Submitted Successfully!
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Ver. Summary Created by Modification Content Size Created at Operation
1 -- 1446 2022-12-08 14:34:25 |
2 format corrected. + 1 word(s) 1447 2022-12-09 04:58:05 |

Video Upload Options

Do you have a full video?


Are you sure to Delete?
If you have any further questions, please contact Encyclopedia Editorial Office.
Arruda, L.V.;  Salomão, N.G.;  Alves, F.D.A.V.;  Rabelo, K. Transmission and Clinical Manifestations of Zika. Encyclopedia. Available online: (accessed on 07 December 2023).
Arruda LV,  Salomão NG,  Alves FDAV,  Rabelo K. Transmission and Clinical Manifestations of Zika. Encyclopedia. Available at: Accessed December 07, 2023.
Arruda, Laíza Vianna, Natália Gedeão Salomão, Felipe De Andrade Vieira Alves, Kíssila Rabelo. "Transmission and Clinical Manifestations of Zika" Encyclopedia, (accessed December 07, 2023).
Arruda, L.V.,  Salomão, N.G.,  Alves, F.D.A.V., & Rabelo, K.(2022, December 08). Transmission and Clinical Manifestations of Zika. In Encyclopedia.
Arruda, Laíza Vianna, et al. "Transmission and Clinical Manifestations of Zika." Encyclopedia. Web. 08 December, 2022.
Transmission and Clinical Manifestations of Zika

Zika virus (ZIKV) is an arthropod-borne virus that belongs to the Flaviviridae family, genus Flavivirus and was first isolated 1947 in Uganda, Africa, from the serum of a sentinel Rhesus monkey. Since its discovery, the virus was responsible for major outbreaks in several different countries, being linked to severe complications in pregnant women, neonatal birth defects and the congenital zika syndrome. Maternal–fetal transmission of ZIKV can occur in all trimesters of pregnancy, and the role of the placenta and its cells in these cases is yet to be fully understood. The decidua basalis and chorionic villi, maternal–fetal components of the placenta, contain a rich immunological infiltrate composed by Hofbauer cells, mastocytes, dendritic cells and macrophages, primary cells of the innate immune response that have a role that still needs to be better investigated in ZIKV infection. 

Zika virus placenta immune response innate immunity

1. Introduction

Zika fever is an arbovirus transmitted mainly by mosquitoes of the Aedes genus (Stegomyia subgenus). The zika virus (ZIKV) was discovered in Africa in 1947 from the blood of Rhesus monkeys inhabiting the zika forest [1][2] and was first detected in humans in Asia in 1966, but its potential impact on public health was not recognized until the virus caused outbreaks in the Pacific from 2007 to 2015, the year it began to spread across America [3][4]. In 2019, autochthonous transmission of ZIKV was confirmed in 87 countries or territories in the Americas [4]. Large outbreaks have clearly occurred in many countries and territories due to the introduction of the virus into immunologically virgin populations and with a widespread presence of vectors. Overall, by region, South America represented 70% of reported cases, the Caribbean 21%, Central America 9% and North America 1%. The highest number of suspected and confirmed cases was reported in Brazil (346,475 cases, 46%) followed by Colombia (107,206, 14%) and Venezuela (62,200; 8%) [5]. ZIKV transmission has significantly declined in the Americas since late 2016; fewer than 30,000 cases were reported in 2018, compared with the more than 500,000 cases reported at the height of the pandemic in 2016 [6].
In 2015, Brazil recorded the first outbreak of ZIKV infection, with cases initially reported in the northeast region [7] but rapidly spreading throughout the country. Some studies with retrospective phylogenetic analysis suggest that the introduction of the virus into Brazil may have occurred in 2013 [6][8][9]. Zika fever is a compulsory notification disease and in 2016, 216,207 cases were reported in Brazil, with 8 laboratory-confirmed deaths. More recent data from Brazil’s Ministry of Health show that there has been variation in the numbers of cases and deaths/year, with 17,594 probable cases reported in 2017 with 8 deaths, 8680 cases in 2018 with 5 deaths, and 10,768 cases in 2019 with 3 deaths [10][11]. During this year, zika cases increased in Brazil, with 9916 probable cases until week 32, corresponding to an incidence rate of 4.6 cases per 100,000 inhabitants in the country. Compared with 2019, there was a 21.1% increase in the number of cases and compared to the year 2021, an increase of 98.8% is observed. However, deaths by zika were not reported in the country until the respective week of the year 2022 [10]. This increase in cases among the different arboviruses is seasonal and predicted by epidemiologists, so it is necessary to monitor the number of zika cases and the progress of studies in this area in order for the scientific community to be prepared to deal with outbreaks, epidemics, and their consequences.
Because of the large number of zika cases in Brazil in 2015, it was declared a Public Health Emergency of National Importance [12], and in February 2016, the World Health Organization (WHO) declared it a Public Health Emergency of International Importance [13]. Along with the cases of zika, there have been alarming reports of microcephaly cases associated with the infection [14], which was observed as one of the signs of a new congenital disease resulting from ZIKV infection during pregnancy and was named congenital zika syndrome (CZS). CZS is characterized by a set of congenital, structural and functional anomalies, with repercussions for the growth and development of fetuses exposed to the virus during pregnancy [15]. Because of the many cases of microcephaly and later, the perception of congenital zika syndrome, the studies about this disease intensified. From 2015 to date, 3707 cases of birth defects associated with ZIKV infection have been reported in Brazil and a slightly higher number in America [4][16].

