Chikungunya

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Chikungunya
Classification and external resources

Rash from Chikungunya on the right foot
ICD-10 A92.0
ICD-9 065.4, 066.3
DiseasesDB 32213
MeSH D018354

Chikungunya (in the Makonde language "that which bends up") virus (CHIKV) is an arthropod-borne virus, of the genus Alphavirus, that is transmitted to humans by virus-carrying Aedes mosquitoes.[1] There have been recent breakouts of CHIKV associated with severe illness.

CHIKV infection causes an illness with symptoms similar to dengue fever, with an acute febrile phase lasting two to five days, followed by a longer period of joint pains in the extremities. The pain associated with CHIKV infection of the joints may persist for weeks or months, or in some cases years.[2][3] Prevention is via mosquito control and preventing bite by infected mosquitoes.[4] There is no specific treatment with medications used to help with symptoms.[4]

Signs and symptoms

The incubation period of chikungunya disease ranges from one to twelve days, usually two to three. Its symptoms include a fever up to 40 °C (104 °F), a petechial or maculopapular rash of the trunk and occasionally the limbs, and arthralgia or arthritis affecting multiple joints.[5] Other nonspecific symptoms can include headache, nausea, vomitting, conjunctivitis, slight photophobia and partial loss of taste.[6] Ocular inflammation from Chikungunya may present as iridocyclitis, and have retinal lesions as well.[7] Pedal oedema (swelling of legs) is observed in many patients, the cause of which remains obscure as it is not related to any cardiovascular, renal or hepatic abnormalities.

Typically, the fever lasts for two days and then ends abruptly. However, other symptoms—namely joint pain, intense headache, insomnia and an extreme degree of prostration—last for a variable period; usually for about five to seven days.[5] Patients have complained of joint pains for much longer time periods; some as long as two years, depending on their age.[8][9] Recovery from the disease varies by age. Younger patients recover within 5 to 15 days; middle-aged patients recover in 1 to 2.5 months. Recovery is longer for the elderly. The severity of the disease as well as its duration is less in younger patients and pregnant women. In pregnant women, no untoward effects are noticed after the infection.

Chronic disease

Observations during recent epidemics have suggested chikungunya may cause long-term symptoms following acute infection. Following the La Reunion outbreak in 2006, greater than 50% of subjects over 45 reported long term musculoskeletal pain[10] with up to 60% of patients reporting prolonged arthralgia 3 years following initial infection.[11] A study of imported cases in France reported that 59% of patients still suffered from arthralgia two years after acute infection.[12] Following a local epidemic of chikungunya in Italy, 66% of patients reported myalgia, arthralgia, or asthenia at one year post acute infection.[13] Long-term symptoms are not an entirely new observation; long-term arthritis was observed following an outbreak in 1979.[14] Common predictors of prolonged symptoms are increased age and prior rheumatalogical disease.[10][11][13][15] The cause of these chronic symptoms is currently not fully known. Markers of autoimmune or rheumatoid disease have not been found in patients reporting chronic symptoms.[11][16] However, some evidence from human patients and animal models suggest that chikungunya may be able to establish chronic infections within the host. Viral antigen was detected in a muscle biopsy of a patient suffering a recurrent episode of disease three months after initial onset.[17] Additionally, viral antigen and RNA were found in synovial macrophages of a patient during a relapse of musculoskeletal disease 18 months post initial infection.[18] Several animal models have also suggested that chikungunya virus may establish persistent infections. In a mouse model viral RNA was detected specifically in joint-associated tissue for at least 16 weeks post inoculation and was associated with chronic synovitis.[19] Similarly, another study reported detection of a viral reporter gene in joint tissue of mice for weeks post inoculation.[20] In a non-human primate model, chikungunya virus was found to persist in the spleen for at least 6 weeks.[21]

Virology

Chikungunya virus
Cryoelectron microscopy reconstruction of Chikungunya virus. FromEMDB entry EMD-5577[22]
Virus classification
Group: Group IV ((+)ssRNA)
Order: Unassigned
Family: Togaviridae
Genus: Alphavirus
Species: Chikungunya virus

