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Therapeutics and vaccines against chikungunya virus

Ahola T, Couderc T, Courderc T, Ng LF, Hallengärd D, Powers A, et al.

Vector Borne Zoonotic Dis, 2015 Apr;15(4):250-7.
PMID: 25897811 DOI: 10.1089/vbz.2014.1681

Currently, there are no licensed vaccines or therapies available against chikungunya virus (CHIKV), and these were subjects discussed during a CHIKV meeting recently organized in Langkawi, Malaysia. In this review, we chart the approaches taken in both areas. Because of a sharp increase in new data in these fields, the present paper is complementary to previous reviews by Weaver et al. in 2012 and Kaur and Chu in 2013 . The most promising antivirals so far discovered are reviewed, with a special focus on the virus-encoded replication proteins as potential targets. Within the vaccines in development, our review emphasizes the various strategies in parallel development that are unique in the vaccine field against a single disease.

Matched MeSH terms: Chikungunya Fever/immunology
Fulltext The neutralizing role of IgM during early Chikungunya virus infection

Chua CL, Sam IC, Chiam CW, Chan YF

PLoS One, 2017;12(2):e0171989.
PMID: 28182795 DOI: 10.1371/journal.pone.0171989

The antibody isotype IgM appears earlier than IgG, within days of onset of symptoms, and is important during the early stages of the adaptive immune response. Little is known about the functional role of IgM during infection with chikungunya virus (CHIKV), a recently reemerging arbovirus that has caused large global outbreaks. In this study, we studied antibody responses in 102 serum samples collected during CHIKV outbreaks in Malaysia. We described the neutralizing role of IgM at different times post-infection and examined the independent contributions of IgM and IgG towards the neutralizing capacity of human immune sera during the early phase of infection, including the differences in targets of neutralizing epitopes. Neutralizing IgM starts to appear as early as day 4 of symptoms, and their appearance from day 6 is associated with a reduction in viremia. IgM acts in a complementary manner with the early IgG, but plays the main neutralizing role up to a point between days 4 and 10 which varies between individuals. After this point, total neutralizing capacity is attributable almost entirely to the robust neutralizing IgG response. IgM preferentially binds and targets epitopes on the CHIKV surface E1-E2 glycoproteins, rather than individual E1 or E2. These findings provide insight into the early antibody responses to CHIKV, and have implications for design of diagnostic serological assays.

Matched MeSH terms: Chikungunya Fever/immunology*
Evaluation of neutralizing antibodies produced by papaya mosaic virus nanoparticles fused to the E2EP3 peptide epitope of Chikungunya envelope

Nor Rashid N, Teoh TC, Al-Harbi SJ, Yusof R, Rothan HA

Trop Biomed, 2021 Mar 01;38(1):36-41.
PMID: 33797522 DOI: 10.47665/tb.38.1.007

Chikungunya virus (CHIKV) infection is the cause of acute symptoms and chronic symmetrical polyarthritis associated with long-term morbidity and mortality. Currently, there is no available licensed vaccine or particularly useful drug for human use against CHIKV infection. This study was conducted to evaluate the efficacy of antibodies produced by papaya mosaic virus (PapMV) nanoparticles fused to E2EP3 peptide of CHIKV envelope as a recombinant CHIKV vaccine. PapMV, PapMV-C- E2EP3, and E2EP3-N-PapMV were produced in E. coli with an approximate size of 27 to 30 kDa. ICR mice (5 to 6 weeks of age) were injected subcutaneously with 25 micrograms of vaccine construct, and ELISA measured the titer of CHIKV specific IgG antibodies. The results showed that both recombinant proteins E2EP3-N-PapMV and PapMVC-E2EP3 were able to induce IgG antibodies production in immunized mice against CHIKV while immunization with recombinant PapMV showed no IgG antibodies induction. The neutralizing activity of the antibodies generated by either E2EP3-N-PapMV or PapMV-C-E2EP3 exhibited similar inhibition to CHIKV replication in Vero cells using the cells based antibody neutralizing assay and analyzed by plaque formation assay. This study showed the effectiveness of nanoparticles vaccine generated by fusing epitope peptide of CHIKV envelope to papaya mosaic virus envelope in inducing a robust immune response in mice against CHIKV. The data showed that levels of neutralizing antibodies correlate with a protective immune response CHIKV replication.

