone. |
| (211) | TB10.4 (Rv0288) 1-13 (MSQIMYNYPAMLG), TB10.4 (Rv0288) 78-94 (ANTMAMMARDTAEAAKW), Rv0476 1-19 (MLVLLVAVLVTAVYAFVHA), CFP10 (Rv3874) 71-90 (EISTNIRQAGVQYSRADEEQ), Acr (Rv2031c) 91-110 (SEFAYGSFVRTVSLPVGADE), and Acr 21-40 (LFAAFPSFAGLRPTFDTRLM) | All six peptide sequences aligned in duplicates were attached by protease-sensitive linker sequence with N terminal secretory signal of human growth hormone | C57BL/6 mice | 100 μg per mouse/s.c. Two boosters at the interval of 2 weeks | – | Mtb H37Rv strain (100 CFUs/aerosol) | Significant reduction in the Mtb burden and enhanced IFN-γ and TNF-α cytokine release. |
| (202) | Hsp65 (Rv0440) 3–13 (KTIAYDEEARR), Ag85B (Rv1886c) 56–64 (PSMGRDIKV), 19 kDa (Rv3763) 51–61 (KVVIDGKDQNV), Acr (Hsp16.3, Rv2031c) 31–50 (LRPTFDTRLMRLEDEMKEGR) and Rv1733c 63–77 (AGTAVQDSRSHVYAH) | Recombinant polyepitope with CpG ODN1826 adjuvant | HLA-DR3 transgenic mice | 25 μg peptide vaccine with 50 μg CpG in 200 μl PBS were injected s.c. three times, two weeks apart. | 50 μg TLR9 agonist CpG (ODN1826) | Mtb H37Rv strain (1×105 CFUs/i.n.) | High IgG levels and polyfunctional CD4(+) T-cells producing IFN-γ, TNF and IL-2, and reduce CFUs in lungs |
| (243) | Four Th1 peptides ESAT-6 1–20 (MTEQQWNFAGIEAAASAIQG), Ag85B 241–255 (VANNTRLWVYCGNGT), PE19 (Rv1791) 4–18 (VTTQPEALAAAAANL), PPE25 (Rv1787) 241–255 (AQFFASIAQQLTFGP), and 1 CTL peptide MTB10.4 (Rv0288) 3–11 (QIMYNYPAM) | HSP65 scaffold + ESAT-6 1–20 + Ag85B 241–255 + MTB10.4 3–11 + AAY + PPE25 241–255 + PE19 4–18 | C57BL/6 mice | Four doses of 50 µg DNA vaccine per mouse/i.m. | – | Intranasally inoculated with 1 × 107 CFUs BCG in 100 µL PBS under anesthesia | Induce higher IFN-γ+ T cell response, granzyme B+ CTL and IL-2+ CD8+ T cell responses, and significantly improved protection |
| (244) | 21 conserved PE/PPE peptides ‡ | PE peptide + ESAT-6 (PE-ESAT-6), PPE peptide + ESAT-6 (PPE-ESAT-6), and PE + PPE peptide + ESAT-6 (PE/PPE-ESAT-6) | C57BL/6J mice | 2 mg per mouse/s.c. Two boosters at the interval of 3 weeks | GLA-SE (5mg/mouse) | Mtb Beijing strain HN878 (100 CFUs/aerosol) | Enhanced IL-2+IFN-γ+ CD4+ T cells, lower CFUs |
| (2) | Mtb8.4 (Rv1174c) 69-83 (LRNFLAAPPPQRAAM), PPE18 115-129 (RAELMILIATNLLGQ), PPE18 (Rv1196) 149-163 (AAAMFGYAAATATAT), PPE68 (Rv3873) 138-152 (DYFIRMWNQAALAME), RpfA (Rv0867c) 377-391 (AYTKKLWQAIRAQDV), and TB10.4 (Rv0288) 21-35 (YAGTLQSLGAEIAVE) | TrxA-tag +6 HTL (GGGGS) + His-tag | Humanized C57BL/6 mice and wild- C57BL/6 mice | 30 µg MP3RT per mouse/s.c. Two booster (20 µg) at the interval of 2 weeks | TLR9 agonist CpG-ODN2395 | Mtb H37Rv strain (2 × 105 CFUs/tail vein injection) | Inducing protection characterized by high levels of IFN-γ and CD3+IFN-γ+ T lymphocytes |