Chikungunya virus is an alphavirus with a positive sense single-stranded RNA genome of approximately 11.6kb. It is a member of the Semliki Forest Virus complex and is closely related to Ross River Virus, O’Nyong Nyong virus and Semliki Forest Virus.[23] In the United States it is classified as a Category C priority pathogen[24] and work requires Biosafety Level III precautions.[25]

Human epithelial, endothelial, primary fibroblasts and monocyte-derived macrophages are permissive for chikungunya virus in vitro and viral replication is highly cytopathic but susceptible to type I and II interferon.[26] In vivo chikungunya virus appears to replicate in fibroblasts, skeletal muscle progenitor cells and myofibers.[17][27][28]

Type 1 interferon

Upon infection with chikungunya, the host's fibroblasts will produce type 1 (alpha and beta) interferon.[29] Mice that lack the interferon alpha receptor die in 2–3 days upon being exposed to 102 chikungunya PFU, while wild type mice survive even when exposed to as much as 102 PFU of the virus.[29] At the same time, mice that are partially type 1 deficient (IFN α/β +/−) are mildly affected and experience symptoms such as muscle weakness and lethargy.[30] Partidos et al. 2011 saw similar results with the live attenuated strain CHIKV181/25. However, rather than dying, the type 1 interferon deficient (IFN α/β −/−) mice were temporarily disabled and the partially type 1 interferon deficient mice did not have any problems.[31]

Several studies have attempted to find the upstream components of the type 1 interferon pathway involved in the host's response to chikungunya infection. So far, no one knows the chikungunya specific pathogen associated molecular pattern.[32] Nonetheless, IPS-1—also known as Cardif, MAVS, and VISA—has been found to be an important factor. In 2011, White et al. found that interfering with IPS-1 decreased the phosphorylation of interferon regulatory factor 3 (IRF3) and the production of IFN-β.[32] Other studies have found that IRF3 and IRF7 are important in an age-dependent manner. Adult mice that lack both of these regulatory factors die upon infection with chikungunya.[33] Neonates, on the other hand, succumb to the virus if they are deficient in one of these factors.[34]

Chikungunya counters the Type I interferon response by producing NS2, a non-structural protein that degrades Rpb and turns off the host cell's ability to transcribe DNA.[35] NS2 interferes with the JAK-STAT signaling pathway and prevents STAT from becoming phosphorylated.[36]

Diagnosis

Common laboratory tests for chikungunya include RT-PCR, virus isolation, and serological tests.

  • Virus isolation provides the most definitive diagnosis, but takes one to two weeks for completion and must be carried out in biosafety level 3 laboratories.[37] The technique involves exposing specific cell lines to samples from whole blood and identifying chikungunya virus-specific responses.
  • RT-PCR using nested primer pairs is used to amplify several chikungunya-specific genes from whole blood. Results can be determined in one to two days.[37]
  • Serological diagnosis requires a larger amount of blood than the other methods, and uses an ELISA assay to measure chikungunya-specific IgM levels. Results require two to three days, and false positives can occur with infection via other related viruses, such as o'nyong'nyong virus and Semliki Forest virus.[37]

Prevention

The Aedes aegypti mosquito biting a person

The most effective means of prevention are protection against contact with the disease-carrying mosquitoes and mosquito control.[4] These include using insect repellents with substances such as DEET (N,N-diethyl-meta-toluamide; also known as N,N'-diethyl-3-methylbenzamide or NNDB), icaridin (also known as picaridin and KBR3023), PMD (p-menthane-3,8-diol, a substance derived from the lemon eucalyptus tree), or IR3535. Wearing bite-proof long sleeves and trousers (pants) also offers protection.

In addition, garments can be treated with pyrethroids, a class of insecticides that often has repellent properties. Vaporized pyrethroids (for example in mosquito coils) are also insect repellents. Securing screens on windows and doors will help to keep mosquitoes out of the house. In the case of the day-active Aedes aegypti and Aedes albopictus, however, this will have only a limited effect, since many contacts between the mosquitoes and humans occur outside.

