Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 + 6951 word(s) 6951 2021-05-20 08:36:02 |
2 format correction -4 word(s) 6947 2021-06-01 03:31:53 |

Video Upload Options

Do you have a full video?

Confirm

Are you sure to Delete?
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Ng, L.F. Antibody-Mediated Alphavirus Immunity. Encyclopedia. Available online: https://encyclopedia.pub/entry/10317 (accessed on 28 March 2024).
Ng LF. Antibody-Mediated Alphavirus Immunity. Encyclopedia. Available at: https://encyclopedia.pub/entry/10317. Accessed March 28, 2024.
Ng, Lisa F.p.. "Antibody-Mediated Alphavirus Immunity" Encyclopedia, https://encyclopedia.pub/entry/10317 (accessed March 28, 2024).
Ng, L.F. (2021, May 31). Antibody-Mediated Alphavirus Immunity. In Encyclopedia. https://encyclopedia.pub/entry/10317
Ng, Lisa F.p.. "Antibody-Mediated Alphavirus Immunity." Encyclopedia. Web. 31 May, 2021.
Antibody-Mediated Alphavirus Immunity
Edit

Alphaviruses are mosquito-borne pathogens distributed worldwide in tropical and temperate areas causing a wide range of symptoms ranging from inflammatory arthritis-like manifestations to the induction of encephalitis in humans. Historically, large outbreaks in susceptible populations have been recorded followed by the development of protective long-lasting antibody responses suggesting a potential advantageous role for a vaccine.

alphavirus antibody immunity alphavirus vaccine

1. Introduction

Mosquito-borne alphaviruses are Group IV viruses that belong to the family Togaviridae [1]. They are enveloped, positive-sense, single-stranded RNA viruses with a size of ≈70 nm bearing a ≈11.7 kilobases genome which encodes four non-structural proteins (nsP1, nsP2, nsP3 and nsP4) that serve as the virus’ replication machinery, and five structural proteins (capsid, E3, E2, 6K and E1) that participate in the envelope assembly process [1]. Clinically, alphavirus infections in humans results in the development of viremia followed by an onset of febrile symptoms [2]. The development of inflammatory conditions compromising joints and muscle tissues has been associated to arthritogenic alphaviruses such as chikungunya virus (CHIKV), O’nyong nyong virus (ONNV), Mayaro virus (MAYV), Ross River virus (RRV), Semliki Forest virus (SFV) and Sindbis virus (SINV) with records of persistent polyarthralgia in a fraction of patients. Conversely, neurotropic alphaviruses such as Eastern Equine Encephalitis virus (EEEV), Western Equine Encephalitis virus (WEEV) and Venezuelan Equine Encephalitis virus (EEEV) have been linked to the induction of lethal encephalitis in humans and animals [3][4].
Historically, alphaviruses have a proven record of causing massive outbreaks in susceptible populations [5][6][7][8]. Additionally, the appearance of mutations favoring their ecological fit to new vectors has fueled alphavirus propagation worldwide [9][10]. A clear example of their potential as a health threat is the re-emergence of CHIKV in 2004 after a hiatus of more than 50 years since its discovery [5]. More recently, tropical emerging alphaviruses such as ONNV and MAYV are believed to have the potential to become future major epidemics [11][12][13]. This is due, in part, to the lack of robust diagnostic tests to differentiate alphavirus infections from other febrile tropical diseases and the absence of continuous epidemiological surveillance masking their real potential for spread beyond endemic areas [14][15][16].
Although alphavirus infections are generally not life threating the economic and social costs incurred during outbreaks are thought to be high [17][18][19]. Moreover, the lack of approved treatments leaves management of alphavirus infections to supportive care [20]. Interestingly, a body of work suggests that the alphavirus infection triggers potent humoral responses in exposed populations which seem to confer protection against re-infection [21]. Therefore, a better understanding of the antibody responses against alphaviruses is crucial for the development of vaccines, which would represent a big advantage in the control of alphavirus infections.

2. Antibody-Mediated Alphavirus Immunity

2.1. Virus-Specific Antibody Kinetics Upon Natural Infection with Alphaviruses

The current knowledge on the role of antibody-mediated immunity upon viral infection has been gathered from cohort studies following major alphavirus outbreaks. Serological surveys following CHIKV re-emergence in 2004 reported the quick development of IgM responses between five to seven days post-illness onset (PIO) [22][23]. IgM is generally detectable for up to three months post-infection [24][25][26]. However, long-lasting IgM has been often reported in patients with long-term CHIKV-induced polyarthralgia, which might indicate a constant antigenic stimulation due to viral persistence [27]. After the initial detection of IgM antibodies, IgG seroconversion reportedly occurs between 4 to 10 days PIO taking over as the main immunoglobulin detected in serum [22][28]. Notably, IgG3 antibodies become the dominant IgG subtype produced upon infection and have been associated to efficient viral clearance and protection against chronic CHIKV symptoms [23]. Importantly, IgG responses persist for several years and might be potentially lifelong [29].
ONNV and MAYV, both closely-related to CHIKV, are re-emerging arthritogenic alphaviruses believed to be confined to sub-Saharan Africa, and Latin America, respectively [6][11][12][15]. Following the largest ONNV outbreak in Uganda involving more than two million cases between 1959–1962 [6][30], the induction of potent neutralizing antibodies was described [31]. The first study cohort that evaluated IgM kinetics upon ONNV infection in Uganda [32] reported the appearance of IgM antibodies during the second week PIO which remained elevated for two months. In contrast, reports from imported ONNV cases in Europe described detectable IgM levels as early as five days PIO [33][34]. ONNV-specific IgG levels are increased in serum after the third week and remain high beyond two months PIO [11][34]. However, whether IgG responses are long-lasting remains unknown. Similarly, endemic MAYV infections are characterized by the early appearance of IgM antibodies (3–8 days PIO) that might last for one to three months [35][36]. IgG becomes detectable around 4–10 days PIO [35] and remains elevated after 6–12 months [37][38]. Interestingly, unlike ONNV and CHIKV infections, persistent arthralgia has been reported in more than half of MAYV-infected individuals and although MAYV-specific antibody responses are critical for disease resolution it is seemingly insufficient to protect patients from the development of chronic joint manifestations [39].
Other alphaviruses linked to continuous small outbreaks associated with arthritic manifestations in human populations are RRV and SINV. RRV is endemic to Australia and is responsible for approximately 4000–5000 cases annually [40]. Typically, antibody kinetics upon RRV infection are characterized by the development of IgM titers between 7–10 days PIO, peaking at two to three weeks and lasting for 1–3 months [41][42]. IgM response rapidly declines after three weeks PIO as IgG becomes dominant [42][43]. Interestingly, IgM persistence has been reported in some RRV cohorts [41]. In one study [44], 19/116 (16.4%) of participants had detectable IgM levels that lasted between seven months to eight years PIO. Likewise, less prevalent SINV has also been linked to the development of persistent virus-specific IgM levels. Although, generally, the antibody response upon SINV infection generates IgM antibodies after 6–9 days PIO and IgG antibodies after 9–14 days, some reports described the presence of detectable IgM levels up to four years suggesting active viral replication [45][46][47]. The clinical relevance of persistent IgM levels following RRV and SINV infection is yet to be determined.
Neurotropic alphaviruses such as EEEV, WEEV and VEEV cause sporadic cases of human encephalitis in the Americas [4]. While the natural reservoirs for these viruses are primarily birds and equines, humans are susceptible to infection when the enzootic cycle of transmission leaks into mosquito populations with a wide range of hosts [48]. Given that human cases are rare, there is a lack of information regarding the development of antibody responses upon natural infections by neurotropic alphaviruses. In a paired serology study [49], virus-specific antibody responses were profiled in a cohort of 20 EEEV and 17 WEEV-infected patients. IgM antibodies were observed as early as 1 PIO, peaking after 1–2 weeks and remaining detectable for up to three months. In contrast, IgG responses appeared during the second week PIO and remained elevated until the end of the follow-up period.

2.2. Experimental Evidence of the Role of Antibodies in Alphavirus Immunity

To better understand the role of antibody-mediated immunity upon alphavirus infection, several animal models have been used allowing the detailed examination of the cellular compartments responsible for the initiation of humoral immunity. The role of B cells in alphavirus immunity has been described in experimental CHIKV infections. Inoculation of µMT mice (lacking mature B cells) with CHIKV resulted in higher viremia that persisted up to 402 days post-infection (DPI). In contrast, infected wild type (WT) mice were able to control the virus during the second week post-inoculation [50]. Similar findings were reported in other studies, where mouse strains lacking B cells (µMT, Rag1, Rag2/IL2rg, NRG) infected with CHIKV displayed increased and persistent viremia for up to 515 DPI [51][52].
B cells also play an important role in alphavirus-induced encephalitis. Although SINV infections in humans are known to cause arthritic manifestations, SINV has been frequently used as a model of alphavirus-induced encephalomyelitis in adult immunocompetent mice given the virus ability to infect neurons [53]. Intracerebral inoculation of SINV in µMT and severe combined immunodeficiency (SCID) mice resulted in defective viral clearance from the brain, brain stem and lumbar spinal cord, virus persistence and recrudescence compared to WT mice [54]. The individual contributions of IgM and IgG antibodies to SINV clearance from brain tissues were assessed in another study [55] where infection in AID−/− (unable to produce IgG), sIgM−/− (unable to produce IgM) and AID−/− sIgM−/− double-knockout mice resulted only in AID−/− sIgM−/− being unable to control infection efficiently suggesting that either IgM or IgG antibodies are sufficient to clear SINV from the central nervous system (CNS). Similar results were obtained in SFV models of encephalitis where infection of µMT [56], SCID [57] and nude mice with impaired antibody switching [58] led to viral persistence.
Infiltrating virus-specific B cells were observed in infected tissues in a murine model of SINV-induced encephalitis [59][60]. Following intracranial virus inoculation, expansion of IgM-secreting plasmablasts was reported in the cervical lymph nodes. Infiltration of CD19+ B cells occurred between 3–7 DPI and coincided with the starting of viral clearance. During the clearance of persistent viral RNA (from 8–80 DPI), the accumulation of SINV-specific IgG and IgA-secreting B cells was observed being associated with increased SINV antibody titers over time [60]. In a subsequent study, it was reported that the brain microenvironment during the early stages of SINV infection facilitates the migration, differentiation, expansion and long term survival of SINV-specific B cells [59].
Follicular helper T cells (TFH) are a subset of CD4 T cells involved in the activation of B lymphocytes and the establishment of robust antibody responses following antigen stimulation. TFH promotes B cell differentiation, isotype switching and affinity maturation. In experimental CHIKV infections, the use of CD4-deficient mice ruled out the role of CD4 T cells in viral clearance from infected tissues [61]. However, one study demonstrated impaired IgM and IgG (IgG2c, IgG1, and IgG2b) production in mice lacking CD4 T cells following CHIKV inoculation [62]. Albeit reduced virus-specific antibody levels, the neutralizing capacity of sera from virus-infected CD4-deficient mice was marginally affected [62]. Likewise, another study showed similar results upon CHIKV inoculation of MHCIIΔ/Δ mice (defective of TFH) [51]. MHCIIΔ/Δ animals were unable to generate IgG1 antibodies and produced ≈100 fold lower IgG2c levels than WT controls. Nonetheless, MHCIIΔ/Δ mice were still able to control virus infection [51]. The generation of virus-specific neutralizing antibodies in MHCIIΔ/Δ mice suggests a T-cell independent B cell activation characterized by the inability to generate memory B cells. Whether CHIKV-specific antibody responses in mice lacking CD4 T cells are long-lasting remains to be elucidated.

2.3. Viral Antigenic Regions Targeted by Neutralizing Antibodies

The notion of targeting humoral immunity as a therapy against alphavirus infection has been investigated since the late 1930s following the isolation of EEEV, WEEV and VEEV. In a series of seminal studies involving immunization of guinea pigs [63][64][65][66], the subcutaneous inoculation of live EEEV and WEEV strains protected guinea pigs from lethal intracranial infection [63]. Additionally, it was observed that immunization with formalin-inactivated virus strains induced the production of neutralizing antibodies at a comparable level than animals immunized with live viruses [64][65][66]. Subsequent studies reported that passive transfer of hyperimmune rabbit serum protected mice, guinea pigs and rabbits from WEEV infection [66][67]. Similarly, passive serum transfer was shown to be effective at protecting mice from the development of neurological complications upon infection with a neuroadapted strain of SINV [68][69]. Comparable observations were reported in experimental infection models of VEEV [70], CHIKV [71][72], RRV [73] and SFV [74].
The first attempts in identifying the exact structural regions, recognized by most neutralizing antibodies produced upon infection, were conducted in experimental infection models of alphavirus encephalitis. Structurally, the envelope of an alphavirus virion has a T = 4 icosahedral symmetry [75]. E1 and E2 are two envelop surface glycoproteins exposed in the viral spike as a heterodimer [75] (Figure 1). It is believed that the E1-E2 heterodimer interacts with host receptors thus mediating viral entry [75]. Additionally, the E1 and E2 glycoproteins were postulated as highly immunogenic regions since their location in the spike facilitates antigenic recognition. In line with this, early works mapped antigenic sites involved in VEEV, SINV and SFV neutralization to the E1 and E2 proteins using competitive binding assays but the exact amino acid sequences were not determined [76][77][78]. Later, a major antigenic region involving three epitopes important in the neutralization of RRV was identified in the E2 protein (incorporating residues 216, 232 and 234) [79]. Similarly, analysis of antibody escape variants determined important antigenic regions between amino acids 181 and 216 on the E2 protein of SINV [80]. A major neutralization domain was also identified between residues 182–207 for VEEV [81].
Figure 1. Structure of the alphavirus E1-E2 heterodimer. Ribbon diagram (PDB: 3N41) highlighting (A) E1 glycoprotein (domain I: red, domain II: yellow, domain III: blue, fusion loop FL: orange, E2: grey) and (B) E2 glycoprotein (domain A: cyan, domain B: green, domain C: pink, beta-ribbons: purple, E1: grey). (C) Table summarizing reported antibody binding regions in the E1 and E2 glycoproteins of arthrogenic and neurotropic alphaviruses. Numbers in the table refer to in-text citations describing such binding sites (See Reference list). Background color matches protein doimains depicted in (A) and (B). To assess for the degree of conservation among common antigenic regions across alphaviruses a sequence aligment analysis was conducted.
Following CHIKV reemergence in 2004 several reports identified major linear antigenic sites in the CHIKV E2 protein that induced the production of potent neutralizing antibodies. Using a CHIKV proteome-wide screening approach, a single linear peptide located at the N-terminus of the E2 glycoprotein, E2EP3, was reported as strongly recognized by convalescent CHIKV patients from different cohorts [23]. Furthermore, experimental CHIKV infection in mice and non-human primates (NHP) validated E2EP3 as an immunodominant linear epitope inducing potent neutralizing antibodies [23][62][82]. Interestingly, mice immunization with E2EP3 alone reduced joint swelling and viremia upon CHIKV challenge [23]. In another study focusing on human antibody responses to SINV in cohort from Finland, 6 linear epitopes, located in the capsid, E2, E1 and PE2 (uncleaved E3-E2) proteins, were reported [83]. Three of these epitopes were located to the glycoprotein spike complex between the residues 209–226 of E1 (E1-P5), 273–290 (E2-P3) and 308–325 (E2-P4) of E2 [83]. Interestingly, the E2EP3 equivalent of SINV remained non-reactive suggesting that antibody kinetics against linear E2EP3 between populations exposed to CHIKV and SINV might differ [83].
The development of mouse and human monoclonal antibodies against different alphaviruses helped further the understanding of antigenic responses upon infection by the identification of conformational epitopes. Early works have shown the therapeutic value of mouse monoclonal antibodies in models of alphavirus encephalitis by SINV [84][85][86][87][88], SFV [56][57][89] and VEEV [78]. Interestingly, it was observed that neutralizing monoclonal antibodies target antigenic regions in the E2 protein. Whereas, non-neutralizing antibodies bind to the E1 protein, yet both are able to confer protection upon alphavirus infection, thereby suggesting other mechanisms of protection in vivo besides virus neutralization [48]. Several monoclonal antibodies targeting both E1 and E2 proteins have been reported in the context of arthritogenic alphavirus infection. Mouse monoclonal antibodies targeting the A and B domain of E2 and the domain II of E1 [90][91][92] and the capsid protein [93][94] have been reported for CHIKV. Likewise, human anti-CHIKV monoclonal antibodies were found to target conformation epitopes in the E2 glycoprotein A (containing a putative RBD [95]) and B (shielding the fusion loop in E1 [96]) domains and proved therapeutic value in experimental NHP infections [90][97][98]. Monoclonal antibodies recognizing epitopes predominantly between residues 58–80 (domains A) or residues 180–215 (domain B) of the E2 glycoprotein have been also reported in the context of SINV [83], VEEV [81], EEEV [99][100][101], RRV [102] and MAYV [103].
The combined evidence suggested the existence of common antigenic sites in the viral spike across alphaviruses, particularly in the E2 protein. These sites are likely required for interaction with host cell receptors suggesting that antibody binding might inhibit infection during viral attachment, entry, fusion or egress [90]. In line with this, a recent study reported the discovery of Mxra8, a cell adhesion molecule, as a host receptor required for viral entry of multiple arthritogenic alphaviruses [104]. Genetically altering mouse or human Mxra8 resulted in diminished infection, conversely, overexpression of Mxra8 in cell lines increased infection rates by CHIKV, ONNV, MAYV and RRV [104][105]. Interestingly, mutagenesis experiments suggested E2 domains A and B as the putative binding site for Mxra8 [104]. This notion was later confirmed by cryo-electron microscopy images of Mxra8 bound to CHIKV [106][107]. Mxra8 sits onto a cleft formed by two contiguous CHIKV E2-E1 heterodimers in one trimeric spike while engaging a neighboring spike [106]. It is believed that this interaction works against the virus by obstructing viral fusion [106]. Importantly, human neutralizing antibodies that recognize regions of the A domain of E2 inhibited the binding of Mxra8 supporting the interactions determined in the cryo-EM atomic model. Notably, Mxra8 seems to not be a receptor for neurotropic alphaviruses [104]. The alignment of CHIKV residues involved in Mxra8 binding reveled a degree of conservation in arthritogenic alphaviruses (44%), but diverged from neurotropic Alphaviruses (14%) which might explain the negative results in the context of SINV, EEEV, WEEV and VEEV infections [106]. In summary, the characterization of alphavirus antigenic epitopes has proven beneficial to pave the way for the development of antibody therapies and vaccines.