| (245) | MPT64 (Rv1980c) 190-198 (FAVTNDGVI) | AMM (Ag85B-Mpt64 190-198 -Mtb8.4) | C57BL/6 mice | 5 × 105 CFU of BCG prime followed by 20 μg of AMM plus 250 μg of DDA and 30 μg of BCG PSN/s.c. Boosting twice at weeks 8 and 10 | 250 μg of DDA and 30 μg of BCG PSN | Mtb H37Rv strain (1×106 CFUs/i.v.) | AMM induced stronger humoral and cell-mediated immune responses than Ag85B alone and could boost BCG-primed immunity and lead to a better protection than BCG alone or BCG-prime followed by Ag85B-boost. |
| (246) | MPT64 (Rv1980c) 190-198 (FAVTNDGVI) | AMH (Ag85B-Mpt64190-198 -HspX) AMM (Ag85B-Mpt64 190-198 -Mtb8.4) |
C57BL/6 mice | 5 × 105 CFU of BCG prime followed by 10 μg of AMM and 10 μg of AMH plus 250 μg of DDA and 30 μg of BCG PSN/s.c. Boosting twice at weeks 8 and 10 | 250 μg of DDA and 30 μg of BCG PSN | Mtb H37Rv strain (1×106 CFUs/i.v.) | Boosted with AMM + AMH had significantly lower bacterial count in the lungs than those receiving BCG, whereas mice boosted with AMH or AMM did not. |
| (247) | MPT64 (Rv1980c) 190-198 (FAVTNDGVI) | ESAT6 + Ag85B + MPT64(190–198) + Mtb8.4-Rv2626c | C57BL/6 mice | 13 μg/dose/mouse, s.c., 3 times at 2-week intervals | 250 μg DDA and 50 μg TLR3 agonist Poly (I:C) | Mtb H37Rv strain (50-100 CFUs/aerosol) | Generated strong antigen-specific humoral and cell-mediated immunity, and induced higher protective efficacy than BCG |
| (203) | Rv1733c 57–84 (IPFAAAAGTAVQDSRSHVYAHQAQTRHP) | Synthetic long peptide (SLP) with CpG ODN1826 adjuvant |
HLA -DRB1*0301/DRA transgenic mice | 25μg Rv1733c p63-77, or Rv1733c p57-84 peptide with CpG/mouse/s.c., 3 times, with a 2-week interval | TLR9 agonist CpG ODN1826 | Mtb H37Rv strain (1×106 CFUs/i.n.) | Had the highest reduction (0.92 log) in bacterial load in their lungs (from 3.6 × 105 to 0.44 × 105) compared to mice vaccinated only with BCG. |
AcMNPV, Autographa californica multicapsid nucleopolyherovirus; BCG PSN, BCG polysaccharide nucleic acid; DDA, N, N’-dimethyl-N, N’-dioctadecylammonium bromide; FL, fms-like tyrosine kinase 3 ligand; IFA, Incomplete Freund’s Adjuvant; RVG, Rabies Virus Glycoprotein; MPLA, Monophosphoryl lipid A; Pam2Cys, lipid moiety S-[2,3-bis(palmitoyloxy)propyl] cysteine; PBMC, Peripheral blood mononuclear cells; p.i., postinfection; Poly (I: C), polyribocytidylic acid; s.c., subcutaneous injection; i.m., intramuscular injection; i.v., intravenous injection; i.n., intranasally; i.p., intraperitoneal injection; †: Rv0203 (TRRRLLAVLIAL), Rv3106 (GHRRMVFRFLTSPIEI), Rv2223c (WRRRPLSSALLSFGLLLGGLPL), Rv3201c (GQLLRRVRSRLARL), Rv3296 (RVILHSPYGLRVHGPLAL), Rv1242 (FLRIATSARVLAAPLPT), Rv1184c (LVPVNHLPLTLPL), Rv3207c (QGGLAPVMMQQTFST), Rv1157c (TQLLMAAASA), Rv1158c (GVNAPIPGI), Rv1291c (FTRRFAASMVG), Rv1860 (RKGRLAALAIA), Rv2190c (ARVIMRSAIG), Rv333c (VMRLYPVRLTTTMTR), Rv0309 (SVVMGVNKAK); ‡These 21 PE/PPE peptides can be found at https://doi.org/10.1016/j.bbrc.2018.06.017.