Vaccine

There are currently no approved vaccines available. A Phase II vaccine trial, used a live, attenuated virus, developing viral resistance in 98% of those tested after 28 days and 85% still showed resistance after one year.[38] However, 8% of people reported transient joint pain and attenuation was found to be due to only two mutations in the E2 glycoprotein.[39] Alternative vaccine strategies have been developed and shown efficacy in mouse models but have so far not reached clinical trials.[40][41]

Treatment

Currently there is no specific treatment.[4] Efforts to improve the symptoms include the use of NSAIDs such as naproxen, paracetamol (acetaminophen) and fluids.[4] Aspirin is not recommended.[42]

Chronic arthritis

In those who have more than two weeks of arthritis ribavirin may be useful.[4] The effect of chloroquine is not clear.[4] It does not appear to help acute disease but there is tentative evidence that it might help the chronic arthritis.[4] Steroids do not appear useful either.[4]

Epidemiology

Cases of chikungunya fever (between 1952 and 2006) have been reported in the countries depicted in red on this map. Since 2006, local transmission have occurred in places like Taiwan, Australia, and the Caribbean.

Chikungunya virus is an alphavirus closely related to the o'nyong'nyong virus,[43] the Ross River virus in Australia, and the viruses that cause eastern equine encephalitis and western equine encephalitis.[44]

Three genotypes of this virus have been described: West African, East/Central/South African and Asian genotypes.[45]

Chikungunya is generally spread through bites from Aedes aegypti mosquitoes, but recent research by the Pasteur Institute in Paris has suggested chikungunya virus strains in the 2005-2006 Reunion Island outbreak incurred a mutation that facilitated transmission by Asian tiger mosquito (Aedes albopictus).[46]

Concurrent studies by arbovirologists at the University of Texas Medical Branch in Galveston, Texas, confirmed definitively that enhanced chikungunya virus infection of A. albopictus was caused by a point mutation in one of the viral envelope genes (E1).[47][48] Enhanced transmission of chikungunya virus by A. albopictus could mean an increased risk for chikungunya outbreaks in other areas where the Asian tiger mosquito is present. A recent epidemic in Italy was likely perpetuated by A. albopictus.[49]

In Africa, chikungunya is spread via a sylvatic cycle in which the virus largely resides in other primates in between human outbreaks.[44]

On 28 May 2009 in Changwat Trang of Thailand where the virus is endemic, the provincial hospital decided to deliver by Caesarean section a male baby from his chikungunya-infected mother, Khwanruethai Sutmueang, 28, a Trang native, to prevent mother-fetus virus transmission. However, after delivering the baby, the physicians discovered the baby was already infected with the virus, and put him into intensive care because the infection had left the baby unable to breathe by himself or to drink milk. The physicians presumed the virus might be able to be transmitted from a mother to her fetus, but without laboratory confirmation.[50]

In December 2013, chikungunya was confirmed on the Caribbean island of St. Martin with 66 confirmed cases and suspected cases of around 181.[51] This is the first time in the Western Hemisphere that the disease has spread to humans from a population of infected mosquitoes.[52] Among other islands, nearby Saint-Barthélemy and farther away Martinique have many suspected cases, while local transmission has been confirmed on Guadeloupe.[51] By January, 2014, the Public Health Agency of Canada reported that cases were confirmed on all of those islands and the British Virgin Islands as well.[53]

History

Main article: Chikungunya outbreaks

The word chikungunya is thought to derive from a description in the Makonde language, meaning "that which bends up", of the contorted posture of patients afflicted with the severe joint pain and arthritic symptoms associated with this disease.[54] The disease was first described by Marion Robinson[55] and W.H.R. Lumsden[56] in 1955, following an outbreak in 1952 on the Makonde Plateau, along the border between Mozambique and Tanganyika (the mainland part of modern day Tanzania).

