Table 1.
Major Vaccines Developed and Under Development for Chikungunya Fever
| Name | Phase | Platform or Method | Doses | Immunogenicity Assay | Preclinical Immunogenicity (Model) | Preclinical Efficacy (Model) | Clinical Immunogenicity | Comments |
|---|---|---|---|---|---|---|---|---|
| Inactivated | ||||||||
| USAMRIID [24, 59] | 1 | Formalin inactivated, grown in green monkey kidney cells or chick embryonic cells | 1 or 2 doses | Log10 serum neutralization index, complement fixation, hemagglutination inhibition | NA | NA | Two doses 28 d apart; all 28 participants developed nAb | Doses determined by volume, not protein quantification; vaccine developed in chicken cells more immunogenic in mice than monkey cell–derived vaccine |
| DRDE-06 [26] | Preclinical | Formalin inactivated, virus grown in Vero cells, formulated with adjuvant | 3 × (10, 20, or 50 µg) | ELISA, PRNT90 | Unknown seroconversion rate; PRNT90 titer dose dependent with highest levels at 50 µg vaccine (Swiss albino mice) | Passive transfer of virus with convalescent mouse sera produced no disease in newborn mice (Swiss albino mice) | NA | Splenocytes from immunized mice produced high levels of IL-4, IL-5, IL-6, and GM-CSF after stimulation |
| Subunit | ||||||||
| CHIK-E1/E2 [27] | Preclinical | Recombinant E1/E2 produced in E. coli and formulated with adjuvant | 3 × 40 µg | ELISA, PRNT90 | Unknown seroconversion rate; PRNT90 = 64–512 (n = 6) 21 d after third dose; peak ELISA titers at 7 d after third dose, waning by day 21 (BALB/c mice) | Passive transfer of purified IgG from vaccinated mice into newborn mice, followed by 6 log10 PFU challenge, showed partial protection from death/viremia (BALB/c mice) | NA | Tested with three different adjuvant formulations, with alum and Freund's complete adjuvant performing the best |
| CHIK-E2 [29] | Preclinical | Recombinant E2 produced in E. coli and formulated with adjuvant | 2 × (10, 20, or 50 µg) | ELISA, CPE inhibition microneutralization | 100% seroconversion 14 d after second dose; nAb titers = 80–320 n = 6) 14 d after second dose; peak ELISA titers 14 d after second dose (BALB/c mice) | Partial protection from viremia/tissue viral load (genome copies) 14 and 140 d after second dose (BALB/c mice) | NA | rE2 derived from ECSA lineage; nAb titers 4-fold lower against Asian lineage |
| Virus-like particle | ||||||||
| VLP- NIH [3, 26] | 1 | VLPs produced from DNA transfected into human embryonic kidney VRC293 (HEK-293 derived) | 3 × (10, 20, or 40 µg) | ELISA and 50% neutralization using GFP reporter chimera | 100% seroconversion after 1 × 20 µg dose, boosted after 2 (n = 6; Rhesus macaque) | No detectable viremia after challenge (10 log10 PFU CHIKV LR2006-OPY-1 isolate, IV; Rhesus macaque) | 100% seroconversion in 10-µg and 40-µg group and 80% in 20-µg group after 1 dose; all titers increased with each booster | No severe adverse events reported |
| VLP-CHIKV-S27 [25, 31] | Preclinical | Baculovirus-vectored CHIKV VLPs formulated with adjuvant | 2 × 1 µg | PRNT95, modified protocol | 100% seroconversion after 2 doses (A129 mice) | 100% protection from lethal CHIKV infection (1000 TCID50 CHIKV S27 isolate) 6 wks after second dose (A129 mice) | NA | E1 or E2 protein-only controls elicited poor immunity and failed to protect all mice from lethal CHIKV challenge |
| Live-Attenuated and Live-Vectored | ||||||||
| 181/clone25 (TSI-GSD-218) [28] | 2 | Attenuation by serial, plaque-to-plaque MRC5 cell passages | (1 dose) 5 log10 PFU |
PRNT80 (preclinical), PRNT50 (clinical) | 100% seroconversion, PRNT80 = 20–2560 14 d after single immunization with 3.5–5.5 log10 PFU (Rhesus macaques) | 67%–100% protection against fatality after single immunization with 4.5–6.5 log10 PFU (18–21-day-old CD-1 outbred mice | 98.3% seroconversion, PRNT50 ≥1:20 (mean = approximately 600) 28 d after single immunization; 85% seropositive 1 y after single vaccination | 5 of 58 volunteers in phase 2 clinical trial developed mild, transient arthralgia; reversions in one of 2 attenuating mutations were detected in viremic vaccinees |
| Chimeric alphavirus [30] | Preclinical | recombinant alphavirus (EEEV, VEEV, or SINV) with CHIKV structural proteins | (1 dose) 4–6 log10PFU | PRNT80 | 100% seroconversion with PRNT80 = 20–320 by day 21 after vaccination (3-week-old Swiss Webster mice) | 100% protection from intranasal neurovirulent CHIKV (6.5 log10 PFU; C57BL/6 mice) | NA | Strong inducers of type I IFN; no viremia seen after vaccination |
| CHIKV/IRES [20, 33, 60] | Preclinical | Attenuation via inactivation of the CHIKV subgenomic promoter and introduction of an IRES to drive translation of the structural polyprotein ORF | (1 dose) 7 log10 PFU | ELISA, PRNT80 | 100% seroconversion, PRNT80 = 80–640 50 d after single immunization with 5.0 log10 PFU (cynomolgus macaques) | 100% protection from fever, hypothermia, and viremia after single immunization with 5.0 log10 PFU (cynomolgus macaques) | NA | Similar immunogenicity and efficacy in A129 mice |