3. Alphavirus Vaccine Development

Recent decades have seen increased rates of geographic dispersal of arboviral re-emergence, due to factors such as growth of global transportation, urbanization and failure of mosquito control [108][109][110][111]. Given that humans appear to be the only amplification hosts and viral reservoir during urban transmission [112][113], another effective means of controlling the spread of infection is through vaccination. While there are currently no licensed or approved vaccines available for alphaviruses, a multitude of approaches have been used to develop vaccine candidates capable of, not only generating high levels of antibodies, but also providing long-lasting protection, with the ease of administration and production requirements. Multiple methods such as live-attenuated viruses, inactivated viruses, virus-like particles (VLP), recombinant subunit vaccines and chimeric vaccines have been explored for vaccine options (Figure 2 and Table 1).
Figure 2. An outline of the current vaccine options against arthritogenic (left panel) and neurotropic (right panel) alphaviruses. Most of these vaccine candidates are currently under preclinical testing (early preclinical—vaccine candidates tested in mouse models; late preclinical—vaccine candidates currently under testing in non-human primates (NHP)), while a minority of them are currently undergoing clinical trials (Phase 1, 2 or 3). LAV; live-attenuated virus; VLP, virus-like particle; SIN, Sindbis virus; ISFV, Isfahan virus; May, Mayaro virus; EILV, Eilat virus, VSV/VSIV, vesicular stomatitis virus; MV, measles virus; MVA, modified vaccinia virus Ankara. Data curated from literature reported through February 2021. Numbers in superscript refer to reference numbers (See Reference list [23][73][114][115][116][117][118][119][120][121][122][123][124][125][126][127][128][129][130][131][132][133][134][135][136][137][138][139][140][141][142][143][144][145][146][147][148][149][150][151][152][153][154][155][156][157][158][159][160][161][162][163][164][165][166][167][168][169][170][171][172][173][174][175][176][177][178][179][180][181][182][183][184][185][186][187][188][189][190][191][192][193][194][195][196][197][198][199][200][201][202][203][204][205][206][207][208][209][210][211][212][213][214][215][216][217][218][219][220]).
Table 1. List of vaccine candidates against relevant alphaviruses currently under development 1.

Vaccine Against Virus

Name

Strain Vaccine Modelled After

Phase

Immunization

Challenge

Humoral Immune Response(s)

Ref

Dose

Route

Schedule

Dose (Strain, Genotype)

Route

Live-attenuated

                 

CHIKV, ONNV

RH-CHIKV

EV-CHIKV

RHEV-CHIKV

LR2006 OPY1

C57BL/6 mice, 3 week old

106 PFU

s.c. in the ventral side of the right hind footpad

Single dose

106 PFU LR2006 OPY1 or WT-ONNV IMTSSA/5163, 3 mpim

s.c. in the ventral side of the right hind footpad

IC50, 613 (RH-CHIKV), 3407 (EV-CHIKV), 921 (RHEV-CHIKV)

[130]

CHIKV

Δ5nsP3 (VLA1553-301 in clinical trials) and Δ6K

LR2006 OPY1

C57BL/6 mice, 5 to 6 week old

104 or 105 PFU

s.c. in both flanks

Single dose

106 PFU LR2006 OPY1, 7 wpim

s.c.

NT50, 100 to 1000

[131][132][133]

Cynomolgus macaques, 3–4 years old

105 PFU

s.c. in the right upper back side

Single dose

100 AID50 (corresponding to 7000–10,000 PFU) LR2006 OPY1, 123 dpim

i.v.

NT50, >1000

Human clinical trial, Phase 1

3.2 × 103,

3.2 × 104 or 3.2 × 105 TCID50

i.m.

Two doses (0 and 6 months, or 0 and 12 months)

NA

NA

GMT, 592.6 to 686.9

CHIKV

CHIKV-NoLS

LR2006 OPY1

C57BL/6 mice, 21 days of age

104 PFU

s.c.

Single dose

104 PFU of LR2006 OPY1 or Ross River virus, 30 dpim

s.c.

<10% cells infected at 10-1 serum dilution

[127]

CHIKV

Stop CHIKV

SuperStop CHIKV

LR2006 OPY1

C57BL/6 mice, 5 week old

104 PFU

s.c.

Single dose

ND

ND

~5–25 (Stop CHIKV) and ~10–25 (SuperStop CHIKV) fold reduction compared to mock

[134]

CHIKV

ChikV HR

37997

C57BL/6 mice, 28 days of age

∼103 PFU

s.c. into the left footpad

Single dose

103 PFU CHIKV SL15649, 28 dpim

s.c. in the footpad

PRNT50, 5 to ~500

[135]

CHIKV

Heparin sulfate cell culture adapted

LR2006 OPY1

CD-1 mice, 21 days old

105 GE

s.c. in the rear footpad

Single dose

103 PFU LR2006 OPY1, 21 dpim

NA

~40 to 1000 fold change compared to mock

[136]

VEEV

V3526

IA/B Trinidad donkey

BALB/c, 6 to 8 week oldC3H/HeN mice, 6 to 8 week old

105 PFU

s.c.

Single dose

105 PFU of TrD, 28 dpim

NP

ND

[137][138][139][140]

Cynomolgus macaques (age not specified)

2.5 × 106 PFU

s.c.

Single dose

∼108 PFU VEEV IE 68U201, 8 wpim

aerosol

PRNT80, 28 to 2560

Rhesus macaques (2 to 4 years old)

1.3 × 105 or 7.5 × 104 PFU

s.c. or i.t./i.s.

Single dose

ND

ND

PRNT80, ~80 to 300

Human clinical trial, Phase 1

25 or 125 PFU

s.c.

Single dose

NA

NA

NA

VEEV

V4020

IA/B Trinidad donkey

BALB/c mice, 4 to 8 week old

104 PFU

s.c.

Single dose

104 PFU of VEEV TrD, 28 dpim

s.c.

PRNT80, 160 to1280

[141][142]

Cynomolgus macaques (age not specified)

~104 PFU

s.c. in the right leg

Single dose (or second dose at 2 x 104 PFU i.m. if did not seroconvert)

106 to 107 PFU of the VEEV TrD, 73 dpim

aerosol

PRNT80, >640

EEEV

5′U4&6 C65-69 E71-77 3′U11337 mutants

FL93-939

CD-1 mice, 5 to 6 week old

1.5 × 105 GE

s.c. in footpad, or i.c.

Single dose

105 PFU EEEV FL93, 21 dpim

s.c. in both footpads

PRNT80, 16 to ~4000

[143]

Live-attenuated (IRES)

                 

CHIKV

CHIKV/IRES

LR2006 OPY1

A129 mice, 3 or 10 week old

104 PFU

i.d.

Single dose

100 PFU LR2006 OPY1, 94 dpim

i.d.

PRNT80, >320

[144][145]

C57BL/6 mice, 3 week old

105 PFU

s.c. in the hind leg

Single dose

106.5 PFU Ross CHIKV, 21 dpim

i.n.

Mean PRNT80, 62

A129 mice, 8 to 10 week old

105 TCID50

s.c.

Single dose

100 PFU LR2006 OPY1, 50 dpim

i.d.

Mean PRNT80, 1152

Cynomolgus macaques, >3 years old

105 PFU

s.c. or i.d.

Single dose

105 PFU LR2006 OPY1, 52 dpim

s.c. in the upper deltoid

PRNT80, 40 to 640PRNT50, 160 to 1280

ONNV

CHIKV/IRES

LR2006 OPY1

A129 mice, 6 to 7 week old

104 PFU

i.d.

Single dose

105 PFU ONNV SG650, 38 dpim

i.d.

PRNT80, 160

[146]

VEEV

ZPC/IRESv1, ZPC/IRESv2

ID ZPC738

CD-1 mice, 6 to 8 week old

105 PFU

s.c. in the scruff of the back

Single dose

105 PFU VEEV 3908, 4 wpim

s.c. or aerosol

PRNT80, 40 to 324

[114]

Cynomologous macaques, age not specified

105 PFU

s.c. in the upper deltoid

Single dose

~ 8 × 105 to 9 × 106 PFU VEEV 3908, 35 dpim

aerosol

PRNT80, <20 to 20PRNT50, <20 to 160

EEEV

EEE/IRES

FL93-939

NIH Swiss mice, 3 to 4 week old

104 PFU

s.c. in the medial thigh

Single dose

103 PFU of FL93-939, 4 wpim

i.p.

PRNT80, 160 to 640

[147]

VEEV

68U201/IRESv1 68U201/IRESv2

IE 68U201

CD1 mice, 6 to 8 week old

105 PFU

s.c. in right hind leg

Single dose

(Lethal dose, NP) 68U201 at 1, 3, or 12 mpim

s.c.

PRNT80, 64 to ~300

[148][149]

Cynomolgus macaques (age not specified)

105 PFU

s.c. in the upper deltoid

Single dose

4 × 104 PFU VEEV IE 68U201, 49 dpim

aerosol

PRNT80, ~100 to 340

VEEV

VEEV/IRES/C

IA/B Trinidad donkey

CD-1 mice, 8 week old

105 PFU

s.c.

Single dose

104 PFU of VEEV 3908, 6 wpim

s.c.

Mean PRNT80, 184

[150]

MAYV

MAYV/IRES

MAYV-CH

BALB/c, 6 week old

2 × 105 PFU

s.c. i.pl. route

Single dose

2 × 105 PFU of WT MAYV, 28 dpim

s.c. i.pl. route

PRNT50, >640 (at 21dpi)

[146][151][152]

AG129

2 × 104, 2 × 103 or 2 × 102 PFU

s.c. i.pl. route

Single dose

2 × 103 PFU of WT MAYV, 14 dpim

s.c. i.pl. route

ND

CD-1, 28-day old

105 PFU

s.c. over the dorsum

Single dose

ND

ND

PRNT80, 160 to ≥ 640

AG129, 5 to 8 week old

104 PFU

i.d. on the left foot

Single dose

104 PFU of WT MAYV, 29 dpim

s.c.

PRNT80, 320 to ≥ 640

Inactivated

                 

CHIKV

Vero cell adapted

DRDE-06

Swiss albino mice, 3 to 4 week old

10, 25 or 50 ug

s.c.

Three doses (0, 14 and 28 days)

ND

ND

PRNT90, 6400

[153]

CHIKV

BPL/formalin-inactivated CHIKV

BBV87 (in clinical trials)

IND-06-AP3

BALB/c mice, 4 to 6 week old

10, 20 or 50 μg

i.m.

Two doses (0 and 14 days)

2.5 x 104 TCID50 IND-06-AP3, 4 or 22 wpim

i.n.

GMT, NT50, 80 to 1280

[154]

Human clinical trial, Phase 1

10, 20 or 30 μg

i.m.

Three doses (0, 29 and 57 days)

NA

NA

NA

[155]

RRV

Vero cell culture-derived whole-virus RRV vaccine Ross River Virus (RRV) Vaccine

T48

CD-1 mice, 7 to 8 week old

0.0025, 0.01, 0.039, 0.156, 0.625, 2.5 or 10 μg

s.c.

Two doses (0 and 28 days)

106 TCID50 RRV T48, 42 dpim

i.v.

Mean NT, ≤2.9 to 46.2

[73][115][128][129]

A129 mice, 7 to 8 week old

0.063, 0.25 or 1 μg

i.m.

Two doses (0 and 21 days)

102.5 TCID50 T48, 42 dpim

s.c. into left footpad

Mean NT, ≤14 to 21

CD-1 mice, age not specified

10 μg

s.c.

Two doses (0 and 28 days)

106 TCID50 T48, 6 wpim

i.v.

1000 TCID50

Guinea pigs (Duncan Hartley), age not specified

10 μg

s.c.

Single or two doses (0 and 6 weeks)

106 TCID50 T48, 10 or 34 wpim

i.v.

NP

Human clinical trial, Phase 1/2

1.25, 2.5, 5, or 10 μg

i.m.

Three doses in escalation (0, 21 days, 6 months)

NA

NA

GMT, 50 to 520.9

Human clinical trial, Phase 3

2.5 ug

i.m.

Three doses (0, 3 weeks, 6 months)

NA

NA

μNT GMT, ~0 to 85

EEEV

TSI-GSD-104 (formalin inactivated)

PE-6

Human clinical trial, Phase 2

NP

s.c. (0 and 28 days), i.d. (6 months)

Three doses (0, 28 days and 6 months)

NA

NA

PRNT80 >40 in 60% subjects (primary doses) versus 84% subjects (completed the 2-dose primary series and the 6-month dose)

[156][157][158]

EEEV

fCVEV1219

iCVEV1219

gCVEV1219

CVEV1219

BALB/c mice, 6 to 8 week old

0.1 to 5 µg of inactivated EEEV

i.n., s.c. or i.m.

Single dose or two doses (0 and 28 days)

Lethal dose of EEEV FL93-939, at 28 dpim (single dose) or 56 dpim (two doses)

aerosol

PRNT80, ~1 to 1000

[159]

VEEV

V3526 virus

V3526

BALB/c mice, 6 week old

0.2 μg (s.c.) or 0.04 μg (i.m.)

s.c. or i.m.

Two doses (0 and 28 days)

104 PFU VEEV TrD, 56 dpim

aerosol or s.c.

GMT PRNT80, ~60 to 2500

[160]

VEEV

F-iV3526

V3526

BALB/c mice, 8 to 10 weeks old

1, 3 or 5 μg

i.n., s.c. (under the skin over the neck) or i.m. (thigh muscle of the hind leg)

Single dose

454 (i.n.), 897 (i.m.) or 55 (s.c.) PFU VEEV-TrD, 56 dpim

aerosol

Microneutralization titer of 100 to 3500

[161][162]

Virus-like particle

                 

CHIKV

VRC 311

Or

VRC-CHKVLP059-00-VP/ PXVX0317 (in clinical trials)

37997

BALB/c mice, 6 to 8 week old

19 μg

i.m.

2 doses (2 and 5 weeks)

ND

ND

IC50, 10703 to 54600

[116][117][118][163]

Cynomolgus macaques, 3 to 4 years old

20 μg

i.m.