According to the initial 1955 report about the epidemiology of the disease, the term chikungunya is derived from the Makonde root verb kungunyala, meaning to dry up or become contorted. In concurrent research, Robinson glossed the Makonde term more specifically as "that which bends up". Subsequent authors apparently overlooked the references to the Makonde language and assumed the term derived from Swahili, the lingua franca of the region. The erroneous attribution of the term as a Swahili word has been repeated in numerous print sources. Many other erroneous spellings and forms of the term are in common use including "chicken guinea", "chicken gunaya", and "chickengunya".[citation needed]

Since its discovery in Tanganyika, Africa, in 1952, chikungunya virus outbreaks have occurred occasionally in Africa, South Asia, and Southeast Asia, but recent outbreaks have spread the disease over a wider range.

The first recorded outbreak of this disease may have been in 1779.[57] This is in agreement with the molecular genetics evidence that suggests it evolved around the year 1700.[58]

Society and culture

Biological weapon

Chikungunya was one of more than a dozen agents the United States researched as potential biological weapons before the nation suspended its biological weapons program.[59]

References

  1. ↑ Lahariya C, Pradhan SK (December 2006). "Emergence of chikungunya virus in Indian subcontinent after 32 years: A review". J Vector Borne Dis 43 (4): 151–60. PMID 17175699. 
  2. ↑ Powers AM, Logue CH (September 2007). "Changing patterns of chikungunya virus: re-emergence of a zoonotic arbovirus". J. Gen. Virol. 88 (Pt 9): 2363–77. doi:10.1099/vir.0.82858-0. PMID 17698645. 
  3. ↑ Sourisseau M, Schilte C, Casartelli N, et al. (June 2007). "Characterization of reemerging chikungunya virus". PLoS Pathog. 3 (6): e89. doi:10.1371/journal.ppat.0030089. PMC 1904475. PMID 17604450. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 Caglioti, C; Lalle, E; Castilletti, C; Carletti, F; Capobianchi, MR; Bordi, L (2013 Jul). "Chikungunya virus infection: an overview.". The new microbiologica 36 (3): 211–27. PMID 23912863. 
  5. ↑ 5.0 5.1 Chhabra M, Mittal V, Bhattacharya D, Rana U, Lal S (2008). "Chikungunya fever: a re-emerging viral infection". Indian J Med Microbiol 26 (1): 5–12. doi:10.4103/0255-0857.38850. PMID 18227590. 
  6. ↑ Vatsal Anand (18 March 2011). "After effects of Chikungunya Fever". Retrieved 2012-06-29. 
  7. ↑ Mahendradas P, Ranganna SK, Shetty R, et al. (February 2008). "Ocular manifestations associated with chikungunya". Ophthalmology 115 (2): 287–91. doi:10.1016/j.ophtha.2007.03.085. PMID 17631967. 
  8. ↑ Simon F, Parola P, Grandadam M, et al. (May 2007). "Chikungunya infection: an emerging rheumatism among travelers returned from Indian Ocean islands. Report of 47 cases". Medicine 86 (3): 123–37. doi:10.1097/MD/0b013e31806010a5. PMID 17505252. 
  9. ↑ Taubitz W, Cramer JP, Kapaun A, et al. (July 2007). "Chikungunya fever in travelers: clinical presentation and course". Clin. Infect. Dis. 45 (1): e1–4. doi:10.1086/518701. PMID 17554689. 