Matched MeSH terms: Chikungunya Fever/immunology
Fulltext Early clearance of Chikungunya virus in children is associated with a strong innate immune response

Simarmata D, Ng DC, Kam YW, Lee B, Sum MS, Her Z, et al.

Sci Rep, 2016 05 16;6:26097.
PMID: 27180811 DOI: 10.1038/srep26097

Chikungunya fever (CHIKF) is a global infectious disease which can affect a wide range of age groups. The pathological and immunological response upon Chikungunya virus (CHIKV) infection have been reported over the last few years. However, the clinical profile and immune response upon CHIKV infection in children remain largely unknown. In this study, we analyzed the clinical and immunological response, focusing on the cytokine/chemokine profile in a CHIKV-infected pediatric cohort from Sarawak, Malaysia. Unique immune mediators triggered upon CHIKV infection were identified through meta-analysis of the immune signatures between this pediatric group and cohorts from previous outbreaks. The data generated from this study revealed that a broad spectrum of cytokines/chemokines is up-regulated in a sub-group of virus-infected children stratified according to their viremic status during hospitalization. Furthermore, different immune mediator profiles (the levels of pro-inflammatory cytokines, chemokines and growth and other factors) were observed between children and adults. This study gives an important insight to understand the immune response of CHIKV infection in children and would aid in the development of better prognostics and clinical management for children.

Matched MeSH terms: Chikungunya Fever/immunology*
Fulltext Current concerns and perspectives on Zika virus co-infection with arboviruses and HIV

Rothan HA, Bidokhti MRM, Byrareddy SN

J Autoimmun, 2018 05;89:11-20.
PMID: 29352633 DOI: 10.1016/j.jaut.2018.01.002

Dissemination of vector-borne viruses, such as Zika virus (ZIKV), in tropical and sub-tropical regions has a complicated impact on the immunopathogenesis of other endemic viruses such as dengue virus (DENV), chikungunya virus (CHIKV) and human immunodeficiency virus (HIV). The consequences of the possible co-infections with these viruses have specifically shown significant impact on the treatment and vaccination strategies. ZIKV is a mosquito-borne flavivirus from African and Asian lineages that causes neurological complications in infected humans. Many of DENV and CHIKV endemic regions have been experiencing outbreaks of ZIKV infection. Intriguingly, the mosquitoes, Aedes Aegypti and Aedes Albopictus, can simultaneously transmit all the combinations of ZIKV, DENV, and CHIKV to the humans. The co-circulation of these viruses leads to a complicated immune response due to the pre-existence or co-existence of ZIKV infection with DENV and CHIKV infections. The non-vector transmission of ZIKV, especially, via sexual intercourse and placenta represents an additional burden that may hander the treatment strategies of other sexually transmitted diseases such as HIV. Collectively, ZIKV co-circulation and co-infection with other viruses have inevitable impact on the host immune response, diagnosis techniques, and vaccine development strategies for the control of these co-infections.

Matched MeSH terms: Chikungunya Fever/immunology
Leptospirosis: Molecular trial path and immunopathogenesis correlated with dengue, malaria and mimetic hemorrhagic infections

Priya SP, Sakinah S, Sharmilah K, Hamat RA, Sekawi Z, Higuchi A, et al.