3 doses (0, 4 and 24 weeks)

1010 PFU LR2006 OPY1, 15 wpim

i.v.

IC50, 10219 to 15072

Human clinical trial, Phase 1

10, 20 or 40 μg

i.m.

3 doses (0, 4 and 24 weeks)

NA

NA

IC50, 4525 to 8745

Human, clinical trial Phase 2

20 μg

i.m.

2 doses (0 and 28 days)

NA

NA

EC50 GMT, 2005

Human clinical trial (Phase 2b, recruitment completed)

6, 10 or 20 μg

NP

Two doses (0 and 14 or 28 days)

NA

NA

NA

CHIKV

Baculovirus-expressed VLP

S27

AG129, 6 week old

1 μg

s.c.

2 doses (0 and 21 days)

1000 TCID50 S27, 6 wpim

i.p.

PRNT95, 40 to 80

[164][165]

C57BL/6 mice, 6 to 12 week old

0.1 or 1 μg

s.c.

Single dose

104 CCID50 LR2006 OPY1, 6 wpim

s.c.

NT95, ~1,100

 

CHIKV

Yeast-expressed VLP

DRDE06/DRDE07

BALB/c mice, 4 week or 2 days old

10, 20 or 40 ug

s.c.

Three doses (0, 14 and 28 days)

ND

ND

NT50, 128 to 2048

[166]

VEEV

Venezuelan Equine Encephalitis Monovalent Virus-Like Particle Vaccine (VEEV)

NA

Human clinical trial (Phase 1, not recruiting)

2, 10, or 20 μg

i.m.

Dose escalation (0, 28 days, and day 140 booster)

NA

NA

NA

[167]

WEEV, EEEV, and VEEV

VRC-WEVVLP073-00-VP (Trivalent vaccine)

WEEV CBA87, EEEV PE-6 and VEEV TC-83

BALB/c mice, 6 to 8 week old

monovalent (5 μg) or trivalent (5 μg each)

i.m.

Two doses (0 and 21 days)

2.5 × 103 PFU WEEV CBA87, 8.9 × 103 PFU EEEV FL93-939, and 1.3 × 103 PFU VEEV Trinidad donkey, 56 dpim

aerosol

PRNT80, ~250 to 100000

[168]

Cynomolgus macaques, age not specified

Monovalent (20 μg) or trivalent (20 μg each)

i.m.

Two doses (0 and 28 days)

106 PFU WEEV CBA87, 108 PFU EEEV FL93-939, and 108 VEEV Trinidad donkey, 56 dpim

aerosol

PRNT80, ~1000 to 10000

Human clinical trial, Phase 1

6, 30 or 60 μg

i.m.

Dose escalation (0 and 8 weeks)

NA

NA

NA

[169]

DNA/RNA

                   

VEEV

VEEV 26S DNA plasmid

I/AB TrD

BALB/c mice, 6 to 8 week old

∼3 μg

DNA/gene gun, delivered to two sites on the abdomen of each mouse

Three doses (at 3-week intervals)

∼104 PFU of TrD, 9 wpim

s.c., aerosol

PRNT50, GMT <1.6 to 2.5

[170][171]

Hartley guinea pigs, age not specified

~5 μg

DNA/gene gun, delivered to two sites on the abdomen of each mouse

Three doses (0, 4 and 8 weeks)

∼104 PFU of TrD, 21 wpim

aerosol

PRNT50, 0 to 640

VEEV

DNA-Ad

TC-83

BALB/c mice, 6 to 8 week old

1 μg of DNA per dose and 107 PFU of RAd/VEEV #3 per boost

gene guni.n.

immunised with the DNA vaccines on day 0, 14 and 28 and Ad-based vaccine on day 42

100 LD50 of virulent airborne VEEV, 63 dpim

aerosol

PRNT50, 160

[172]

VEEV

AG4-1C7

AG4-1G2 AG2-5A7

AG2-5A10 plasmid DNA

I/AB TrD

BALB/c mice, 6 to 8 week old

4 μg

particle-mediated epidermal delivery (i.d.)

Three doses (at 3-week intervals)

∼104 PFU of VEEV TrD (≥1000 LD50), 70 dpim

aerosol

PRNT80, ~1 to 5.5 log10 GMT

[173]

VEEV

pTC83 iDNA

TC-83

BALB/c mice, 3 week old

50 μg

i.m. electroporation

Single dose

105 PFU VEEV 3908, 21 dpim

s.c.

PRNT80, 10 to 320

[174]

WEEV

pE3-E2-6K-E1

pE3-E2

P6K-E1

71V-1658

BALB/c, age not specified

2 μg

gene gun

Three doses (14 days apart)

1500 PFU WEEV 71V-1658,

Fleming, or CBA87, 42 dpim

i.n.

ND

[175]

CHIKV

pCHIKV-Capsid, pCHIKV-Envelope (pMCE321)

Consensus

C57BL/6 mice, 3 to 4 week old

25 µg, 2–3 times

Electroporation

Two doses (2 weeks apart)

ND

ND

ND

[176][177][178]

C57BL/6 mice, 6 to 8 week old

25 μg

i.m. electroporation

Three doses (0, 14 and 21 days)

7log10 PFU of PC-08, 35 dpim

i.n.

NP

BALB/c mice

25 μg

i.m. electroporation

Two doses (2 weeks apart)

7log10 PFU PC-08

i.n.

TCID50, 20 to 320

Rhesus macaques, age not specified

1 mg

i.m. electroporation

Three doses (4 weeks apart)

ND

ND

TCID50, 80 to 1280

CHIKV

Δ5nsP3 and Δ6K DNA

LR2006 OPY1

C57BL/6 mice, 5 to 6 week old

20 μg

i.d. with DermaVax electroporation

Single dose or two doses (0 and 3 weeks)

106 PFU LR2006 OPY1, 7 wpim

s.c.

NT50, 100 to 10000

[131]

CHIKV

CHIKV-NoLS RNA

LR2006 OPY1

C57BL/6 mice, 28 days of age

2 μg

s.c. in the ventral/lateral side of the right foot

Single dose

104 PFU LR2006 OPY1, 30 dpim

s.c. in the ventral/lateral side of the right (ipsilateral) or left (contralateral)

PRNT80, 0

[126]

AG129 mice, 28 days old

2 μg

s.c. in the ventral/lateral side of the right foot

Single dose

104 PFU LR2006 OPY1, 30 dpim

s.c. in the ventral/lateral side of the right (ipsilateral) or left (contralateral)

ND

VEEV, WEEV and EEEV

3-EEV

VEEV IAB TrD, WEEV CBA874 and EEEV FL91-46794

C57BL/6 mice, 6 to 8 week old

15 μg

i.m. electroporation

Two doses (0 and 21 days)

104 PFU VEEV IAB TrD or 2 × 104 PFU WEEV CBA874 or 105 PFU EEEV FL91-46794, 7 wpim

aerosol

PRNT80, ~1 to 1000

[179]

MAYV

scMAYV-E

NA

C57BL/6 mice, 5 to 8 week old

25 μg

i.m. electroporation

Single, two doses or three doses (at 2 week intervals)

ND

ND

PRNT50, 789.8

[180]

A129 mice, 4 to 6 week old

25 μg

i.m. electroporation

Single, two doses or three doses (at 2 week intervals)

102 PFU MAYV 15537

i.p.

ND

CHIKV

p181/25-7

TSI-GSD-28

BALB/c mice, 3 week old

10 μg

i.m. electroporation

Single dose

6 × 106 PFU CHIKV Ross, 28 dpim

i.n.

PRNT80, 160 to 1280

[181]

CHIKV

dMaB

NA

BALB/c mice, age not specified

100 μg

Electroporation

Single dose

107 PFU Del-03

s.c. or i.n.

IC50, 3 to 4.5log10

[182]

CHIKV

iRNAΔ5nsP3

iDNAΔ5nsP3

LR2006 OPY1

C57BL/6 mice, 8 week old

0.125, 1.25 or 10 μg

i.m. in the gastrocnemius muscle of the left hind leg

Single dose

106 PFU LR2006 OPY1, 5 wpim

s.c. at the dorsal side of each hind foot

NT50, ~1 to 104

[183]

VEEV

pMG4020 DNA plasmid

TC-83

BALB/c, 4 to 8 week old

0.5 or 5 ug

i.m. electroporation

Single dose

104 PFU VEEV TrD, 28 dpim

s.c.

PRNT80, 320 to >1280

[141]

VEEV

VEEVWT VEEVCOCAP

VEEVCO

IAB TrD

BALB/c, 6 to 8 week old

25, 5, or 1 μg

i.m. electroporation

Two doses (3 weeks apart)

∼104 PFU VEEV IAB strain TrD, 7 wpim

aerosol

PRNT80, 1 to ~4.5log10

[184][185]

New Zealand White rabbits, age not specified

500 μg of VEEVCO

i.m. electroporation

Three doses (0, 28 and 230 days)

ND

ND

PRNT80, ~3log10 to 5log10

Cynomolgus macaques, age not specified

50 or 500 μg of VEEVCO

i.m. electroporation

Two doses (0 and 56 days)

3 × 108 PFU VEEV IAB TrD

aerosol

PRNT80, ~0.8log10 to 3.5log10

Human clinical trial, Phase 1

0.5 or 2 mg

i.m. electroporation or i.d. electroporation

Three doses (days 0, 28, and 56)

NA

NA

GMT PRNT80, 7 to 78

WEEV

pVHX-671V-1658

pVHX-6 CBA87

pVHX-6 Fleming

Fleming, CBA 87 or 71V-1658,

BALB/c mice, age not specified

2 shots × 2.5 μg precipitated on 0.5 mg gold

gene gun

Four doses (2 weeks apart)

1.5 × 103 PFU WEEV Fleming, CBA 87 or 71V-1658, 8 wpim

i.n.

ND

[186]

WEEV and EEEV

LANAC E1ecto

WEEV McMillan

CD-1 mice, 4 to 6 week old

10 μg

s.c. injection dorsal to the cervical spine

Two doses (2 weeks apart)

104 PFU WEEV McMillan, Montana-64, or EEEV Florida-93, 4, 5, 9, 11, or 13 wpim

i.n. or s.c.

PRNT50, <40 to 200

[187]

CHIKV

mRNA-1388 (or VAL-181388 in clinical trials)

NA

Human clinical trial, Phase 1

25, 50 or 100 μg

i.m.

Dose escalation procedure (0 and 4 weeks)

ND

ND

‘dose-dependent increase’ in neutralizing and binding antibody titers

[188]

CHIKV

mRNA-1944

SL15649

AG129, age not specified

0.4, 1 or 10 mg/kg

i.v. tail vein injection

Single dose

102.5 TCID50 of CHK

subcutaneous injection in the footpad and hock of the right leg

ND

[189][190]

Cynomolgus macaques, 2 to 3 year old

0.5 mg/kg

i.v.

Single dose

ND

ND

FRNT50, 5 to 12

Human clinical trial, Phase 1 (active, not recruiting)

0.1, 0.3 and 0.6 mg/kg

i.v.

Dose escalation

NA

NA

NT50, ‘all participants also showed circulating neutralizing antibody activity’

Subunit

                   

CHIKV

CHIKV-sE1 and -sE2

S27

AG129 mice, 6 week old

2 μg

s.c.

Two doses (0 and 21 days)

1000 TCID50 of S27 isolate, 9 wpim

i.p.

NT95, <25

[164][165][191]

CHIKV

rE2p

IND-06-AP3

BALB/c, 6 to 8 week old

10, 20 or 50 μg

i.m.

Two doses (2 weeks apart)

Mice immunized with 50 μg challenged with 7 log10 TCID50 /mL, 4 or 22 wpim

i.n.

NT50, 0.25log10 to 2.5log10

[154]

CHIKV

CHIKE1 and CHIKE2 recombinant proteins

DRDE-06

BALB/c

40 μg

s.c.

Three doses (0, 21 and 35 days)

ND

ND

PRNT90, 32 to 512

[192]

Chimeric virus

                 

Measles virus-based chimeras

             

CHIKV (VLP)

MV-CHIKV

06–49

CD46-IFNAR, 6 week old

103 to 105 TCID50

i.p.

Single or two doses (30 days apart)

100 PFU of CHIKV 06-49, 2 mpim

i.p.

PRNT50, 450 to 4050

PRNT90, 50 to 450

[193][194][195][196][197]

Cynomolgus macaques, age not specified

5 × 105 (± 0.5 log) TCID50

i.m.

Two doses (28 days apart)

1.4 × 105 PFU LR2006 OPY1, 56 dpim

s.c.

PRNT80, 40 to >640

Human clinical trial, Phase 1

1.5 × 104, 7.5 × 104 or 3.0 × 105 TCID50

i.m. or s.c.

Dose escalation (0 and 28 days, or 0 and 90 days)

NA

NA

PRNT50, 5 to 433

Human clinical trial, Phase 2

5 × 104 or 5 × 105 TCID50

i.m.

Three doses (0, 28, and 196 days)

NA

NA

PRNT50, ~5 to 5000

Alphavirus-based chimeras

             

CHIKV

VEE/CHIKV

EEE/CHIKV

SIN/CHIKV

LR2006 OPY1

NIH Swiss, C57BL/6, >3 week old

5.8 log10 PFU (VEE/CHIKV and SIN/CHIKV), 5.3 log10 PFU (EEE/CHIKV)

s.c. in the medial thigh

Single dose

6.5 log10 PFU (Ross CHIKV strain), 21 dpim

i.n.

PRNT80, 20 to 320

[198]

CHIKV

VEE/IRES-CHIKV

VEE/IRES-C/CHIKV

NA

A129 mice, 6 to 9 week old

104 PFU

s.c.

Single dose

102 PFU of LR2006 OPY1, 5 weeks post immunization

s.c.

PRNT80, >640

[199]

CHIKV

EILV-CHIKV

CHIKV 996659

C57BL/6 mice, 4 week old

8.8 log10 PFU

s.c.

Single dose

6 log10 PFU 99659, 30 dpim

i.d.

PRNT80, ≥ 80

[125][220]

IFNα/βR−/−, 6 week old

8.8 log10 PFU

s.c.

Single dose

3 log10 PFU 99659, 292 dpim

i.d.

PRNT80, 160 to 1280

Cynomolgus macaques, 3 to 5 years

8.1 log10 PFU

i.m. into the right quadriceps

Single dose

5 log10 PFU LR2006 OPY1, 31 dpim

s.c.

PRNT80, 80 to 640

EEEV

EILV/EEEV

EEEV FL-93

Adult CD-1 mice (age not specified)

108 PFU

s.c.

Single dose

105 PFU EEEV-FL93, 70 dpim

i.p.

PRNT80, 80 to 640

[125][220]

EEEV

Trivalent EILV/EEEV EILV/VEEV EILV/CHIKV

EEEV FL-93, VEEV IAB TC-83, CHIKV 996659

Adult CD-1 mice (age not specified)

108 PFU

s.c.

Single dose

105 PFU EEEV-FL93, 70 dpim

i.p.

PRNT80, 40 to 640 and 20 to 640 for mono- and trivalent vaccines respectively

VEEV

EILV/EEEV

VEEV IAB TC-83

Adult CD-1 mice (age not specified)

108 PFU

s.c.

Single dose

103 PFU VEEV-IC 3908, 70 dpim

s.c.

PRNT80, 80 to 1280

VEEV

Trivalent EILV/EEEV, EILV/VEEV EILV/CHIKV

EEEV FL-93, VEEV IAB TC-83, CHIKV 996659

Adult CD-1 mice (age not specified)

108 PFU

s.c.

Single dose

103 PFU VEEV-IC 3908, 70 dpim

s.c.

PRNT80, 40 to 640 and 20 to 80 for mono- and trivalent vaccines respectively

EEEV (Sindbis virus)

SIN/NAEEEV

EEEV FL93-939

NIH Swiss mice, 8 week old

3.7, 4.7 or 5.7 log10 PFU

s.c.

Single dose

6 log10 PFU FL93-939, 28 dpim

i.p.

PRNT80, 125 to 660

[200]

SIN/SAEEEV

EEEV BeAr436087

NIH Swiss mice, 8 week old

3.8, 4.8 or 5.8 log10 PFU

s.c.

Single dose

6 log10 PFU FL93-939, 28 dpim

i.p.