  10. ↑ 10.0 10.1 Gérardin, P; Fianu, A; Michault, A; Mussard, C; Boussaïd, K; Rollot, O; Grivard, P; Kassab, S; Bouquillard, E; Borgherini, G; Gaüzère, BA; Malvy, D; Bréart, G; Favier, F (Jan 9, 2013). "Predictors of Chikungunya rheumatism: a prognostic survey ancillary to the TELECHIK cohort study.". Arthritis research & therapy 15 (1): R9. doi:10.1186/ar4137. PMID 23302155. 
  11. ↑ 11.0 11.1 11.2 Schilte, C; Staikowsky, F; Couderc, T; Madec, Y; Carpentier, F; Kassab, S; Albert, ML; Lecuit, M; Michault, A (2013). "Chikungunya virus-associated long-term arthralgia: a 36-month prospective longitudinal study.". PLoS neglected tropical diseases 7 (3): e2137. doi:10.1371/journal.pntd.0002137. PMID 23556021. 
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  13. ↑ 13.0 13.1 Moro, ML; Grilli, E; Corvetta, A; Silvi, G; Angelini, R; Mascella, F; Miserocchi, F; Sambo, P; Finarelli, AC; Sambri, V; Gagliotti, C; Massimiliani, E; Mattivi, A; Pierro, AM; Macini, P; Study Group “Infezioni da Chikungunya in, Emilia-Romagna” (Aug 2012). "Long-term chikungunya infection clinical manifestations after an outbreak in Italy: a prognostic cohort study.". The Journal of infection 65 (2): 165–72. doi:10.1016/j.jinf.2012.04.005. PMID 22522292. 
  14. ↑ Fourie, ED; Morrison, JG (Jul 28, 1979). "Rheumatoid arthritic syndrome after chikungunya fever.". South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde 56 (4): 130–2. PMID 494034. 
  15. ↑ Sissoko, D; Malvy, D; Ezzedine, K; Renault, P; Moscetti, F; Ledrans, M; Pierre, V (2009). "Post-epidemic Chikungunya disease on Reunion Island: course of rheumatic manifestations and associated factors over a 15-month period.". PLoS neglected tropical diseases 3 (3): e389. doi:10.1371/journal.pntd.0000389. PMID 19274071. 
  16. ↑ Manimunda, SP; Vijayachari, P; Uppoor, R; Sugunan, AP; Singh, SS; Rai, SK; Sudeep, AB; Muruganandam, N; Chaitanya, IK; Guruprasad, DR (Jun 2010). "Clinical progression of chikungunya fever during acute and chronic arthritic stages and the changes in joint morphology as revealed by imaging.". Transactions of the Royal Society of Tropical Medicine and Hygiene 104 (6): 392–9. doi:10.1016/j.trstmh.2010.01.011. PMID 20171708. 
  17. ↑ 17.0 17.1 Ozden, S; Huerre, M; Riviere, JP; Coffey, LL; Afonso, PV; Mouly, V; de Monredon, J; Roger, JC; El Amrani, M; Yvin, JL; Jaffar, MC; Frenkiel, MP; Sourisseau, M; Schwartz, O; Butler-Browne, G; Desprès, P; Gessain, A; Ceccaldi, PE (Jun 13, 2007). "Human muscle satellite cells as targets of Chikungunya virus infection.". PLoS ONE 2 (6): e527. doi:10.1371/journal.pone.0000527. PMID 17565380. 
  18. ↑ Hoarau, JJ; Jaffar Bandjee, MC; Krejbich Trotot, P; Das, T; Li-Pat-Yuen, G; Dassa, B; Denizot, M; Guichard, E; Ribera, A; Henni, T; Tallet, F; Moiton, MP; Gauzère, BA; Bruniquet, S; Jaffar Bandjee, Z; Morbidelli, P; Martigny, G; Jolivet, M; Gay, F; Grandadam, M; Tolou, H; Vieillard, V; Debré, P; Autran, B; Gasque, P (May 15, 2010). "Persistent chronic inflammation and infection by Chikungunya arthritogenic alphavirus in spite of a robust host immune response.". Journal of immunology (Baltimore, Md. : 1950) 184 (10): 5914–27. doi:10.4049/jimmunol.0900255. PMID 20404278. 
