Chikungunya vaccines in development

Figures & data

Table 1. Monoclonal antibodies against CHIKV.

ORIGIN	NAME	TARGET	EFFECT	DOSAGE	REFERENCES
Human	5F10; 8B10	E2 (5F10), E2	Prophylactic: 100% protection	250μg	Warter et al. 2011^101
		and/or E1 (8B10)	Therapeutic: Delay in lethality but did not fully protect		Fric et al. 2013^103
	C9	E2	Prophylactic: 100% protection	100μg	Selvarajah et al. 2013^106
			Therapeutic: 100% protection
Mouse	CHK-102; CHK-152; CHK-166; CHK-263	E1 and E2	Prophylactic: 100% protection in immunocompromised mice	100μg	Pal et al. 2013^50
			Therapeutic: Mouse model: 58% (CHK-152) & 63% (CHK-166) protection from death
			Rhesus macaques: Significant reduction of viral load and spread (combination of CHK-152&CHK-166)	15mg/kg	Pal et al. 2014^172
	1.3A2; 4.6F5	E2	Prophylactic: 100% protection against CHIKV arthritis, significant suppression of viremia	400μg	Goh et al. 2013^105
	CK47	E1	In vitro: Inhibits virus release from infected cells		Masrinoul et al. 2014^104
	1.7B2; 4.1H11; 4.8E2; 4.10A11; 5.1B12; 5.2F8, 5.2H7; 5.4G8; 5.5A11; 5.5D11; 5.5G9	Capsid Protein	In vitro: Reactivity was demonstrated in ELISA, western blot and IFA		Goh et al. 2015^107

Table 2. Studies evaluating heterogeneous vaccine types within the past 44 years. IRES, Internal Ribosome Entry Site; NHP, non-human primates; nsP, non-structural protein.

VACCINE TYPE	STUDY TYPE	MODE	REFERENCE
LIVE ATTENUATED	Mice	Subgenomic promoter replaced by IRES from encephalomyocarditis virus	Plante et al. 2011^135
	Primates		Roy et al. 2014^115
	Mice	Passages in green monkey kidney cells and MRC 5 cells	Levitt et al. 1986^163
	Humans: Phase I		McClain et al. 1998^131
	Humans: Phase II		Edelman et al. 2000^132
	Mice	Deleting E2 and passages in baby hamster cells and mosquito cell lines	Piper et al. 2013^164
	Mice	Passage in Chinese hamster ovarian fibroblasts and mosquito cells	Gardner et al. 2014^173
	Mice	Deleting nsP	Hallengärd et al. 2014^22
	Mice	Deleting 6K	Hallengärd et al. 2014^22
INACTIVATED	Humans: Phase I	Formalin inactivated	Harrison et al. 1971^128
	Primates	Formalin or UV-light inactivated	Nakao and Hotta 1973^165
	Mice	Formalin inactivated	Tiwari et al. 2009^125
	Mice	Formalin inactivated	Kumar et al. 2012^124
	Mice	BPL inactivated	Kumar et al. 2012^124
SUBUNITS	Mice	Bacterially produced E1	Khan et al. 2012^123
	Mice	Bacterially produced E2	Khan et al. 2012^123
	Mice	Bacterially produced E2	Kumar et al. 2012^124
DNA	Mice	Expression of E1, E2, E3	Muthumani et al. 2008^166
	Mice	Expression of C, E1, E2	Mallilankaraman et al. 2011^167
			Bao et al. 2013^168
	Mice	Expression of nsP3	Hällengard et al. 2014^22
	Mice	Expression of 6K	Hällengard et al. 2014^22
	Mice	Immunization DNA encoding the full length infectious genome	Tretyakova et al. 2014^122
	Mice	Expression of 6K, E1, E2, E3	Hällengard et al. 2014^22
VIRUS-LIKE PARTICLES/SUBUNITS	Mice	Transfection of human embryonic kidney cells with plasmid	Akahata et al. 2010^139
	Primates	DNA encoding C, 6K, E1, E2, E3	Akahata and Nabel 2012^169
	Humans: Phase I		Chang et al. 2014^133
	Mice	Production in insect cells (Baculovirus)	Metz et al. 2013^138
RECOMBINANT VECTOR	Mice	Eastern equine encephalitis virus as vector	Wang et al. 2008^117
	Mice	Adenovirus as vector	Wang et al. 2011^118
	Mice	Vesicular stomatitis virus as vector	Chattopadhyay et al. 2013^119
	Mice	Poxvirus as vector	Garcia-Arriaza et al. 2014^120
	Mice	Measles virus as vector	Brandler et al. 2013^48
	Humans: Phase I		Ramsauer et al. 2015^127

Table 3. Potential assets and drawbacks of CHIK vaccines that have reached human clinical trial testing.

VACCINE	CHIKV STRAIN	ADVANTAGE	DISADVANTAGE	CURRENT STATUS
VRC-CHKVLP059-00-VP^133	West African CHIKV strain 37997	•  VLPs are effective immunogens^153 eliciting high titer neutralizing antibodies^139 • High safety: Contains no live or replicating virus • No infection of insect cells (favorable for use in endemic regions) • No live-virus production needed • Plant-based or insect cell-based development possible^140 • Phase I:^133 No serious adverse events, vaccine-induced antibodies were detected in all participants up to 6 months after vaccination	• Multiple doses required; • Adjuvant required for dose-reduction • Expensive manufacturing of in vitro VLPs^48 • Large-scale DNA transfection needed^153 • Lack of strategies for cost-effective production	Finished Phase 1 in 2014
CHIKV/IRESv2^115	La Réunion LR2006 OPY1 (ECSA lineage)	• High immunogenicity and long-term protection by single immunization • More stable attenuation by IRES sequence insertion compared to single point mutations • No transmission to insects/vectors • Comparably lower manufacturing costs	• Safety concerns regarding reversion of mutation and recovering to wild type pathogenicity • Safety concerns regarding immunosuppressed conditions	Projected for Phase 1
MV-CHIK^127	La Réunion 06-46 (ECSA lineage)	• Live attenuated Schwarz strain elicits a robust humoral and cellular immune response • Long-term experience in safety of MV as vaccine vector; contains no replicating CHIKV; replication of RNA virus is limited to cytoplasm • MV optimal vector for reverse genetics^170 • No adjuvant required: comparably low effective doses • Measles vaccine can be easily produced on a large scale in most countries and distributed at low cost^171	• Pre-existing immunity to measles may impede or prevent immunogenicity of a recombinant MV vaccine • Safety concerns about use in immunocompromised patients • Phase 1: Adverse event rate 17% (n=6)	Finished Phase 1 in early 2015, Projected for Phase II in late 2015
TSI-GSD-218^132	Clone 25/181 (SE Asian isolated strain AF15561)	• Highly immunogenic upon one-time immunization	• Concerns about insufficient or unstable attenuation by single-point mutation • Phase 2: 8% rate of arthralgia	Development stopped due to lack of funding

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