PRNT80, 28 to 308

VEEV

SIN-83

VEEV IAB TC-83

Weanling NIH Swiss mice, 6 day old

103, 104, 105 or 106 PFU

s.c.

Single dose

106 PFU VEEV IC ZPC738 IC SH3

s.c.in medial thigh

PRNT80, 30 to 960

[201][202]

NIH Swiss mice, 6 week old

5 × 105 PFU

s.c.

Two doses

2 x 105 or 106 PFU VEEV ZPC738, 8 wpim

s.c., i.c., or i.n.

PRNT80, 55 to 73 (single), 100 to 160 (booster)

SAAR/TRD

VEEV IAB TrD

NIH Swiss mice, 6 week old

5 × 105 PFU

s.c.

Two doses

2 x 105 or 106 PFU VEEV ZPC738, 8 wpim

s.c., i.c., or i.n.

PRNT80, 126 to 167 (single), 152 to 160 (booster)

SIN/TRD

VEEV IAB TrD

NIH Swiss mice, 6 week old

5 × 105 PFU

s.c.

Two doses

2 x 105 or 106 PFU VEEV ZPC738, 8 wpim

s.c., i.c., or i.n.

PRNT80, 37 to 57 (single), 50 to 73 (booster)

SIN/ZPC

VEEV ID ZPC738

NIH Swiss mice, 6 week old

5 × 105 PFU

s.c.

Two doses

2 x 105 or 106 PFU VEEV ZPC738, 8 wpim

s.c., i.c., or i.n.

PRNT80, 187 to 253 (single), 253 to 487 (booster)

All the above

VEEV IAB TC-83, IAB TrD, ID ZPC738

Syrian golden hamsters, 6 week old

5 × 105 PFU

s.c. in the medial thigh

Single dose

106 PFU

s.c.in medial thigh

ND

WEEV

SIN/CO92

WEEV CO92-1356

NIH Swiss mice, 6 week old

3.5, 4.5, or 5.0 log10 PFU

s.c. in the medial thigh

Single dose

5.3 log10 PFU WEEV TBT235, 28 dpim

i.n.

PRNT80, 20 to 640

[203]

SIN/SIN/McM

WEEV McMillan

NIH Swiss mice, 6 week old

4.8 or 5.8 log10 PFU

s.c. in the medial thigh

Single dose

5.0 log10 PFU WEEV McMillan, 28 dpim

i.n.

PRNT80, 600 to 604

SIN/EEE/McM

EEEV 436087 and WEEV McMillan

NIH Swiss mice, 6 week old

4.6 or 5.6 log10 PFU

s.c. in the medial thigh

Single dose

5.0 log10 PFU WEEV McMillan, 28 dpim

i.n.

PRNT80, 416 to 420

Vaccinia virus-based chimeras

             

CHIKV

MVA-CHIKV

LR2006-OPY1

C57BL/6 mice, 6 to 8 week old

107 PFU (first dose), 2 × 107 PFU (second dose)

i.p.

Two doses (2 weeks apart)

106 PFU LR2006-OPY1, 9 wpim

s.c. in the dorsal side of each hind foot

NT50, ~100 to 3000

[204]

CHIKV

MVA-CHIK

LR2006-OPY1

BALB/c mice, 4 to 6 week old

107 TCID50 units

i.d. injection into the left hind footpad.

Single or two doses (28 days apart)

104

LR2006 OPY1 TCID50 units at 39 or 42 dpim

i.d.

TCID50, 5 to 15

[205]

AG129, 6 to 10 week old

107 TCID50 units

i.d. injection into the left hind footpad.

Single or two doses (28 days apart)

102

LR2006 OPY1 TCID50 units at 39 or 42 dpim

i.d.

TCID50, 4 to 8

CHIKV

MVA-6KE1, MVA-E3E2, MVA-6KE1E3E2

CHIKV S27

AG129 mice, 7 week old

5 × 106 TCID50

i.m. into the quadriceps muscles of the left leg

Two doses (3 weeks apart)

103

TCID50 CHIKV-S27 and CHIKV-IND/NL10, 63 dpim

i.p.

NT100, 10 to 160

[206]

EEEV, VEEV, and WEEV

MVA-BN-E/V/W (monovalent)

MVA-BN-E + MVA-BN-V + MVA-BN-W (triple mixture of monovalent vaccines)

MVA-BN-WEV (trivalent)

WEEV 71 V-1658, EEEV FL93-939NA and VEEV TrD

BALB/c mice, age not specified

108 TCID50

s.c. or i.m.

Two doses (28 days apart)

5 × 103 or 104 PFU of WEEV Fleming, EEEV PE6, or VEEV TrD, 14 days post booster

i.n.

NT50, ~750 to 3800 (monovalent), ~<60 to 340 (triple mixture of monovalent vaccines) and ~<60 to 380 (trivalent)

[207]

Adenovirus-based chimeras

             

CHIKV

CAdVax-CHIK

LR2006 OPY1

CD-1 or C57BL/6, 6 to 8 week old

108 IU

i.p.

Single dose

104 CCID50 LR2006 OPY1 or QIMR, 6.5 wpim

s.c. into side of each hind foot towards the ankle

NT100, ~2000

[208]

CHIKV

ChAdOx1 Chik

NA

BALB/c, 6 to 8 week old

108 IU

i.m.

Single dose

ND

ND

NT50, 5.39 × 103

[209][210]

 

AG129, 5 week old

108 IU

i.m. in each leg

Single dose

9.7 × 104 PFU LR2006 OPY1, 30 dpim

i.d. into the left foot

ND

 

ChAdOx1 Chik

ChAdOx1 Chik ΔCap

AG129, 5 week old

108 IU

i.m. in each hind leg

Single dose

9.7 × 104 PFU of LR2006 OPY1, 30 dpim

i.d. into the left foot towards the ankle

PRNT80, 32 to 64 (Chik), 16 to 32 (Chik ΔCap)

[211]

 

CHIK001 (in clinical trials)

Human clinical trial, Phase 1

5 × 109, 2.5 × 1010 or 5 × 1010 vp

i.m.

Single dose

ND

ND

ND

[212]

MAYV

ChAdOx1 May

NA

AG129, 5 week old

1.6 × 104 PFU

i.m. in each leg

Single dose

1.6 × 104 PFU MAYV-CH, 30 dpim

i.d. into the left foot

PRNT50, 160 to 620

[210]

VEEV

Rad/VEEV#3

VEEV IAB TC-83

BALB/c, 6 to 8 week old

107 PFU

i.n.

Three doses (at 0, 7 and 21 days)

Dose ND, 28 dpim

aerosol

PRNT50 (NP)

[213]

BALB/c, 6 to 8 week old

107 PFU

i.n.

Two doses (at 0, 21 days)

5000 LD50 TrD, 42 dpim

aerosol

ND

[214]

WEEV

Ad5-WEEV

WEEV 71V-1658

BALB/c mice, age not specified

107 PFU

i.m.

Single or two doses (at 4 weeks)

1.5 × 103 PFU Fleming or 71V-1658, 13 wpim

i.n.

PRNT50, 160

[215]

WEEV

Ad5-E1

WEEV 71V-1658

BALB/c mice, 6 to 9 week old

107 PFU

i.m. in both leg

Single dose

50 LD50 of 71V-1658, 7 dpim, or

400 LD50 CBA87, 1, 3, 5 or 7 dpim

i.n.

PRNT50, <10

[216]

Vesiculovirus-based chimeras

             

CHIKV

rVSVΔG-CHIKV

CHIKV S27

C57BL/6, 3 week old

106 PFU

i.m. into the right hind leg muscle

Single dose

104 PFU LR 2006 OPY1, 30 dpim

s.c. in the left rear footpad

PRNT80, 80 to 640

[217]

VEEV

rVSIV-VEEV

VEEV ZPC738

CD-1, 4 to 6 week old

108/107 PFU

i.m.

Single dose

104 PFU VEEV ZPC738, 35 or 245 dpim

s.c.

PRNT80, 288 to 600 at 25 and 35 dpim, 304 to 360 at 245 dpim

[218]

VEEV

rISFV-VEEV

VEEV ZPC738

CD-1, 4 to 6 week old

108 PFU

i.m.

Single dose

104 PFU VEEV ZPC738, 28 dpim

s.c.

PRNT80, ≥20

CD-1, 4 to 6 week old

108 PFU

i.m.

Single dose

104 PFU VEEV ZPC738, 35 or 245 dpim

s.c.

PRNT80, 40 to 160 at 25 and 35 dpim, 25 to 64 at 245 dpim

EEEV

rISFV-EEEV

EEEV FL93-939

CD-1, 4 to 6 week old

108 PFU

i.m.

Single dose

104 PFU EEEV FL93-939, 28 dpim

s.c.

PRNT80, ≥20

Epitope-based

                 

CHIKV

E2EP3

NA

C57BL/6 mice, 3 week old

100 μg (50 μg for booster doses)

s.c. in the abdominal flank

Three doses (0, 14 and 21 days)

106 PFU CHIKV SGP11, 30 dpim

s.c. region at the ventral side of the right hind footpad, towards the ankle

~40% reduction from mock control

[23]

1 s.c., subcutaneous; i.v., intravenous; i.m., intramuscular; i.d., intradermal; i.p., intraperitoneal; i.n., intranasal; i.t./i.s., intrathalamic/ intraspinal; i.pl., intraplantar; i.c., intracranial; dpim, days post immunization; wpim, weeks post immunization; mpim, months post immunization; IRES, internal ribosome entry site; PFU, plaque forming units; TCID50, 50% tissue culture infective dose; CCID50, 50% cell culture infectious dose; IC50, 50% inhibitory concentration; GE, genomic equivalents; IU, infectious units; AID50, 50% animal infectious dose; PRNT50, 50% plaque reduction neutralizing antibody titer; PRNT80, 80% plaque reduction neutralizing antibody titer; PRNT90, 90% plaque reduction neutralizing antibody titer; LD50, median lethal dose; NT50, 50% neutralizing titer; GMT, geometric mean titer; μNT, neutralizing titer; SIN, Sindbis virus; ISFV, Isfahan virus; May, Mayaro virus; EILV, Eilat virus, VSV/VSIV, vesicular stomatitis virus; MV, measles virus; MVA, modified vaccinia virus Ankara; NP, not provided; NA, not applicable; WT, wild type. Data curated from literature reported through February 2021.