Acta Trop, 2017 Dec;176:206-223.
PMID: 28823908 DOI: 10.1016/j.actatropica.2017.08.007

Immuno-pathogenesis of leptospirosis can be recounted well by following its trail path from entry to exit, while inducing disastrous damages in various tissues of the host. Dysregulated, inappropriate and excessive immune responses are unanimously blamed in fatal leptospirosis. The inherent abilities of the pathogen and inabilities of the host were debated targeting the severity of the disease. Hemorrhagic manifestation through various mechanisms leading to a fatal end is observed when this disease is unattended. The similar vascular destructions and hemorrhage manifestations are noted in infections with different microbes in endemic areas. The simultaneous infection in a host with more than one pathogen or parasite is referred as the coinfection. Notably, common endemic infections such as leptospirosis, dengue, chikungunya, and malaria, harbor favorable environments to flourish in similar climates, which is aggregated with stagnated water and aggravated with the poor personal and environmental hygiene of the inhabitants. These factors aid the spread of pathogens and parasites to humans and potential vectors, eventually leading to outbreaks of public health relevance. Malaria, dengue and chikungunya need mosquitoes as vectors, in contrast with leptospirosis, which directly invades human, although the environmental bacterial load is maintained through other mammals, such as rodents. The more complicating issue is that infections by different pathogens exhibiting similar symptoms but require different treatment management. The current review explores different pathogens expressing specific surface proteins and their ability to bind with array of host proteins with or without immune response to enter into the host tissues and their ability to evade the host immune responses to invade and their affinity to certain tissues leading to the common squeal of hemorrhage. Furthermore, at the host level, the increased susceptibility and inability of the host to arrest the pathogens' and parasites' spread in different tissues, various cytokines accumulated to eradicate the microorganisms and their cellular interactions, the antibody dependent defense and the susceptibility of individual organs bringing the manifestation of the diseases were explored. Lastly, we provided a discussion on the immune trail path of pathogenesis from entry to exit to narrate the similarities and dissimilarities among various hemorrhagic fevers mentioned above, in order to outline future possibilities of prevention, diagnosis, and treatment of coinfections, with special reference to endemic areas.

Matched MeSH terms: Chikungunya Fever/immunology
Fulltext Antigenic Variation of East/Central/South African and Asian Chikungunya Virus Genotypes in Neutralization by Immune Sera

Chua CL, Sam IC, Merits A, Chan YF

PLoS Negl Trop Dis, 2016 08;10(8):e0004960.
PMID: 27571254 DOI: 10.1371/journal.pntd.0004960

BACKGROUND: Chikungunya virus (CHIKV) is a re-emerging mosquito-borne virus which causes epidemics of fever, severe joint pain and rash. Between 2005 and 2010, the East/Central/South African (ECSA) genotype was responsible for global explosive outbreaks across India, the Indian Ocean and Southeast Asia. From late 2013, Asian genotype CHIKV has caused outbreaks in the Americas. The characteristics of cross-antibody efficacy and epitopes are poorly understood.
METHODOLOGY/PRINCIPAL FINDINGS: We characterized human immune sera collected during two independent outbreaks in Malaysia of the Asian genotype in 2006 and the ECSA genotype in 2008-2010. Neutralizing capacity was analyzed against representative clinical isolates as well as viruses rescued from infectious clones of ECSA and Asian CHIKV. Using whole virus antigen and recombinant E1 and E2 envelope glycoproteins, we further investigated antibody binding sites, epitopes, and antibody titers. Both ECSA and Asian sera demonstrated stronger neutralizing capacity against the ECSA genotype, which corresponded to strong epitope-antibody interaction. ECSA serum targeted conformational epitope sites in the E1-E2 glycoprotein, and E1-E211K, E2-I2T, E2-H5N, E2-G118S and E2-S194G are key amino acids that enhance cross-neutralizing efficacy. As for Asian serum, the antibodies targeting E2 glycoprotein correlated with neutralizing efficacy, and I2T, H5N, G118S and S194G altered and improved the neutralization profile. Rabbit polyclonal antibody against the N-terminal linear neutralizing epitope from the ECSA sequence has reduced binding capacity and neutralization efficacy against Asian CHIKV. These findings imply that the choice of vaccine strain may impact cross-protection against different genotypes.
CONCLUSION/SIGNIFICANCE: Immune serum from humans infected with CHIKV of either ECSA or Asian genotypes showed differences in binding and neutralization characteristics. These findings have implications for the continued outbreaks of co-circulating CHIKV genotypes and effective design of vaccines and diagnostic serological assays.

Matched MeSH terms: Chikungunya Fever/immunology