  19. ↑ Hawman, DW; Stoermer, KA; Montgomery, SA; Pal, P; Oko, L; Diamond, MS; Morrison, TE (Dec 2013). "Chronic joint disease caused by persistent chikungunya virus infection is controlled by the adaptive immune response.". Journal of Virology 87 (24): 13878–88. doi:10.1128/JVI.02666-13. PMID 24131709. 
  20. ↑ Teo, TH; Lum, FM; Claser, C; Lulla, V; Lulla, A; Merits, A; Rénia, L; Ng, LF (Jan 1, 2013). "A pathogenic role for CD4+ T cells during Chikungunya virus infection in mice.". Journal of immunology (Baltimore, Md. : 1950) 190 (1): 259–69. doi:10.4049/jimmunol.1202177. PMID 23209328. 
  21. ↑ Labadie, K; Larcher, T; Joubert, C; Mannioui, A; Delache, B; Brochard, P; Guigand, L; Dubreil, L; Lebon, P; Verrier, B; de Lamballerie, X; Suhrbier, A; Cherel, Y; Le Grand, R; Roques, P (Mar 2010). "Chikungunya disease in nonhuman primates involves long-term viral persistence in macrophages.". The Journal of Clinical Investigation 120 (3): 894–906. doi:10.1172/JCI40104. PMID 20179353. 
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  24. ↑ "NIAID Category A, B, and C Priority Pathogens". Retrieved 1 January 2014. 
  25. ↑ "Biosafety in Microbiological and Biomedical Laboratories (BMBL) 5th Edition". Retrieved 1 January 2014. 
  26. ↑ Sourisseau, M; Schilte, C; Casartelli, N; Trouillet, C; Guivel-Benhassine, F; Rudnicka, D; Sol-Foulon, N; Le Roux, K; Prevost, MC; Fsihi, H; Frenkiel, MP; Blanchet, F; Afonso, PV; Ceccaldi, PE; Ozden, S; Gessain, A; Schuffenecker, I; Verhasselt, B; Zamborlini, A; Saïb, A; Rey, FA; Arenzana-Seisdedos, F; Desprès, P; Michault, A; Albert, ML; Schwartz, O (Jun 2007). "Characterization of reemerging chikungunya virus.". PLoS Pathogens 3 (6): e89. doi:10.1371/journal.ppat.0030089. PMC 1904475. PMID 17604450. 
  27. ↑ Schilte, C; Couderc, T; Chretien, F; Sourisseau, M; Gangneux, N; Guivel-Benhassine, F; Kraxner, A; Tschopp, J; Higgs, S; Michault, A; Arenzana-Seisdedos, F; Colonna, M; Peduto, L; Schwartz, O; Lecuit, M; Albert, ML (Feb 15, 2010). "Type I IFN controls chikungunya virus via its action on nonhematopoietic cells.". The Journal of experimental medicine 207 (2): 429–42. doi:10.1084/jem.20090851. PMC 2822618. PMID 20123960. 
  28. ↑ Rohatgi, A; Corbo, JC; Monte, K; Higgs, S; Vanlandingham, DL; Kardon, G; Lenschow, DJ (Dec 11, 2013). "Infection of myofibers contributes to the increased pathogenicity during infection with an epidemic strain of Chikungunya Virus.". Journal of Virology. doi:10.1128/JVI.02716-13. PMID 24335291. 
  29. ↑ 29.0 29.1 Schilte C, Couderc T, Chretien F, et al. (February 2010). "Type I IFN controls chikungunya virus via its action on nonhematopoietic cells". J. Exp. Med. 207 (2): 429–42. doi:10.1084/jem.20090851. PMC 2822618. PMID 20123960. 
  30. ↑ Couderc T, Chrétien F, Schilte C, et al. (February 2008). "A mouse model for Chikungunya: young age and inefficient type-I interferon signaling are risk factors for severe disease". PLoS Pathog. 4 (2): e29. doi:10.1371/journal.ppat.0040029. PMC 2242832. PMID 18282093. 
  31. ↑ Partidos CD, Weger J, Brewoo J, et al. (April 2011). "Probing the attenuation and protective efficacy of a candidate chikungunya virus vaccine in mice with compromised interferon (IFN) signaling". Vaccine 29 (16): 3067–73. doi:10.1016/j.vaccine.2011.01.076. PMC 3081687. PMID 21300099. 