References

  1. Atkins, G.J. The Pathogenesis of Alphaviruses. ISRN Virol. 2013, 2013, 22.
  2. Zaid, A.; Burt, F.J.; Liu, X.; Poo, Y.S.; Zandi, K.; Suhrbier, A.; Weaver, S.; Texeira, M.; Mahalingam, S. Arthritogenic alphaviruses: Epidemiological and clinical perspective on emerging arboviruses. Lancet Infect. Dis. 2020.
  3. Suhrbier, A.; Jaffar-Bandjee, M.C.; Gasque, P. Arthritogenic alphaviruses—An overview. Nat. Rev. Rheumatol. 2012, 8, 420–429.
  4. Zacks, M.A.; Paessler, S. Encephalitic alphaviruses. Vet. Microbiol. 2010, 140, 281–286.
  5. Wahid, B.; Ali, A.; Rafique, S.; Idrees, M. Global expansion of chikungunya virus: Mapping the 64-year history. Int. J. Infect. Dis. 2017, 58, 69–76.
  6. Haddow, A.; Davies, C.W.; Walker, A.J. O’nyong-nyong fever: An epidemic virus disease in East Africa 1. Introduction. Trans. R. Soc. Trop. Med. Hyg. 1960, 54, 517–522.
  7. Bessaud, M.; Peyrefitte, C.N.; Pastorino, B.A.; Tock, F.; Merle, O.; Colpart, J.J.; Dehecq, J.S.; Girod, R.; Jaffar-Bandjee, M.C.; Glass, P. J.; et al. Chikungunya virus strains, Reunion Island outbreak. Emerg. Infect. Dis. 2006, 12, 1604–1606.
  8. Aaskov, J.G.; Mataika, J.U.; Lawrence, G.W.; Rabukawaqa, V.; Tucker, M.M.; Miles, J.A.; Dalglish, D.A. An epidemic of Ross River virus infection in Fiji, 1979. Am. J. Trop. Med. Hyg. 1981, 30, 1053–1059.
  9. Tsetsarkin, K.A.; Vanlandingham, D.L.; McGee, C.E.; Higgs, S. A single mutation in chikungunya virus affects vector specificity and epidemic potential. PLoS Pathog. 2007, 3, e201.
  10. Tsetsarkin, K.A.; McGee, C.E.; Volk, S.M.; Vanlandingham, D.L.; Weaver, S.C.; Higgs, S. Epistatic roles of E2 glycoprotein mutations in adaption of chikungunya virus to Aedes albopictus and Ae. aegypti mosquitoes. PLoS ONE 2009, 4, e6835.
  11. Rezza, G.; Chen, R.; Weaver, S.C. O’nyong-nyong fever: A neglected mosquito-borne viral disease. Pathog. Glob. Health 2017, 111, 271–275.
  12. Acosta-Ampudia, Y.; Monsalve, D.M.; Rodriguez, Y.; Pacheco, Y.; Anaya, J.M.; Ramirez-Santana, C. Mayaro: An emerging viral threat? Emerg. Microbe. Infect. 2018, 7, 163.
  13. Ganjian, N.; Riviere-Cinnamond, A. Mayaro virus in Latin America and the Caribbean. Rev. Panam. Salud. Publica 2020, 44, 14.
  14. Pezzi, L.; LaBeaud, A.D.; Reusken, C.B.; Drexler, J.F.; Vasilakis, N.; Diallo, M.; Simon, F.; Jaenisch, T.; Gallian, P.; Sall, A.; et al. GloPID-R report on chikungunya, o’nyong-nyong and Mayaro virus, part 2: Epidemiological distribution of o’nyong-nyong virus. Antivir. Res. 2019, 172, 104611.
  15. Pezzi, L.; Rodriguez-Morales, A.J.; Reusken, C.B.; Ribeiro, G.S.; LaBeaud, A.D.; Lourenço-de-Oliveira, R.; Brasil, P.; Lecuit, M.; Failloux, A.B.; Gallian, P.; et al. GloPID-R report on chikungunya, o’nyong-nyong and Mayaro virus, part 3: Epidemiological distribution of Mayaro virus. Antivir. Res. 2019, 172, 104610.
  16. Pezzi, L.; Reusken, C.B.; Weaver, S.C.; Drexler, J.F.; Busch, M.; LaBeaud, A.D.; Diamond, M. S.; Vasilakis, N.; Drebot, M. A.; Siqueira, A.M.; et al. GloPID-R report on Chikungunya, O’nyong-nyong and Mayaro virus, part I: Biological diagnostics. Antivir. Res. 2019, 166, 66–81.
  17. Seyler, T.; Hutin, Y.; Ramanchandran, V.; Ramakrishnan, R.; Manickam, P.; Murhekar, M. Estimating the burden of disease and the economic cost attributable to chikungunya, Andhra Pradesh, India, 2005–2006. Trans. R. Soc. Trop. Med. Hyg. 2010, 104, 133–138.
  18. Alvis-Zakzuk, N.J.; Diaz-Jimenez, D.; Castillo-Rodriguez, L.; Castaneda-Orjuela, C.; Paternina-Caicedo, A.; Pinzon-Redondo, H.; Carrasquilla-Sotomayor, M.; Alvis-Guzmán, N.; De La Hoz-Restrepo, F. Economic Costs of Chikungunya Virus in Colombia. Value Health Reg. Issues 2018, 17, 32–37.
  19. Thompson, R.; del Martin Campo, J.; Constenla, D. A review of the economic evidence of Aedes-borne arboviruses and Aedes-borne arboviral disease prevention and control strategies. Expert Rev. Vaccin. 2020, 19, 143–162.
  20. Cunha, R.V.D.; Trinta, K.S. Chikungunya virus: Clinical aspects and treatment—A Review. Mem. Inst. Oswaldo Cruz 2017, 112, 523–531.
  21. Lundstrom, K. Alphavirus-based vaccines. Viruses 2014, 6, 2392–2415.
  22. Panning, M.; Grywna, K.; van Esbroeck, M.; Emmerich, P.; Drosten, C. Chikungunya fever in travelers returning to Europe from the Indian Ocean region, 2006. Emerg. Infect. Dis. 2008, 14, 416–422.
  23. Kam, Y.W.; Lum, F.M.; Teo, T.H.; Lee, W.W.; Simarmata, D.; Harjanto, S.; Chua, C.L.; Chan, Y.F.; Wee, J.K.; Chow, A.; et al. Early neutralizing IgG response to Chikungunya virus in infected patients targets a dominant linear epitope on the E2 glycoprotein. EMBO Mol. Med. 2012, 4, 330–343.
  24. Pierro, A.; Rossini, G.; Gaibani, P.; Finarelli, A.C.; Moro, M.L.; Landini, M.P.; Sambri, V. Persistence of anti-chikungunya virus-specific antibodies in a cohort of patients followed from the acute phase of infection after the 2007 outbreak in Italy. New Microbe. New Infect. 2015, 7, 23–25.
  25. Chua, C.L.; Sam, I.C.; Chiam, C.W.; Chan, Y.F. The neutralizing role of IgM during early Chikungunya virus infection. PLoS ONE 2017, 12, e0171989.
  26. Borgherini, G.; Poubeau, P.; Staikowsky, F.; Lory, M.; Le Moullec, N.; Becquart, J.P.; Wengling, C.; Michault, A.; Paganin, F. Outbreak of chikungunya on Reunion Island: Early clinical and laboratory features in 157 adult patients. Clin. Infect. Dis. 2007, 44, 1401–1407.
  27. Malvy, D.; Ezzedine, K.; Mamani-Matsuda, M.; Autran, B.; Tolou, H.; Receveur, M-C.; Pistone, T.; Rambert, J.; Moynet, D.; Mossalayi, D. Destructive arthritis in a patient with chikungunya virus infection with persistent specific IgM antibodies. BMC Infect. Dis. 2009, 9, 200.
  28. Bozza, F.A.; Moreira-Soto, A.; Rockstroh, A.; Fischer, C.; Nascimento, A.D.; Calheiros, A.S.; Drosten, C.; Bozza, P.T.; Souza, T.; Ulbert, S.; et al. Differential Shedding and Antibody Kinetics of Zika and Chikungunya Viruses, Brazil. Emerg. Infect. Dis. 2019, 25, 311–315.
  29. Nitatpattana, N.; Kanjanopas, K.; Yoksan, S.; Satimai, W.; Vongba, N.; Langdatsuwan, S.; Nakgoi, K.; Ratchakum, S.; Wauquier, N.; Souris, M.; et al. Long-term persistence of Chikungunya virus neutralizing antibodies in human populations of North Eastern Thailand. Virol. J. 2014, 11, 183.
  30. Shore, H. O’nyong-nyong fever: An epidemic virus disease in East Africa: III Some clinical and epidemiological observations in the Northern Province of Uganda. Trans. R. Soc. Trop. Med. Hyg. 1961, 55, 361–373.
  31. Williams, M.C.; Woodall, J.P.; Corbet, P.S.; Gillett, J.D. O’nyong-Nyong Fever: An Epidemic Virus Disease in East Africa. 8. Virus Isolations from Anopheles Mosquitoes. Trans. R. Soc. Trop. Med. Hyg. 1965, 59, 300–306.
  32. Kiwanuka, N.; Sanders, E.J.; Rwaguma, E.B.; Kawamata, J.; Ssengooba, F.P.; Najjemba, R.; Were, W.A.; Lamunu, M.; Bagambisa, G.; Burkot, T.R.; et al. O’nyong-nyong fever in south-central Uganda, 1996–1997: Clinical features and validation of a clinical case definition for surveillance purposes. Clin. Infect. Dis. 1999, 29, 1243–1250.
  33. Tappe, D.; Kapaun, A.; Emmerich, P.; de Mendonca Campos, R.; Cadar, D.; Gunther, S.; Schmidt-Chanasit, J. O’nyong-nyong virus infection imported to Europe from Kenya by a traveler. Emerg. Infect. Dis. 2014, 20, 1766–1767.
  34. Bessaud, M.; Peyrefitte, C.N.; Pastorino, B.A.; Gravier, P.; Tock, F.; Boete, F.; Tolou, H.J.; Grandadam, M. O’nyong-nyong Virus, Chad. Emerg. Infect. Dis. 2006, 12, 1248–1250.
  35. Diagne, C.T.; Bengue, M.; Choumet, V.; Hamel, R.; Pompon, J.; Misse, D. Mayaro Virus Pathogenesis and Transmission Mechanisms. Pathogens 2020, 9, 738.
  36. Mourao, M.P.; Bastos, M.D.S.; de Figueiredo, R.P.; Gimaque, J.B.; Galusso Edos, S.; Kramer, V.M.; de Oliveira, C.M.; Naveca, F.G.; Figueiredo, L.T. Mayaro fever in the city of Manaus, Brazil, 2007–2008. Vector Borne Zoonotic Dis. 2012, 12, 42–46.
  37. Halsey, E.S.; Siles, C.; Guevara, C.; Vilcarromero, S.; Jhonston, E.J.; Ramal, C.; Aguilar, P.V.; Ampuero, J.S. Mayaro virus infection, Amazon Basin region, Peru, 2010–2013. Emerg. Infect. Dis. 2013, 19, 1839–1842.
  38. Figueiredo, L.T.; Nogueira, R.M.; Cavalcanti, S.M.; Schatzmayr, H.; da Rosa, A.T. Study of two different enzyme immunoassays for the detection of Mayaro virus antibodies. Mem. Inst. Oswaldo Cruz 1989, 84, 303–307.
  39. Santiago, F.W.; Halsey, E.S.; Siles, C.; Vilcarromero, S.; Guevara, C.; Silvas, J.A.; Ramal, C.; Ampuero, J.S.; Aguilar, P.V. Long-Term Arthralgia after Mayaro Virus Infection Correlates with Sustained Pro-inflammatory Cytokine Response. PLoS Negl. Trop. Dis. 2015, 9, e0004104.
  40. Harley, D.; Sleigh, A.; Ritchie, S. Ross River virus transmission, infection, and disease: A cross-disciplinary review. Clin. Microbiol. Rev. 2001, 14, 909–932.
  41. Farmer, J.F.; Suhrbier, A. Interpreting paired serology for Ross River virus and Barmah Forest virus diseases. Aust. J. Gen. Pract. 2019, 48, 645–649.
  42. Barton, A.J.; Bielefeldt-Ohmann, H. Clinical Presentation, Progression, and Management of Five Cases of Ross River Virus Infection in Performance Horses Located in Southeast Queensland: A Longitudinal Case Series. J. Equin. Vet. Sci. 2017, 51, 34–40.
  43. Azuolas, J.K.; Wishart, E.; Bibby, S.; Ainsworth, C. Isolation of Ross River virus from mosquitoes and from horses with signs of musculo-skeletal disease. Aust. Vet. J. 2003, 81, 344–347.
  44. Kapeleris, J.; Lowe, P.; Phillips, D.; Wyatt, D.; Batham, M.; Devine, P. IgG avidity in the diagnosis of acute Ross River virus infection. Dis. Marker. 1996, 12, 279–282.
  45. Calisher, C.H.; Meurman, O.; Brummer-Korvenkontio, M.; Halonen, P.E.; Muth, D.J. Sensitive enzyme immunoassay for detecting immunoglobulin M antibodies to Sindbis virus and further evidence that Pogosta disease is caused by a western equine encephalitis complex virus. J. Clin. Microbiol. 1985, 22, 566–571.
  46. Kurkela, S.; Manni, T.; Myllynen, J.; Vaheri, A.; Vapalahti, O. Clinical and laboratory manifestations of Sindbis virus infection: Prospective study, Finland, 2002–2003. J. Infect. Dis. 2005, 191, 1820–1829.
  47. Niklasson, B.; Espmark, A.; Lundstrom, J. Occurrence of arthralgia and specific IgM antibodies three to four years after Ockelbo disease. J. Infect. Dis. 1988, 157, 832–835.
  48. Griffin, D.E. Neurotropic Alphaviruses. In Neurotropic Viral Infections, 2nd ed.; Reis, C.S., Ed.; Springer International Publishing: Cham, Switzerland, 2016; pp. 175–204.
  49. Calisher, C.H.; Berardi, V.P.; Muth, D.J.; Buff, E.E. Specificity of immunoglobulin M and G antibody responses in humans infected with eastern and western equine encephalitis viruses: Application to rapid serodiagnosis. J. Clin. Microbiol. 1986, 23, 369–372.
  50. Gardner, J.; Anraku, I.; Le, T.T.; Larcher, T.; Major, L.; Roques, P.; Schroder, W.A.; Higgs, S.; Suhrbier, A. Chikungunya virus arthritis in adult wild-type mice. J. Virol. 2010, 84, 8021–8032.
  51. Poo, Y.S.; Rudd, P.A.; Gardner, J.; Wilson, J.A.; Larcher, T.; Colle, M.A.; Le, T.T.; Nakaya, H.I.; Warrilow, D.; Allcock, R.; et al. Multiple immune factors are involved in controlling acute and chronic chikungunya virus infection. PLoS Negl. Trop. Dis. 2014, 8, e3354.
  52. Hawman, D.W.; Stoermer, K.A.; Montgomery, S.A.; Pal, P.; Oko, L.; Diamond, M.S.; Morrison, T.E. Chronic joint disease caused by persistent Chikungunya virus infection is controlled by the adaptive immune response. J. Virol. 2013, 87, 13878–13888.
  53. Johnson, R.T. Virus Invasion of the Central Nervous System: A Study of Sindbis Virus Infection in the Mouse Using Fluorescent Antibody. Am. J. Pathol. 1965, 46, 929–943.
  54. Burdeinick-Kerr, R.; Wind, J.; Griffin, D.E. Synergistic roles of antibody and interferon in noncytolytic clearance of Sindbis virus from different regions of the central nervous system. J. Virol. 2007, 81, 5628–5636.
  55. Nilaratanakul, V.; Chen, J.; Tran, O.; Baxter, V.K.; Troisi, E.M.; Yeh, J.X.; Griffin, D.E. Germ Line IgM Is Sufficient, but Not Required, for Antibody-Mediated Alphavirus Clearance from the Central Nervous System. J. Virol. 2018, 92, e02081-17.
  56. Fragkoudis, R.; Ballany, C.M.; Boyd, A.; Fazakerley, J.K. In Semliki Forest virus encephalitis, antibody rapidly clears infectious virus and is required to eliminate viral material from the brain, but is not required to generate lesions of demyelination. J. Gen. Virol. 2008, 89, 2565–2568.
  57. Amor, S.; Scallan, M.F.; Morris, M.M.; Dyson, H.; Fazakerley, J.K. Role of immune responses in protection and pathogenesis during Semliki Forest virus encephalitis. J. Gen. Virol. 1996, 77, 281–291.
  58. Fazakerley, J.K.; Webb, H.E. Semliki Forest virus-induced, immune-mediated demyelination: Adoptive transfer studies and viral persistence in nude mice. J. Gen. Virol. 1987, 68, 377–385.
  59. Metcalf, T.U.; Baxter, V.K.; Nilaratanakul, V.; Griffin, D.E. Recruitment and retention of B cells in the central nervous system in response to alphavirus encephalomyelitis. J. Virol. 2013, 87, 2420–2429.
  60. Metcalf, T.U.; Griffin, D.E. Alphavirus-induced encephalomyelitis: Antibody-secreting cells and viral clearance from the nervous system. J. Virol. 2011, 85, 11490–11501.
  61. Teo, T.H.; Lum, F.M.; Claser, C.; Lulla, V.; Lulla, A.; Merits, A.; Renia, L.; Ng, L. F. A pathogenic role for CD4+ T cells during Chikungunya virus infection in mice. J. Immunol. 2013, 190, 259–269.
  62. Lum, F.M.; Teo, T.H.; Lee, W.W.; Kam, Y.W.; Renia, L.; Ng, L.F. An essential role of antibodies in the control of Chikungunya virus infection. J. Immunol. 2013, 190, 6295–6302.
  63. Olitsky, P.K.; Cox, H.R. Active Immunication of Guinea Pigs with the Virus of Equine Encephalomyelitis: I. Quantitative Experiments with Various Preparations of Active Virus. J. Exp. Med. 1936, 63, 311–324.