| Measles-CHIKV [36, 37] | 1 | Recombinant measles virus (Schwartz strain) expressing CHIKV VLPs | Preclinical: 103–105 PFU; clinical trials: 1.5 × 104 TCID50 (low), 7.5 × 104 TCID50 (medium), 3 × 105 TCID50 (high) | ELISA, PRNT50, PRNT90 | 100% seroconversion after 1 dose by PRNT50, titers increased with dose and boost (CD46-IFNAR) | 100% protection from lethal CHIKV infection (100 PFU intraperitoneally with CHIKV06–49 isolate) at vaccine doses >4 log10 PFU (CD46-IFNAR) | 44% (n = 4), 92% (n = 11), or 90% (n = 10) seroconversion from low, medium, and high doses, respectively, after 1 immunization; 100% seroconversion after 2 doses | Preexisting immunity to measles did not affect vaccination |
| VSV-CHIKV [38] | Preclinical | Recombinant VSV with or without G protein gene expressing CHIKV structural proteins | (1 dose) 6 log10 PFU | PRNT80 | 100% seroconversion; PRNT80 = 160 to >640 (ΔG) or PRNT80 = 80–320 (G) 30 d after 1 dose (C57BL/6 mice) | 100% protection from viremia after challenge and partial protection from footpad swelling (C57BL/6 mice) | NA | Strong cellular immunity seen (ELISPOT) |
| Replication-Defective | ||||||||
| CAdVax-CHIKV [48] | Preclinical | Recombinant adenovirus expressing structural polyprotein genes of CHIKV and produced in HEK293 packaging cell line | (1 dose) 8 log10 infectious units | ELISA, CPE inhibition microneutralization | 100% seroconversion; nAb titers = 2000 (mean) 39 d after single immunization (C57BL/6 mice) | 100% protection from viremia and footpad swelling 46 d after single immunization (C57BL/6 mice) | NA | No data for preexisting immunity to Ad5 |
| MVA-CHIKV [41] | Preclinical | Host-restricted poxvirus vector expressing complete structural polyprotein of CHIKV | (1 dose) 7 log10 PFU | ELISA, 50% neutralization using luciferase reporter replicon | 100% seroconversion; nAb titers = 100–1000 (n = 5) 42 d after single immunization (C57BL/6 mice) | 100% protection from viremia and footpad swelling 49 d after single immunization (C57BL/6 mice) | NA | 1- and 2-dose regimens were tested, with the single-dose proving sufficient for protection |
| Plasmid DNA | ||||||||
| pMCE321 [46] | Preclinical | DNA plasmid containing sequence of E3, E2, and E1 genes under a CMV promoter (intramuscular electroporation) | 5 × 1 mg | CPE inhibition microneutralization | 100% seroconversion 14 d after fifth dose; nAb titers = 80–1280 (n = 4), 14 days after 5th dose (Rhesus macaque) | 100% protection against >30% weight loss after 3 doses (25 µg) on day following third dose, with no protection from viremia (BALB/c mice, intranasal challenge) | NA | Plasmids expressing E2 and E1 alone were also tested and proved less immunogenic than E3, E2, and E1 combined |
| iDNA [47] | Preclinical | DNA plasmid containing full genome of CHIKV strain 181/25. Launches live-attenuated vaccine in vivo (intramuscular electroporation) | 1 × 10 µg | PRNT80 | 100% seroconversion 21 d after 1 dose; PRNT80 = 160–1280 (n = 10 BALB/c mice) | 100% protection from viremia following 6.8 log10 PFU intranasal challenge with neurovirulent CHIKV strain | NA | Still need to assess potential reversion of 2 point mutations in 181/25 backbone |
| DREP-Env [61] | Preclinical | DNA plasmid encoding CHIKV replicon (nsP1 to nsP4) and CHIKV envelope (E1 to E3) (intradermal electroporation) | 2 × 10 µg | ELISA, 50% neutralization using luciferase reporter replicon | 100% seroconversion; nAb titers approximately 100–5000 (n = 5) 6 wk after 2 doses (C57BL/6 mice) | 100% protection from viremia and footpad swelling 7 wk after 2 doses (C57BL/6 mice) | NA | Also tested combinations of DREP-Env with adjuvanted peptide, MVA-CHIKV, or both |
Abbreviations: Ad5, adenovirus type 5; CAdVax, complex adenovirus vaccine vector; CHIK, chikungunya; CMV, cytomegalovirus; CPE, cytopathic effect; DRDE, Defense Research and Development Establishment; E. coli, Escherichia coli; EEEV, eastern equine encephalitis virus; ELISA, enzyme-linked immunosorbent assay; ELISPOT, enzyme-linked immunospot; GFP, green fluorescent protein; GM-CS, granulocyte macrophage colony-stimulating factor; IFN, interferon; IgG, immunoglobulin G.; IL-4, interleukin 4; IL-5, interleukin 5; IL-6, interleukin 6; IRES, internal ribosomal entry site; MVA, modified vaccinia Ankara; nAb, neutralizing antibody; ORF, open reading frame; PFU, plaque-forming units; PRNT, plaque reduction neutralization test; SINV, Sindbis virus virus; TCID, tissue culture infectious dose; USAMRIID, US Army Medical Research Institute of Infectious Diseases; VEEV, Venezuelan equine encephalitis virus; VLP, virus-like particle; VSV, vesicular stomatitis virus.