  32. ↑ 32.0 32.1 White LK, Sali T, Alvarado D, et al. (January 2011). "Chikungunya virus induces IPS-1-dependent innate immune activation and protein kinase R-independent translational shutoff". J. Virol. 85 (1): 606–20. doi:10.1128/JVI.00767-10. PMC 3014158. PMID 20962078. 
  33. ↑ Rudd PA, Wilson J, Gardner J, et al. (September 2012). "Interferon response factors 3 and 7 protect against Chikungunya virus hemorrhagic fever and shock". J. Virol. 86 (18): 9888–98. doi:10.1128/JVI.00956-12. PMC 3446587. PMID 22761364. 
  34. ↑ Schilte C, Buckwalter MR, Laird ME, Diamond MS, Schwartz O, Albert ML (April 2012). "Cutting edge: independent roles for IRF-3 and IRF-7 in hematopoietic and nonhematopoietic cells during host response to Chikungunya infection". J. Immunol. 188 (7): 2967–71. doi:10.4049/jimmunol.1103185. PMID 22371392. 
  35. ↑ Akhrymuk I, Kulemzin SV, Frolova EI (July 2012). "Evasion of the innate immune response: the Old World alphavirus nsP2 protein induces rapid degradation of Rpb1, a catalytic subunit of RNA polymerase II". J. Virol. 86 (13): 7180–91. doi:10.1128/JVI.00541-12. PMC 3416352. PMID 22514352. 
  36. ↑ Fros JJ, Liu WJ, Prow NA, et al. (October 2010). "Chikungunya virus nonstructural protein 2 inhibits type I/II interferon-stimulated JAK-STAT signaling". J. Virol. 84 (20): 10877–87. doi:10.1128/JVI.00949-10. PMC 2950581. PMID 20686047. 
  37. ↑ 37.0 37.1 37.2 "Laboratory Diagnosis of Chikungunya Fevers". World Health Organization. Archived from the original on September 8, 2012. Retrieved May 20, 2013. 
  38. ↑ Edelman R, Tacket CO, Wasserman SS, Bodison SA, Perry JG, Mangiafico JA (June 2000). "Phase II safety and immunogenicity study of live chikungunya virus vaccine TSI-GSD-218". Am. J. Trop. Med. Hyg. 62 (6): 681–5. PMID 11304054. 
  39. ↑ Gorchakov, R; Wang, E; Leal, G; Forrester, NL; Plante, K; Rossi, SL; Partidos, CD; Adams, AP; Seymour, RL; Weger, J; Borland, EM; Sherman, MB; Powers, AM; Osorio, JE; Weaver, SC (Jun 2012). "Attenuation of Chikungunya virus vaccine strain 181/clone 25 is determined by two amino acid substitutions in the E2 envelope glycoprotein.". Journal of Virology 86 (11): 6084–96. doi:10.1128/JVI.06449-11. PMID 22457519. 
  40. ↑ Plante, K; Wang, E; Partidos, CD; Weger, J; Gorchakov, R; Tsetsarkin, K; Borland, EM; Powers, AM; Seymour, R; Stinchcomb, DT; Osorio, JE; Frolov, I; Weaver, SC (Jul 2011). "Novel chikungunya vaccine candidate with an IRES-based attenuation and host range alteration mechanism.". PLoS Pathogens 7 (7): e1002142. doi:10.1371/journal.ppat.1002142. PMID 21829348. 
  41. ↑ Hallengärd, D; Kakoulidou, M; Lulla, A; Kümmerer, BM; Johansson, DX; Mutso, M; Lulla, V; Fazakerley, JK; Roques, P; Le Grand, R; Merits, A; Liljeström, P (Dec 26, 2013). "Novel attenuated Chikungunya vaccine candidates elicit protective immunity in C57BL/6 mice.". Journal of Virology. doi:10.1128/JVI.03453-13. PMID 24371047. 
  42. ↑ "Chikungunya—Fact sheet". European Centre for Disease Prevention and Control (ECDC). Retrieved 2013-12-17. 
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