  64. Cox, H.R.; Olitsky, P.K. Active Immunization of Guinea Pigs with the Virus of Equine Encephalomyelitis: Iii. Quantitative Studies of Serum Antiviral Bodies in Animals Immunized with Active and Inactive Virus. J. Exp. Med. 1936, 64, 217–222.
  65. Cox, H.R.; Olitsky, P.K. Active Immunization of Guinea Pigs with the Virus of Equine Encephalomyelitis: Iv. Effect of Immune Serum on Antigenicity of Active and Inactive Virus. J. Exp. Med. 1936, 64, 223–232.
  66. Olitsky, P.K.; Harford, C.G. Intraperitoneal and Intracerebral Routes in Serum Protection Tests with the Virus of Equine Encephalomyelitis: Iii. Comparison of Antiviral Serum Constituents from Guinea Pigs Immunized with Active or Formolized Inactive Virus. J. Exp. Med. 1938, 68, 779–787.
  67. Morgan, I.M.; Schlesinger, R.W.; Olitsky, P.K. Induced Resistance of the Central Nervous System to Experimental Infection with Equine Encephalomyelitis Virus: I. Neutralizing Antibody in the Central Nervous System in Relation to Cerebral Resistance. J. Exp. Med. 1942, 76, 357–369.
  68. Griffin, D.E.; Johnson, R.T. Role of the immune response in recovery from Sindbis virus encephalitis in mice. J. Immunol. 1977, 118, 1070–1075.
  69. Kimura, T.; Griffin, D.E. Extensive immune-mediated hippocampal damage in mice surviving infection with neuroadapted Sindbis virus. Virology 2003, 311, 28–39.
  70. Rabinowitz, S.G.; Adler, W.H. Host defenses during primary Venezuelan equine encephalomyelitis virus infection in mice. I. Passive transfer of protection with immune serum and immune cells. J. Immunol. 1973, 110, 1345–1353.
  71. Couderc, T.; Khandoudi, N.; Grandadam, M.; Visse, C.; Gangneux, N.; Bagot, S.; Prost, J. F.; Lecuit, M. Prophylaxis and therapy for Chikungunya virus infection. J. Infect. Dis. 2009, 200, 516–523.
  72. Lee, C.Y.; Kam, Y.W.; Fric, J.; Malleret, B.; Koh, E.G.; Prakash, C.; Huang, W.; Lee, W. W.; Lin, C.; Lin, R. T. Chikungunya virus neutralization antigens and direct cell-to-cell transmission are revealed by human antibody-escape mutants. PLoS Pathog. 2011, 7, e1002390.
  73. Holzer, G.W.; Coulibaly, S.; Aichinger, G.; Savidis-Dacho, H.; Mayrhofer, J.; Brunner, S.; Schmid, K.; Kistner, O.; Aaskov, J. G.; Falkner, F.G.; et al. Evaluation of an inactivated Ross River virus vaccine in active and passive mouse immunization models and establishment of a correlate of protection. Vaccine 2011, 29, 4132–4141.
  74. Kraaijeveld, C.A.; Benaissa-Trouw, B.J.; Harmsen, M.; Snippe, H. Adoptive transfer of immunity against virulent Semliki Forest virus with immune spleen cells from mice infected with avirulent Semliki Forest virus. Arch. Virol. 1986, 91, 83–92.
  75. Jose, J.; Snyder, J.E.; Kuhn, R.J. A structural and functional perspective of alphavirus replication and assembly. Future Microbiol. 2009, 4, 837–856.
  76. Stec, D.S.; Waddell, A.; Schmaljohn, C.S.; Cole, G.A.; Schmaljohn, A.L. Antibody-selected variation and reversion in Sindbis virus neutralization epitopes. J. Virol. 1986, 57, 715–720.
  77. Boere, W.A.; Harmsen, T.; Vinje, J.; Benaissa-Trouw, B.J.; Kraaijeveld, C.A.; Snippe, H. Identification of distinct antigenic determinants on Semliki Forest virus by using monoclonal antibodies with different antiviral activities. J. Virol. 1984, 52, 575–582.
  78. Roehrig, J.T.; Mathews, J.H. The neutralization site on the E2 glycoprotein of Venezuelan equine encephalomyelitis (TC-83) virus is composed of multiple conformationally stable epitopes. Virology 1985, 142, 347–356.
  79. Vrati, S.; Fernon, C.A.; Dalgarno, L.; Weir, R.C. Location of a major antigenic site involved in Ross River virus neutralization. Virology 1988, 162, 346–353.
  80. Navaratnarajah, C.K.; Kuhn, R.J. Functional characterization of the Sindbis virus E2 glycoprotein by transposon linker-insertion mutagenesis. Virology 2007, 363, 134–147.
  81. Hunt, A.R.; Frederickson, S.; Maruyama, T.; Roehrig, J.T.; Blair, C.D. The first human epitope map of the alphaviral E1 and E2 proteins reveals a new E2 epitope with significant virus neutralizing activity. PLoS Negl. Trop. Dis. 2010, 4, e739.
  82. Kam, Y.W.; Lee, W.W.; Simarmata, D.; Le Grand, R.; Tolou, H.; Merits, A.; Roques, P.; Ng, L. F. Unique epitopes recognized by antibodies induced in Chikungunya virus-infected non-human primates: Implications for the study of immunopathology and vaccine development. PLoS ONE 2014, 9, e95647.
  83. Adouchief, S.; Smura, T.; Vapalahti, O.; Hepojoki, J. Mapping of human B-cell epitopes of Sindbis virus. J. Gen. Virol. 2016, 97, 2243–2254.
  84. Chanas, A.C.; Gould, E.A.; Clegg, J.C.; Varma, M.G. Monoclonal antibodies to Sindbis virus glycoprotein E1 can neutralize, enhance infectivity, and independently inhibit haemagglutination or haemolysis. J. Gen. Virol. 1982, 58, 37–46.
  85. Despres, P.; Griffin, J.W.; Griffin, D.E. Antiviral activity of alpha interferon in Sindbis virus-infected cells is restored by anti-E2 monoclonal antibody treatment. J. Virol. 1995, 69, 7345–7348.
  86. Despres, P.; Griffin, J.W.; Griffin, D.E. Effects of anti-E2 monoclonal antibody on sindbis virus replication in AT3 cells expressing bcl-2. J. Virol. 1995, 69, 7006–7014.
  87. Mendoza, Q.P.; Stanley, J.; Griffin, D.E. Monoclonal antibodies to the E1 and E2 glycoproteins of Sindbis virus: Definition of epitopes and efficiency of protection from fatal encephalitis. J. Gen. Virol. 1988, 69, 3015–3022.
  88. Stanley, J.; Cooper, S.J.; Griffin, D.E. Monoclonal antibody cure and prophylaxis of lethal Sindbis virus encephalitis in mice. J. Virol. 1986, 58, 107–115.
  89. Boere, W.A.; Benaissa-Trouw, B.J.; Harmsen, T.; Erich, T.; Kraaijeveld, C.A.; Snippe, H. Mechanisms of monoclonal antibody-mediated protection against virulent Semliki Forest virus. J. Virol. 1985, 54, 546–551.
  90. Smith, S.A.; Silva, L.A.; Fox, J.M.; Flyak, A.I.; Kose, N.; Sapparapu, G.; Khomandiak, S.; Ashbrook, A. W.; Kahle, K. M.; Fong, R. H; et al. Isolation and Characterization of Broad and Ultrapotent Human Monoclonal Antibodies with Therapeutic Activity against Chikungunya Virus. Cell Host Microbe 2015, 18, 86–95.
  91. Chua, C.L.; Chan, Y.F.; Sam, I.C. Characterisation of mouse monoclonal antibodies targeting linear epitopes on Chikungunya virus E2 glycoprotein. J. Virol. Method. 2014, 195, 126–133.
  92. Pal, P.; Dowd, K.A.; Brien, J.D.; Edeling, M.A.; Gorlatov, S.; Johnson, S.; Lee, I.; Akahata, W.; Nabel, G. J.; Richter, M. K.; et al. Development of a highly protective combination monoclonal antibody therapy against Chikungunya virus. PLoS Pathog. 2013, 9, e1003312.
  93. Goh, L.Y.; Hobson-Peters, J.; Prow, N.A.; Baker, K.; Piyasena, T.B.; Taylor, C.T.; Rana, A.; Hastie, M. L.; Gorman, J. J.; Hall, R. A. The Chikungunya Virus Capsid Protein Contains Linear B Cell Epitopes in the N- and C-Terminal Regions that are Dependent on an Intact C-Terminus for Antibody Recognition. Viruses 2015, 7, 2943–2964.
  94. Goh, L.Y.H.; Hobson-Peters, J.; Prow, N.A.; Gardner, J.; Bielefeldt-Ohmann, H.; Suhrbier, A.; Hall, R. A. Monoclonal antibodies specific for the capsid protein of chikungunya virus suitable for multiple applications. J. Gen. Virol. 2015, 96, 507–512.
  95. Sun, S.; Xiang, Y.; Akahata, W.; Holdaway, H.; Pal, P.; Zhang, X.; Diamond, M. S.; Nabel, G. J.; Rossmann, M. G. Structural analyses at pseudo atomic resolution of Chikungunya virus and antibodies show mechanisms of neutralization. eLife 2013, 2, e00435.
  96. Voss, J.E.; Vaney, M.C.; Duquerroy, S.; Vonrhein, C.; Girard-Blanc, C.; Crublet, E.; Thompson, A.; Bricogne, G.; Rey, F. A. Glycoprotein organization of Chikungunya virus particles revealed by X-ray crystallography. Nature 2010, 468, 709–712.
  97. Broeckel, R.; Fox, J.M.; Haese, N.; Kreklywich, C.N.; Sukulpovi-Petty, S.; Legasse, A.; Smith, P. P.; Denton, M.; Corvey, C.; Krishnan, S.; et al. Therapeutic administration of a recombinant human monoclonal antibody reduces the severity of chikungunya virus disease in rhesus macaques. PLoS Negl. Trop. Dis. 2017, 11, e0005637.
  98. Fox, J.M.; Long, F.; Edeling, M.A.; Lin, H.; van Duijl-Richter, M.K.S.; Fong, R.H.; Kahle, K. M.; Smit, J. M.; Jin, J.; Simmons, G.; et al. Broadly Neutralizing Alphavirus Antibodies Bind an Epitope on E2 and Inhibit Entry and Egress. Cell 2015, 163, 1095–1107.
  99. Kim, A.S.; Austin, S.K.; Gardner, C.L.; Zuiani, A.; Reed, D.S.; Trobaugh, D.W.; Sun, C.; Basore, K.; Williamson, L. E.; Crowe, J. E; et al. Protective antibodies against Eastern equine encephalitis virus bind to epitopes in domains A and B of the E2 glycoprotein. Nat. Microbiol. 2019, 4, 187–197.
  100. Zhao, J.; Sun, E.C.; Liu, N.H.; Yang, T.; Xu, Q.Y.; Qin, Y.L.; Yang, Y. H.; Wu, D. L. Phage display identifies an Eastern equine encephalitis virus glycoprotein E2-specific B cell epitope. Vet. Immunol. Immunopathol. 2012, 148, 364–368.
  101. Sun, E.C.; Zhao, J.; Yang, T.; Xu, Q.Y.; Qin, Y.L.; Wang, W.S.; Wei, P.; Sun, L.; Sun, J.; Wu, D.L. Analysis of murine B-cell epitopes on Eastern equine encephalitis virus glycoprotein E2. Appl. Microbiol. Biotechnol. 2013, 97, 6359–6372.
  102. Powell, L.A.; Fox, J.M.; Kose, N.; Kim, A.S.; Majedi, M.; Bombardi, R.; Carnahan, R. H.; Slaughter, J. C.; Morrison, T. E.; Diamond, M.; et al. Human monoclonal antibodies against Ross River virus target epitopes within the E2 protein and protect against disease. PLoS Pathog. 2020, 16, e1008517.
  103. Earnest, J.T.; Basore, K.; Roy, V.; Bailey, A.L.; Wang, D.; Alter, G.; Fremont, D. H.; Diamond, M. S. Neutralizing antibodies against Mayaro virus require Fc effector functions for protective activity. J. Exp. Med. 2019, 216, 2282–2301.
  104. Zhang, R.; Kim, A.S.; Fox, J.M.; Nair, S.; Basore, K.; Klimstra, W.B.; Rimkunas, R.; Fong, R. H.; Lin, H.; Poddar, S.; et al. Mxra8 is a receptor for multiple arthritogenic alphaviruses. Nature 2018, 557, 570–574.
  105. Zhang, R.; Earnest, J.T.; Kim, A.S.; Winkler, E.S.; Desai, P.; Adams, L.J.; Hu, G.; Bullock, C.; Gold, B.; Cherry, S.; et al. Expression of the Mxra8 Receptor Promotes Alphavirus Infection and Pathogenesis in Mice and Drosophila. Cell Rep. 2019, 28, 2647–2658.e5.
  106. Basore, K.; Kim, A.S.; Nelson, C.A.; Zhang, R.; Smith, B.K.; Uranga, C.; Vang, L.; Cheng, M.; Gross, M. L.; Smith, J.; et al. Cryo-EM Structure of Chikungunya Virus in Complex with the Mxra8 Receptor. Cell 2019, 177, 1725–1737.e16.
  107. Song, H.; Zhao, Z.; Chai, Y.; Jin, X.; Li, C.; Yuan, F.; Liu, S.; Gao, Z.; Wang, H.; Song, J.; et al. Molecular Basis of Arthritogenic Alphavirus Receptor MXRA8 Binding to Chikungunya Virus Envelope Protein. Cell 2019, 177, 1714–1724.e12.
  108. Gould, E.; Pettersson, J.; Higgs, S.; Charrel, R.; de Lamballerie, X. Emerging arboviruses: Why today? One Health 2017, 4, 1–13.
  109. Weaver, S.C. Urbanization and geographic expansion of zoonotic arboviral diseases: Mechanisms and potential strategies for prevention. Trends Microbiol. 2013, 21, 360–363.
  110. Zahouli, J.B.Z.; Koudou, B.G.; Muller, P.; Malone, D.; Tano, Y.; Utzinger, J. Urbanization is a main driver for the larval ecology of Aedes mosquitoes in arbovirus-endemic settings in south-eastern Cote d’Ivoire. PLoS Negl. Trop. Dis. 2017, 11, e0005751.
  111. Kilpatrick, A.M.; Randolph, S.E. Drivers, dynamics, and control of emerging vector-borne zoonotic diseases. Lancet 2012, 380, 1946–1955.
  112. Vazeille, M.; Moutailler, S.; Pages, F.; Jarjaval, F.; Failloux, A.B. Introduction of Aedes albopictus in Gabon: What consequences for dengue and chikungunya transmission? Trop. Med. Int. Health 2008, 13, 1176–1179.
  113. Naish, S.; Hu, W.; Mengersen, K.; Tong, S. Spatio-temporal patterns of Barmah Forest virus disease in Queensland, Australia. PLoS ONE 2011, 6, e25688.
  114. Reed, D.S.; Glass, P.J.; Bakken, R.R.; Barth, J.F.; Lind, C.M.; da Silva, L.; Hart, M.K.; Rayner, J.; Alterson, K.; Custer, M.; et al. Combined alphavirus replicon particle vaccine induces durable and cross-protective immune responses against equine encephalitis viruses. J. Virol. 2014, 88, 12077–12086.
  115. Wressnigg, N.; van der Velden, M.V.; Portsmouth, D.; Draxler, W.; O’Rourke, M.; Richmond, P.; Hall, S.; McBride, W.J.H.; Redfern, A.; Aaskvo, J.; et al. An inactivated Ross River virus vaccine is well tolerated and immunogenic in an adult population in a randomized phase 3 trial. Clin. Vaccine Immunol. 2015, 22, 267–273.
  116. Chang, L.J.; Dowd, K.A.; Mendoza, F.H.; Saunders, J.G.; Sitar, S.; Plummer, S.H.; Yamshchikov, G.; Sarwar, U.N.; Hu, Z.; Enama, M.E.; et al. Safety and tolerability of chikungunya virus-like particle vaccine in healthy adults: A phase 1 dose-escalation trial. Lancet 2014, 384, 2046–2052.
  117. Chen, G.L.; Coates, E.E.; Plummer, S.H.; Carter, C.A.; Berkowitz, N.; Conan-Cibotti, M.; Cox, J.H.; Beck, A.; O’Callahan, M.; Andrews, C.; et al. Effect of a Chikungunya Virus-Like Particle Vaccine on Safety and Tolerability Outcomes: A Randomized Clinical Trial. JAMA 2020, 323, 1369–1377.
  118. Akahata, W.; Nabel, G.J. A specific domain of the Chikungunya virus E2 protein regulates particle formation in human cells: Implications for alphavirus vaccine design. J. Virol. 2012, 86, 8879–8883.
  119. Chen, R.; Puri, V.; Fedorova, N.; Lin, D.; Hari, K.L.; Jain, R.; Rodas, J.D.; Das, S.R.; Shabman, R.S.; Weaver, S.C. Comprehensive Genome Scale Phylogenetic Study Provides New Insights on the Global Expansion of Chikungunya Virus. J. Virol. 2016, 90, 10600–10611.
  120. Xavier, J.; Fonseca, V.; Bezerra, J.F.; do Monte Alves, M.; Mares-Guia, M.A.; Claro, I.M.; de Jesus, R.; Adelino, T.; Araújo, E.; Cavalcante, K.R.L.J; et al. Chikungunya virus ECSA lineage reintroduction in the northeasternmost region of Brazil. Int. J. Infect. Dis. 2021, 105, 120–123.
