Table 4.
Strategies for DENV subunit vaccines produced in E. coli for preclinical evaluation.
| Target | Strategy | Immune Response | Protection | Refolding | Ref. |
|---|---|---|---|---|---|
| E protein | Fusion with P64k protein from N. meningitidis | Mice and monkeys: ↑ IgG and neutralizing Ab titers after 4 doses | Mice: 50% survival (DENV2 i.c.) Monkeys: reduction of viremia after challenge (DENV2) |
No | [168,169,170] |
| E protein | Chimeric protein with 11 peptides from DENV1-4 E protein | Mice: ↑ IgG titers; ↑ CD8 and CD4 T cells; splenocytes (↑IFNy, IL-2,IL-4 and IL-17) | ND | Yes | [171] |
| E protein | DENV2 E protein | Mice: ↑ IgG titers | ND | Yes | [172] |
| E protein | Fragment of DENV1-4 E proteins fused with maltose binding protein (MBP) | Mice and monkey: ↑ IgG and neutralizing Ab titers | Mice: 80% of survival (i.c. challenge); Monkeys: no protection |
No | [173,174,175,176] |
| EDIII and C proteins | EDIII fused with C proteins from DENV1-4 | Monkeys and mice: ↑ IgG and neutralizing Ab titers, ↑ B cells antigen-specific; ↑ IFNy (splenocytes or PBMC); ↑ CD8 e CD8 T cells (IFNy) | Mice: ↑ survival (DENV1-4) Monkeys: ↓ viremia and ↑ survival against DENV1-4 |
Yes | [177,178,179,180,181,182,183] |
| EDIII protein | DENV1-4 EDIII protein fused to fliC (S. typhimurium) | Mice: ↑ IgG and neutralizing Ab titers (heterologous prime-boost with LATV vaccine); ↓ADE effect | Mice: ↑ survival (DENV1-4) | No | [184] |
| EDIII protein | DENV1-4 EDIII in tandem (B1234 protein) | Mice: ↑ IgG and neutralizing Ab titers | Mice: ↑ survival (DENV1-4) | Yes | [185] |
| EDIII protein | DENV2 EDIII fused with pIII coat protein | Mice: ↑ IgG and neutralizing Ab titers | Mice: no protection; ↑ ADE | Yes | [186] |
| EDIII protein | DENV2 EDIII with different adjuvants (LT1, LTB and Alum) | Mice: ↑ IgG and neutralizing Ab titers | ND | Yes | [187] |
| EDIII protein | DENV2 EDIII | Mice: ↑ IgG and neutralizing Ab titers | Mice: ↑ survival (DENV2) | Yes | [188] |
| EDIII protein | DENV1-4 EDIII fused with lipid signal peptide of the lipoprotein Ag473 | Mice: ↑ IgG and neutralizing Ab titers; ↑ IgG avidity; ↑ neutralization (PRNT); ↓ ADE in vitro | Mice: ↓ viremia | Yes | [189,190,191,192] |
| EDIII protein | DENV1 EDIII with different adjuvants (PELC and CpG) | Mice: ↑ IgG and neutralizing Ab titers; ↑ IFNy (ELISPOT) | ND | No | [193] |
| EDIII protein | DENV1-2 EDIII or DENV3-4 EDIII in tandem | Mice: ↑ IgG and neutralizing Ab titers | Mice: ↑ survival (DENV1-4) | Yes | [194,195] |
| EDIII protein | DENV2 EDIII with Freund’s adjuvant | Mice: ↑ IgG and neutralizing Ab titers | Mice: ↑ survival (DENV2) | Yes | [196] |
| EDIII protein | DENV3 EDIII consensus | Mice: ↑ IgG titers; ↑ proliferation of splenocytes; ↑ IFNy and IL-4 (splenocytes) | ND | No | [197] |
| EDIII protein | DENV1-4 EDIII consensus | Mice: ↑ IgG and neutralizing (DENV1-4) Ab titers | ND | No | [198] |
| EDIII protein | DENV (1,2) EDIII protein | Mice: ↑ IgG titers | ND | Yes | [199] |
| EDIII protein | DENV1-4 EDIII | Mice: ↑ IgG and neutralizing Ab titers; ↑ CD4 and CD8 T cells (producing IFNy and IL-2); ↑ IFNy, IL-2, IL-12p40 (splenocytes) | ND | Yes | [200] |
| EDIII protein | DENV2 EDIII in Chimeric VLP (HBcAg-EDIII-2) | Mice: ↑ IgG and neutralizing Ab titers | ND | Yes | [201] |
| EDII protein | Fubc protein (peptides from fusion and bc loop regions of EDII fused by link sequence) | Mice: ↑ IgG titers | ND | Yes | [202] |
| NS1 protein | DENV2 NS1 with LTG33D, Alum or Freund’s adjuvant | Mice: ↑ IgG titers | Mice: ↑ survival (DENV2) | Yes | [37,203] |
| NS5 protein | DENV2 NS5 | Mice: ↑ IgG titers; ↑ IFNy and TNFα (splenocytes) | Mice: ↑ survival (DENV2) | No | [38] |
| NS3 protein | DENV2 NS3 protein | Mice: ↑ IgG titers; ↑ IFNy (splenocytes) | ND | Yes | [39] |
| NS3/NS1 | DJ NS1 chimera (DENV2 and JEV) and NS3 | Mice: ↑ IgG titers;↑ CD4 and CD8 T cells; ↑ CTL responses against NS3 | Mice: ↓ viremia; ↓ soluble NS1 levels; ↓ mouse tail bleeding time, and vascular leakage at skin injection sites | Yes | [40] |
ND = not determined; ↑ = increased and ↓ = decreased.