  121. Phadungsombat, J.; Imad, H.; Rahman, M.; Nakayama, E.E.; Kludkleeb, S.; Ponam, T.; Rahim, R.; Hasan, A.; Poltep, K.; Yamanaka, A.; et al. A Novel Sub-Lineage of Chikungunya Virus East/Central/South African Genotype Indian Ocean Lineage Caused Sequential Outbreaks in Bangladesh and Thailand. Viruses 2020, 12, 1319.
  122. Fabri, A.A.; Rodrigues, C.; Santos, C.C.D.; Chalhoub, F.L.L.; Sampaio, S.A.; Faria, N.; Torres, M.C.; Fonseca, V.; Brasil, P.; Calvet, G.; et al. Co-Circulation of Two Independent Clades and Persistence of CHIKV-ECSA Genotype during Epidemic Waves in Rio de Janeiro, Southeast Brazil. Pathogens 2020, 9, 984.
  123. Harsha, P.K.; Reddy, V.; Rao, D.; Pattabiraman, C.; Mani, R.S. Continual circulation of ECSA genotype and identification of a novel mutation I317V in the E1 gene of Chikungunya viral strains in southern India during 2015–2016. J. Med. Virol. 2020, 92, 1007–1012.
  124. Akahata, W.; Yang, Z.Y.; Andersen, H.; Sun, S.; Holdaway, H.A.; Kong, W.P; Lewis, M.G.; Higgs, S.; Rossmann, M.G.; Rao, S.; et al. A virus-like particle vaccine for epidemic Chikungunya virus protects nonhuman primates against infection. Nat. Med. 2010, 16, 334–338.
  125. Erasmus, J.H.; Seymour, R.L.; Kaelber, J.T.; Kim, D.Y.; Leal, G.; Sherman, M.B.; Frolov, I.; Chiu, W.; Weaver, S.C.; Nasar, F. Novel Insect-Specific Eilat Virus-Based Chimeric Vaccine Candidates Provide Durable, Mono- and Multivalent, Single-Dose Protection against Lethal Alphavirus Challenge. J. Virol. 2018, 92, e01274-17.
  126. Abeyratne, E.; Tharmarajah, K.; Freitas, J.R.; Mostafavi, H.; Mahalingam, S.; Zaid, A.; Zaman, M.; Taylor, A. Liposomal Delivery of the RNA Genome of a Live-Attenuated Chikungunya Virus Vaccine Candidate Provides Local, but Not Systemic Protection After One Dose. Front. Immunol. 2020, 11, 304.
  127. Taylor, A.; Liu, X.; Zaid, A.; Goh, L.Y.; Hobson-Peters, J.; Hall, R.A.; Merits, A.; Mahalingam, S. Mutation of the N-Terminal Region of Chikungunya Virus Capsid Protein: Implications for Vaccine Design. mBio 2017, 8, e01970-16.
  128. Kistner, O.; Barrett, N.; Bruhmann, A.; Reiter, M.; Mundt, W.; Savidis-Dacho, H.; Schober-Bendixen, S.; Dorner, F.; Aaskov, J. The preclinical testing of a formaldehyde inactivated Ross River virus vaccine designed for use in humans. Vaccine 2007, 25, 4845–4852.
  129. Aichinger, G.; Ehrlich, H.J.; Aaskov, J.G.; Fritsch, S.; Thomasser, C.; Draxler, W.; Wolzt, M.; Muller, M.; Pinl, F.; Van Damme, P.; et al. Safety and immunogenicity of an inactivated whole virus Vero cell-derived Ross River virus vaccine: A randomized trial. Vaccine 2011, 29, 9376–9384.
  130. Chan, Y.H.; Teo, T.H.; Utt, A.; Tan, J.J.; Amrun, S.N.; Abu Bakar, F.; Yee, W.-X.; Becht, E.; Lee, C.Y.-P.; Lee, B.; et al. Mutating chikungunya virus non-structural protein produces potent live-attenuated vaccine candidate. EMBO Mol. Med. 2019, 11, e10092.
  131. Hallengard, D.; Kakoulidou, M.; Lulla, A.; Kummerer, B.M.; Johansson, D.X.; Mutso, M.; Lulla, V.; Fazakerley, J.K.; Roques, P.; Le Grand, R.; et al. Novel attenuated Chikungunya vaccine candidates elicit protective immunity in C57BL/6 mice. J. Virol. 2014, 88, 2858–2866.
  132. Roques, P.; Ljungberg, K.; Kummerer, B.M.; Gosse, L.; Dereuddre-Bosquet, N.; Tchitchek, N.; Hallengard, D.; Garcia-Arriaza, J.; Meinke, A.; Esteban, M.; et al. Attenuated and vectored vaccines protect nonhuman primates against Chikungunya virus. JCI Insight 2017, 2, e83527.
  133. Wressnigg, N.; Hochreiter, R.; Zoihsl, O.; Fritzer, A.; Bezay, N.; Klingler, A.; Lingnau, K.; Schneider, M.; Lundberg, U.; Meinke, A.; et al. Single-shot live-attenuated chikungunya vaccine in healthy adults: A phase 1, randomised controlled trial. Lancet Infect. Dis. 2020, 20, 1193–1203.
  134. Carrau, L.; Rezelj, V.V.; Noval, M.G.; Levi, L.I.; Megrian, D.; Blanc, H.; Weger-Lucarelli, J.; Moratorio, G.; Stapleford, K.A.; Vignuzzi, M. Chikungunya Virus Vaccine Candidates with Decreased Mutational Robustness Are Attenuated In Vivo and Have Compromised Transmissibility. J. Virol. 2019, 93, e00775-19.
  135. Piper, A.; Ribeiro, M.; Smith, K.M.; Briggs, C.M.; Huitt, E.; Nanda, K.; Spears, C.J.; Quiles, M.; Cullen, J.; Thomas, M.E.; et al. Chikungunya virus host range E2 transmembrane deletion mutants induce protective immunity against challenge in C57BL/6J mice. J. Virol. 2013, 87, 6748–6757.
  136. Gardner, C.L.; Hritz, J.; Sun, C.; Vanlandingham, D.L.; Song, T.Y.; Ghedin, E.; Higgs, S.; Klimstra, W.B.; Ryman, K.D. Deliberate attenuation of chikungunya virus by adaptation to heparan sulfate-dependent infectivity: A model for rational arboviral vaccine design. PLoS Negl. Trop. Dis. 2014, 8, e2719.
  137. Ludwig, G.V.; Turell, M.J.; Vogel, P.; Kondig, J.P.; Kell, W.K.; Smith, J.F.; Pratt, W.D. Comparative neurovirulence of attenuated and non-attenuated strains of Venezuelan equine encephalitis virus in mice. Am. J. Trop. Med. Hyg. 2001, 64, 49–55.
  138. Reed, D.S.; Lind, C.M.; Lackemeyer, M.G.; Sullivan, L.J.; Pratt, W.D.; Parker, M.D. Genetically engineered, live, attenuated vaccines protect nonhuman primates against aerosol challenge with a virulent IE strain of Venezuelan equine encephalitis virus. Vaccine 2005, 23, 3139–3147.
  139. Fine, D.L.; Roberts, B.A.; Terpening, S.J.; Mott, J.; Vasconcelos, D.; House, R.V. Neurovirulence evaluation of Venezuelan equine encephalitis (VEE) vaccine candidate V3526 in nonhuman primates. Vaccine 2008, 26, 3497–3506.
  140. Main, C.F.D.; Snow, D.; Mallory, R.M.; Helber, S.; Terpening, S.; Holley, H.P. Safety of an Attenuated Venezuelan Equine Encephalitis Virus (VEEV) Vaccine in Humans. In Proceedings of the America Infectious Diseases Society of America 2008 Annual Meeting, Washington, DC, USA, 25–28 October 2008.
  141. Tretyakova, I.; Tibbens, A.; Jokinen, J.D.; Johnson, D.M.; Lukashevich, I.S.; Pushko, P. Novel DNA-launched Venezuelan equine encephalitis virus vaccine with rearranged genome. Vaccine 2019, 37, 3317–3325.
  142. Tretyakova, I.; Plante, K.S.; Rossi, S.L.; Lawrence, W.S.; Peel, J.E.; Gudjohnsen, S.; Wang, E.; Mirchandani, D.; Tibbens, A.; Lamichhane, T.N.; et al. Venezuelan equine encephalitis vaccine with rearranged genome resists reversion and protects non-human primates from viremia after aerosol challenge. Vaccine 2020, 38, 3378–3386.
  143. Trobaugh, D.W.; Sun, C.; Dunn, M.D.; Reed, D.S.; Klimstra, W.B. Rational design of a live-attenuated eastern equine encephalitis virus vaccine through informed mutation of virulence determinants. PLoS Pathog. 2019, 15, e1007584.
  144. Plante, K.; Wang, E.; Partidos, C.D.; Weger, J.; Gorchakov, R.; Tsetsarkin, K.; Borland, E.M.; Powers, A.M.; Seymour, R.; Stinchcomb, D.T.; et al. Novel chikungunya vaccine candidate with an IRES-based attenuation and host range alteration mechanism. PLoS Pathog. 2011, 7, e1002142.
  145. Roy, C.J.; Adams, A.P.; Wang, E.; Plante, K.; Gorchakov, R.; Seymour, R.L.; Vinet-Oliphant, H.; Weaver, S.C. Chikungunya vaccine candidate is highly attenuated and protects nonhuman primates against telemetrically monitored disease following a single dose. J. Infect. Dis. 2014, 209, 1891–1899.
  146. Partidos, C.D.; Paykel, J.; Weger, J.; Borland, E.M.; Powers, A.M.; Seymour, R.; Weaver, S.C.; Stinchcomb, D.T.; Osorio, J.E. Cross-protective immunity against o’nyong-nyong virus afforded by a novel recombinant chikungunya vaccine. Vaccine 2012, 30, 4638–4643.
  147. Pandya, J.; Gorchakov, R.; Wang, E.; Leal, G.; Weaver, S.C. A vaccine candidate for eastern equine encephalitis virus based on IRES-mediated attenuation. Vaccine 2012, 30, 1276–1282.
  148. Rossi, S.L.; Guerbois, M.; Gorchakov, R.; Plante, K.S.; Forrester, N.L.; Weaver, S.C. IRES-based Venezuelan equine encephalitis vaccine candidate elicits protective immunity in mice. Virology 2013, 437, 81–88.
  149. Rossi, S.L.; Russell-Lodrigue, K.E.; Killeen, S.Z.; Wang, E.; Leal, G.; Bergren, N.A.; Vinet-Oliphant, H.; Weaver, S.C. IRES-Containing VEEV Vaccine Protects Cynomolgus Macaques from IE Venezuelan Equine Encephalitis Virus Aerosol Challenge. PLoS Negl. Trop. Dis. 2015, 9, e0003797.
  150. Guerbois, M.; Volkova, E.; Forrester, N.L.; Rossi, S.L.; Frolov, I.; Weaver, S.C. IRES-driven expression of the capsid protein of the Venezuelan equine encephalitis virus TC-83 vaccine strain increases its attenuation and safety. PLoS Negl. Trop. Dis. 2013, 7, e2197.
  151. Mota, M.T.O.; Costa, V.V.; Sugimoto, M.A.; Guimaraes, G.F.; Queiroz, C.M., Jr.; Moreira, T.P.; de Sousa, C.D.; Santos, F.M.; Queiroz, V.F.; Passos, I.; et al. In-depth characterization of a novel live-attenuated Mayaro virus vaccine candidate using an immunocompetent mouse model of Mayaro disease. Sci. Rep. 2020, 10, 5306.
  152. Weise, W.J.; Hermance, M.E.; Forrester, N.; Adams, A.P.; Langsjoen, R.; Gorchakov, R.; Wang, E.; Alcorn, M.D.H.; Tsetsarkin, K.; Weaver, S.C. A novel live-attenuated vaccine candidate for mayaro Fever. PLoS Negl. Trop. Dis. 2014, 8, e2969.
  153. Tiwari, M.; Parida, M.; Santhosh, S.R.; Khan, M.; Dash, P.K.; Rao, P.V. Assessment of immunogenic potential of Vero adapted formalin inactivated vaccine derived from novel ECSA genotype of Chikungunya virus. Vaccine 2009, 27, 2513–2522.
  154. Kumar, M.; Sudeep, A.B.; Arankalle, V.A. Evaluation of recombinant E2 protein-based and whole-virus inactivated candidate vaccines against chikungunya virus. Vaccine 2012, 30, 6142–6149.
  155. Mohan, K. Phase-I Open Label, Dose-Escalation Clinical Trial to Evaluate the Safety, Tolerability and Immunogenicity of Chikungunya Vaccine in Healthy Adults of 18 to 50 Years Age: U.S National Library of Medicine. 2020. Available online: (accessed on 18 March 2021).
  156. Pittman, P.R.; Liu, C.T.; Cannon, T.L.; Mangiafico, J.A.; Gibbs, P.H. Immune interference after sequential alphavirus vaccine vaccinations. Vaccine 2009, 27, 4879–4882.
  157. Maryam, K.-J.; Reisler, R.B.; Purcell, B.K.; Rivard, R.G.; Cardile, A.P.; Liggett, D.; Norris, S.; Pitttman, P.R. 2773. Safety and Immunogenicity Study of Eastern Equine Encephalitis Vaccine. Open Forum Infect. Dis. 2019, 6, 978–979.
  158. Rivard, R. Phase 2 Open-Label Safety and Immunogenicity Study of the Eastern Equine Encephalitis (EEE) Vaccine, Inactivated, Dried, TSI-GSD 104, Lot 2-1-89, in Healthy Adult Subjects at Risk of Exposure to Eastern Equine Encephalitis Virus: U.S. National Library of Medicine. 2016. Available online: (accessed on 18 March 2021).
  159. Honnold, S.P.; Bakken, R.R.; Fisher, D.; Lind, C.M.; Cohen, J.W.; Eccleston, L.T.; Spurgers, K.B.; Maheshwari, R.K.; Glass, P.J. Second generation inactivated eastern equine encephalitis virus vaccine candidates protect mice against a lethal aerosol challenge. PLoS ONE 2014, 9, e104708.
  160. Martin, S.S.; Bakken, R.R.; Lind, C.M.; Garcia, P.; Jenkins, E.; Glass, P.J.; Parker, M.D.; Hart, M.K.; Fine, D.L. Evaluation of formalin inactivated V3526 virus with adjuvant as a next generation vaccine candidate for Venezuelan equine encephalitis virus. Vaccine 2010, 28, 3143–3151.
  161. Gupta, P.; Sharma, A.; Spurgers, K.B.; Bakken, R.R.; Eccleston, L.T.; Cohen, J.W.; Honnold, S.P.; Glass, P.J.; Maheshwari, R.K. 1,5-Iodonaphthyl azide-inactivated V3526 protects against aerosol challenge with virulent venezuelan equine encephalitis virus. Vaccine 2016, 34, 2762–2765.
  162. Fine, D.L.; Jenkins, E.; Martin, S.S.; Glass, P.; Parker, M.D.; Grimm, B. A multisystem approach for development and evaluation of inactivated vaccines for Venezuelan equine encephalitis virus (VEEV). J. Virol. Method. 2010, 163, 424–432.
  163. McCarty, J. A Phase 2 Parallel-Group, Randomized, Double-Blind Study to Assess the Safety and Immunogenicity of PXVX0317 (Chikungunya Virus Virus-Like Particle Vaccine [CHIKV-VLP], Unadjuvanted or Alum-adjuvanted): U.S. National Library of Medicine. 2018. Available online: (accessed on 18 March 2021).
  164. Metz, S.W.; Martina, B.E.; van den Doel, P.; Geertsema, C.; Osterhaus, A.D.; Vlak, J.M.; Pijlman, G.P. Chikungunya virus-like particles are more immunogenic in a lethal AG129 mouse model compared to glycoprotein E1 or E2 subunits. Vaccine 2013, 31, 6092–6096.
  165. Metz, S.W.; Gardner, J.; Geertsema, C.; Le, T.T.; Goh, L.; Vlak, J.M.; Pijlman, G.P. Effective chikungunya virus-like particle vaccine produced in insect cells. PLoS Negl. Trop. Dis. 2013, 7, e2124.
  166. Saraswat, S.; Athmaram, T.N.; Parida, M.; Agarwal, A.; Saha, A.; Dash, P.K. Expression and Characterization of Yeast Derived Chikungunya Virus Like Particles (CHIK-VLPs) and Its Evaluation as a Potential Vaccine Candidate. PLoS Negl. Trop. Dis. 2016, 10, e0004782.
  167. Goonewardena, S. A Phase 1 Dose Escalation Study to Assess the Safety and Immunogenicity of a Monovalent Virus-Like Particle (VLP) Venezuelan Equine Encephalitis Vaccine in Healthy Adults: U.S. National Library of Medicine. 2017. Available online: (accessed on 18 March 2021).
  168. Ko, S.Y.; Akahata, W.; Yang, E.S.; Kong, W.P.; Burke, C.W.; Honnold, S.P.; Nichols, D.K.; Huang, Y.-J.S.; Schieber, G.L.; Carlton, K.; et al. A virus-like particle vaccine prevents equine encephalitis virus infection in nonhuman primates. Sci. Transl. Med. 2019, 11, 492.
  169. Ledgerwood, J.C.G. A Phase 1 Open Label, Dose-Escalation Clinical Trial to Evaluate the Safety and Immunogenicity of a Trivalent Virus-Like Particle (VLP) Encephalitis Vaccine, VRC-WEVVLP073-00-VP, in Healthy Adults: U.S. National Library of Medicine. 2019. Available online: (accessed on 18 March 2021).
  170. Riemenschneider, J.; Garrison, A.; Geisbert, J.; Jahrling, P.; Hevey, M.; Negley, D.; Schmaljohn, A.; Lee, J.; Hart, M.K.; Vanderzanden, L.; et al. Comparison of individual and combination DNA vaccines for B. anthracis, Ebola virus, Marburg virus and Venezuelan equine encephalitis virus. Vaccine 2003, 21, 4071–4080.
  171. Hart, M.K.; Pratt, W.; Panelo, F.; Tammariello, R.; Dertzbaugh, M. Venezuelan equine encephalitis virus vaccines induce mucosal IgA responses and protection from airborne infection in BALB/c, but not C3H/HeN mice. Vaccine 1997, 15, 363–369.
  172. Perkins, S.D.; O‘Brien, L.M.; Phillpotts, R.J. Boosting with an adenovirus-based vaccine improves protective efficacy against Venezuelan equine encephalitis virus following DNA vaccination. Vaccine 2006, 24, 3440–3445.
  173. Dupuy, L.C.; Locher, C.P.; Paidhungat, M.; Richards, M.J.; Lind, C.M.; Bakken, R.; Parker, M.D.; Wahlen, R.G.; Schmaljohn, C.S. Directed molecular evolution improves the immunogenicity and protective efficacy of a Venezuelan equine encephalitis virus DNA vaccine. Vaccine 2009, 27, 4152–4160.
  174. Tretyakova, I.; Lukashevich, I.S.; Glass, P.; Wang, E.; Weaver, S.; Pushko, P. Novel vaccine against Venezuelan equine encephalitis combines advantages of DNA immunization and a live attenuated vaccine. Vaccine 2013, 31, 1019–1025.
  175. Gauci, P.J.; Wu, J.Q.; Rayner, G.A.; Barabe, N.D.; Nagata, L.P.; Proll, D.F. Identification of Western equine encephalitis virus structural proteins that confer protection after DNA vaccination. Clin. Vaccine Immunol. 2010, 17, 176–179.
  176. Muthumani, K.; Lankaraman, K.M.; Laddy, D.J.; Sundaram, S.G.; Chung, C.W.; Sako, E.; Wu, L.; Khan, A.; Sardesai, N.; Kim, J.J.; et al. Immunogenicity of novel consensus-based DNA vaccines against Chikungunya virus. Vaccine 2008, 26, 5128–5134.
  177. Bao, H.; Ramanathan, A.A.; Kawalakar, O.; Sundaram, S.G.; Tingey, C.; Bian, C.B.; Muruganandam, N.; Vijauachari, P.; Sardesai, N.Y.; Weiner, D.B.; et al. Nonstructural protein 2 (nsP2) of Chikungunya virus (CHIKV) enhances protective immunity mediated by a CHIKV envelope protein expressing DNA Vaccine. Viral Immunol. 2013, 26, 75–83.
  178. Mallilankaraman, K.; Shedlock, D.J.; Bao, H.; Kawalekar, O.U.; Fagone, P.; Ramanathan, A.A.; Ferraro, B.; Stabenow, J.; Vijayachari, P.; Sundaran, S.G.; et al. A DNA vaccine against chikungunya virus is protective in mice and induces neutralizing antibodies in mice and nonhuman primates. PLoS Negl. Trop. Dis. 2011, 5, e928.
  179. Dupuy, L.C.; Richards, M.J.; Livingston, B.D.; Hannaman, D.; Schmaljohn, C.S. A Multiagent Alphavirus DNA Vaccine Delivered by Intramuscular Electroporation Elicits Robust and Durable Virus-Specific Immune Responses in Mice and Rabbits and Completely Protects Mice against Lethal Venezuelan, Western, and Eastern Equine Encephalitis Virus Aerosol Challenges. J. Immunol. Res. 2018, 2018, 8521060.
  180. Choi, H.; Kudchodkar, S.B.; Reuschel, E.L.; Asija, K.; Borole, P.; Ho, M.; Wojtak, K.; Reed, C.; Ramos, S.; Bopp, N.E.; et al. Protective immunity by an engineered DNA vaccine for Mayaro virus. PLoS Negl. Trop. Dis. 2019, 13, e0007042.
  181. Tretyakova, I.; Hearn, J.; Wang, E.; Weaver, S.; Pushko, P. DNA vaccine initiates replication of live attenuated chikungunya virus in vitro and elicits protective immune response in mice. J. Infect. Dis. 2014, 209, 1882–1890.
  182. Muthumani, K.; Block, P.; Flingai, S.; Muruganantham, N.; Chaaithanya, I.K.; Tingey, C.; Wise, M.; Reuschel, E.L.; Chung, C.; Muthumani, A.; et al. Rapid and Long-Term Immunity Elicited by DNA-Encoded Antibody Prophylaxis and DNA Vaccination Against Chikungunya Virus. J. Infect. Dis. 2016, 214, 369–378.
  183. Szurgot, I.; Ljungberg, K.; Kummerer, B.M.; Liljestrom, P. Infectious RNA vaccine protects mice against chikungunya virus infection. Sci. Rep. 2020, 10, 21076.
  184. Dupuy, L.C.; Richards, M.J.; Ellefsen, B.; Chau, L.; Luxembourg, A.; Hannaman, D.; Livingston, B.D.; Schmaljohn, C.S. A DNA vaccine for venezuelan equine encephalitis virus delivered by intramuscular electroporation elicits high levels of neutralizing antibodies in multiple animal models and provides protective immunity to mice and nonhuman primates. Clin. Vaccine Immunol. 2011, 18, 707–716.
  185. Hannaman, D.; Dupuy, L.C.; Ellefsen, B.; Schmaljohn, C.S. A Phase 1 clinical trial of a DNA vaccine for Venezuelan equine encephalitis delivered by intramuscular or intradermal electroporation. Vaccine 2016, 34, 3607–3612.
  186. Nagata, L.P.; Hu, W.G.; Masri, S.A.; Rayner, G.A.; Schmaltz, F.L.; Das, D.; Wu, J.; Long, M.C.; Chan, C.; Proll, D.; et al. Efficacy of DNA vaccination against western equine encephalitis virus infection. Vaccine 2005, 23, 2280–2283.
  187. Phillips, A.T.; Schountz, T.; Toth, A.M.; Rico, A.B.; Jarvis, D.L.; Powers, A.M.; Olson, K.E. Liposome-antigen-nucleic acid complexes protect mice from lethal challenge with western and eastern equine encephalitis viruses. J. Virol. 2014, 88, 1771–1780.
  188. Shaw, C.; Panther, L.; August, A.; Zaks, T.; Smolenov, I.; Bart, S.; Watson, M. Safety and immunogenicity of a mRNA-based chikungunya vaccine in a phase 1 dose-ranging trial. Int. J. Infect. Dis. 2019, 79, 17.
  189. Kose, N.; Fox, J.M.; Sapparapu, G.; Bombardi, R.; Tennekoon, R.N.; de Silva, A.D.; Elbashir, S.M.; Theisen, M.A.; Humphris-Narayanan, E.; Ciaramella, G.; et al. A lipid-encapsulated mRNA encoding a potently neutralizing human monoclonal antibody protects against chikungunya infection. Sci. Immunol. 2019, 4, eaaw6647.
  190. Moderna, T.X. A Phase 1, Randomized, Placebo-Controlled, Dose Ranging Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of mRNA-1944, Encoding for an Anti-Chikungunya Virus Monoclonal Antibody, in Healthy Adults: U.S. National Library of Medicine. 2019. Available online: (accessed on 18 March 2021).
  191. Metz, S.W.; Geertsema, C.; Martina, B.E.; Andrade, P.; Heldens, J.G.; van Oers, M.M.; Goldbach, R.W.; Vlak, J.M.; Pijlman, G.P. Functional processing and secretion of Chikungunya virus E1 and E2 glycoproteins in insect cells. Virol. J. 2011, 8, 353.
  192. Khan, M.; Dhanwani, R.; Rao, P.V.; Parida, M. Subunit vaccine formulations based on recombinant envelope proteins of Chikungunya virus elicit balanced Th1/Th2 response and virus-neutralizing antibodies in mice. Virus Res. 2012, 167, 236–246.
  193. Brandler, S.; Ruffie, C.; Combredet, C.; Brault, J.B.; Najburg, V.; Prevost, M.C.; Habel, A.; Tauber, E.; Despres, P.; Tangy, F. A recombinant measles vaccine expressing chikungunya virus-like particles is strongly immunogenic and protects mice from lethal challenge with chikungunya virus. Vaccine 2013, 31, 3718–3725.
  194. Gerke, C.; Frantz, P.N.; Ramsauer, K.; Tangy, F. Measles-vectored vaccine approaches against viral infections: A focus on Chikungunya. Expert Rev. Vaccines 2019, 18, 393–403.
  195. Rossi, S.L.; Comer, J.E.; Wang, E.; Azar, S.R.; Lawrence, W.S.; Plante, J.A.; Ramsauer, K.; Schrauf, S.; Weaver, S.C. Immunogenicity and Efficacy of a Measles Virus-Vectored Chikungunya Vaccine in Nonhuman Primates. J. Infect. Dis. 2019, 220, 735–742.
  196. Ramsauer, K.; Schwameis, M.; Firbas, C.; Mullner, M.; Putnak, R.J.; Thomas, S.J.; Despres, P.; Tauber, E.; Jilma, B.; Tangy, F. Immunogenicity, safety, and tolerability of a recombinant measles-virus-based chikungunya vaccine: A randomised, double-blind, placebo-controlled, active-comparator, first-in-man trial. Lancet Infect. Dis. 2015, 15, 519–527.
  197. Reisinger, E.C.; Tschismarov, R.; Beubler, E.; Wiedermann, U.; Firbas, C.; Loebermann, M.; Pfeiffer, A.; Muellner, M.; Tauber, E.; Ramsauer, L. Immunogenicity, safety, and tolerability of the measles-vectored chikungunya virus vaccine MV-CHIK: A double-blind, randomised, placebo-controlled and active-controlled phase 2 trial. Lancet 2019, 392, 2718–2727.
  198. Wang, E.; Volkova, E.; Adams, A.P.; Forrester, N.; Xiao, S.Y.; Frolov, I.; Weaver, S.C. Chimeric alphavirus vaccine candidates for chikungunya. Vaccine 2008, 26, 5030–5039.
  199. Wang, E.; Kim, D.Y.; Weaver, S.C.; Frolov, I. Chimeric Chikungunya viruses are nonpathogenic in highly sensitive mouse models but efficiently induce a protective immune response. J. Virol. 2011, 85, 9249–9252.
  200. Wang, E.; Petrakova, O.; Adams, A.P.; Aguilar, P.V.; Kang, W.; Paessler, S.; Volk, S.M.; Frolov, I.; Weaver, S.C. Chimeric Sindbis/eastern equine encephalitis vaccine candidates are highly attenuated and immunogenic in mice. Vaccine 2007, 25, 7573–7581.
  201. Paessler, S.; Fayzulin, R.Z.; Anishchenko, M.; Greene, I.P.; Weaver, S.C.; Frolov, I. Recombinant sindbis/Venezuelan equine encephalitis virus is highly attenuated and immunogenic. J. Virol. 2003, 77, 9278–9286.
  202. Paessler, S.; Ni, H.; Petrakova, O.; Fayzulin, R.Z.; Yun, N.; Anishchenko, M.; Weaver, S.C.; Frolov, I. Replication and clearance of Venezuelan equine encephalitis virus from the brains of animals vaccinated with chimeric SIN/VEE viruses. J. Virol. 2006, 80, 2784–2796.
  203. Atasheva, S.; Wang, E.; Adams, A.P.; Plante, K.S.; Ni, S.; Taylor, K.; Miller, M.E.; Frolov, I.; Weaver, S.C. Chimeric alphavirus vaccine candidates protect mice from intranasal challenge with western equine encephalitis virus. Vaccine 2009, 27, 4309–4319.
  204. Garcia-Arriaza, J.; Cepeda, V.; Hallengard, D.; Sorzano, C.O.; Kummerer, B.M.; Liljestrom, P.; Esteban, M. A novel poxvirus-based vaccine, MVA-CHIKV, is highly immunogenic and protects mice against chikungunya infection. J. Virol. 2014, 88, 3527–3547.
  205. Weger-Lucarelli, J.; Chu, H.; Aliota, M.T.; Partidos, C.D.; Osorio, J.E. A novel MVA vectored Chikungunya virus vaccine elicits protective immunity in mice. PLoS Negl. Trop. Dis. 2014, 8, e2970.
  206. Van den Doel, P.; Volz, A.; Roose, J.M.; Sewbalaksing, V.D.; Pijlman, G.P.; van Middelkoop, I.; Duiverman, V.; van de Wetering, E.; Sutter, G.; Osterhaus, A.D.M.E.; et al. Recombinant modified vaccinia virus Ankara expressing glycoprotein E2 of Chikungunya virus protects AG129 mice against lethal challenge. PLoS Negl. Trop. Dis. 2014, 8, e3101.
  207. Hu, W.G.; Steigerwald, R.; Kalla, M.; Volkmann, A.; Noll, D.; Nagata, L.P. Protective efficacy of monovalent and trivalent recombinant MVA-based vaccines against three encephalitic alphaviruses. Vaccine 2018, 36, 5194–5203.
  208. Wang, D.; Suhrbier, A.; Penn-Nicholson, A.; Woraratanadharm, J.; Gardner, J.; Luo, M.; Le, T.T.; Anraku, I.; Sakalian, M.; Einfeld, D.; et al. A complex adenovirus vaccine against chikungunya virus provides complete protection against viraemia and arthritis. Vaccine 2011, 29, 2803–2809.
  209. Lopez-Camacho, C.; Kim, Y.C.; Blight, J.; Lazaro Moreli, M.; Montoya-Diaz, E.; Huiskonen, J.T.; Kummerer, B.M.; Reyes-Sandoval, A. Assessment of Immunogenicity and Neutralisation Efficacy of Viral-Vectored Vaccines Against Chikungunya Virus. Viruses 2019, 11, 322.
  210. Kroon Campos, R.; Preciado-Llanes, L.; Azar, S.R.; Kim, Y.C.; Brandon, O.; Lopez-Camacho, C.; Reyes-Sandoval, A.; Rossi, S.L. Adenoviral-Vectored Mayaro and Chikungunya Virus Vaccine Candidates Afford Partial Cross-Protection From Lethal Challenge in A129 Mouse Model. Front. Immunol. 2020, 11, 591885.
  211. Campos, R.K.; Preciado-Llanes, L.; Azar, S.R.; Lopez-Camacho, C.; Reyes-Sandoval, A.; Rossi, S.L. A Single and Un-Adjuvanted Dose of a Chimpanzee Adenovirus-Vectored Vaccine against Chikungunya Virus Fully Protects Mice from Lethal Disease. Pathogens 2019, 8, 231.
  212. Hill, A.V. Safety and Immunogenicity of a Candidate CHIKV Vaccine (CHIK001): National Library of Medicine (U.S.). 2018. Available online: (accessed on 18 March 2021).
  213. Phillpotts, R.J.; O’Brien, L.; Appleton, R.E.; Carr, S.; Bennett, A. Intranasal immunisation with defective adenovirus serotype 5 expressing the Venezuelan equine encephalitis virus E2 glycoprotein protects against airborne challenge with virulent virus. Vaccine 2005, 23, 1615–1623.
  214. Perkins, S.D.; Williams, A.J.; O’Brien, L.M.; Laws, T.R.; Phillpotts, R.J. CpG used as an adjuvant for an adenovirus-based Venezuelan equine encephalitis virus vaccine increases the immune response to the vector, but not to the transgene product. Viral. Immunol. 2008, 21, 451–457.
  215. Wu, J.Q.; Barabe, N.D.; Chau, D.; Wong, C.; Rayner, G.R.; Hu, W.G.; Nagata, L.P. Complete protection of mice against a lethal dose challenge of western equine encephalitis virus after immunization with an adenovirus-vectored vaccine. Vaccine 2007, 25, 4368–4375.
  216. Swayze, R.D.; Bhogal, H.S.; Barabe, N.D.; McLaws, L.J.; Wu, J.Q. Envelope protein E1 as vaccine target for western equine encephalitis virus. Vaccine 2011, 29, 813–820.
  217. Chattopadhyay, A.; Wang, E.; Seymour, R.; Weaver, S.C.; Rose, J.K. A chimeric vesiculo/alphavirus is an effective alphavirus vaccine. J. Virol. 2013, 87, 395–402.
  218. Nasar, F.; Matassov, D.; Seymour, R.L.; Latham, T.; Gorchakov, R.V.; Nowak, R.M.; Leal, G.; Hamm, S.; Eldridge, J.H.; Tesh, R.B.; et al. Recombinant Isfahan Virus and Vesicular Stomatitis Virus Vaccine Vectors Provide Durable, Multivalent, Single-Dose Protection against Lethal Alphavirus Challenge. J. Virol. 2017, 91, e01729-16.
  219. Fierro, C. Phase 1 Vaccination Trial to Evaluate Safety, Tolerability and Immunogenicity of a Recombinant MVA-BN-WEV Vaccine in Healthy Adult Subjects: National Library of Medicine (U.S.). 2019. Available online: (accessed on 18 March 2021).
  220. Erasmus, J.H.; Auguste, A.J.; Kaelber, J.T.; Luo, H.; Rossi, S.L.; Fenton, K.; Leal, G.; Kim, D.Y.; Chiu, W.; Wang, T.; et al. A chikungunya fever vaccine utilizing an insect-specific virus platform. Nat. Med. 2017, 23, 192–199.
More
Information
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
View Times: 410
Revisions: 2 times (View History)
Update Date: 04 Aug 2021
1000/1000