2. The Zika Virus

Few studies have reported the evolutionary biology of ZIKV [17][18][19], but such studies describe three main lineages of ZIKV, one from Asia and two from Africa. The etiologic agent of this disease is zika virus, belonging to the genus Flavivirus, which is approximately 25–50 nm in size and shares the same family (Flaviviridae) as other widely known viruses, such as dengue, West Nile, Japanese encephalitis virus, and yellow fever virus [17][20][21]. Flaviviruses are icosahedral viruses formed by an envelope composed of a lipid bilayer in which the envelope (E) and membrane (M) proteins are inserted. In the inner portion of the viral envelope, there is a nucleocapsid composed of multiple molecules of the capsid protein (C) complexed to the viral genome, a single-stranded RNA molecule with positive polarity [22].
The virus genome is approximately 11 kb in length and has the cap structure at its 5′ end, being devoid of a poly-A tail at the 3′ end, and comprises a single open reading frame encoding a polyprotein precursor to flavivirus proteins. This polyprotein is initially anchored to the endoplasmic reticulum via transmembrane helices that cross the membrane, and is subsequently cleaved by cellular proteases and the viral protease (NS3/2B protein), generating three structural proteins, capsid, premembrane and envelope, and seven nonstructural proteins, NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5. Proteins C, prM and E are incorporated into the viral particles during their maturation, while the non-structural proteins are involved in the replication and/or assembly of the virions. The 3′ and 5′ non-coding regions (3′UTR and 5′UTR) are also important for viral replication [22][23].

3. Zika, Transmission and Clinical Manifestations

In general, most individuals are asymptomatic or develop mild clinical disease [24], which has as classic symptoms headache, fever, myalgia, exanthema, arthralgia and conjunctivitis [4][24][25][26][27].
As with other arboviruses such as dengue (DENV) and chikungunya (CHIKV), ZIKV is transmitted mainly by vectors: Aedes aegypti and Aedes albopictus [28]. However, transmission of ZIKV can occur through different routes, including sexual transmission, with the presence of virus being detected in semen [29] and in uterine cells [30], evidencing that the virus can be transmitted between both sexes, although women are more susceptible [31].
In addition, the virus has been detected in the blood of infected patients, and its transmission has even been reported in platelet transfusions [32]. Transmission via breast milk can also occur since the presence of ZIKV in breast milk has already been studied and described in some studies, however none of them confirmed transmission [33].
During the 2015 epidemic, the possibility of the vertical transmission of the Zika virus was confirmed, being associated with CZS [34][35][36] Maternal–fetal transmission of ZIKV can occur in all trimesters of pregnancy, whether the infection in the mother is symptomatic or asymptomatic [4]. The way in which ZIKV crosses the placental barrier and infects the fetus has not been fully understood. The mechanisms by which viruses can be transmitted vertically are multifaceted and may involve direct hematogenous, transcellular trophoblastic, or paracellular pathways, in addition to transport within immune cells [37]. The multiplication of Hofbauer cells during placental inflammation caused by the infection is believed to facilitate vertical transmission [38][39]. Some studies have identified the ZIKV genome in the amniotic fluid, intervillar space, decidual and chorionic villi of the placenta, in addition to fetal tissues, including the brain [40][41].
In addition, Zika virus infection in pregnant women is also associated with adverse pregnancy outcomes including miscarriage, intrauterine growth restriction, perinatal death, and others [42][43]. As a result, Zika fever is now part of a group of tropical diseases that disproportionately affects maternal, fetal and reproductive health [38].
It has been found that Zika virus infection in pregnant women can cause a spectrum of congenital malformations that include: microcephaly (which determines incomplete brain development and reduced head size), severe global hypertonia, hyperexcitability, ocular changes, facial disproportion, and congenital contractures [34][36][44]. These congenital malformations are associated with disruption in fetal brain development during pregnancy, and may involve a disorder of neuronal and glial migration [4][39]. The researchers' group conducted a study in which they observed histopathological changes, detection of the virus, and evidence of replication in all organs of the stillborn that were analyzed [45]. To date, studies that follow the development of children with congenital Zika syndrome are scarce and, therefore, the long-term effects of this condition remain unknown.
Another serious complication related to Zika virus infection in adults is the occurrence of Guillain-Barré syndrome—an autoimmune disease in which the immune system attacks part of the peripheral nervous system [46]. The pathogenesis of Guillain-Barré syndrome associated with Zika virus is not has been fully elucidated and may involve: direct neuropathogenic mechanisms, hyperacute immune response, and immune dysregulation [45][47][48].


  1. Dick, G.W.A. Zika Virus (I). Isolations and Serological Specificity. Trans. R. Soc. Trop. Med. Hyg. 1952, 46, 509–520.
  2. McCrae, A.W.R.; Kirya, B.G. Yellow Fever and Zika Virus Epizootics and Enzootics in Uganda. Trans. R. Soc. Trop. Med. Hyg. 1982, 76, 552–562.
  3. Longo, D.L.; Musso, D.; Ko, A.I.; Baud, D. Zika Virus Infection—After the Pandemic. N. Engl. J. Med. 2019, 381, 1444–1457.
  4. Rasmussen, S.A.; Jamieson, D.J.; Honein, M.A.; Petersen, L.R. Zika Virus and Birth Defects—Reviewing the Evidence for Causality. N. Engl. J. Med. 2016, 374, 1981–1987.
  5. Hills, S.L.; Fischer, M.; Petersen, L.R. Epidemiology of Zika Virus Infection. J. Infect. Dis. 2017, 216, S868–S874.
  6. Villinger, F.; de Noronha, L.; Nunes Duarte dos Santos, C.; Ld, N.; Zanluca, C.; Burger, M.; Akemi Suzukawa, A.; Azevedo, M.; Rebutini, P.Z.; Maria Novadzki, I.; et al. Zika Virus Infection at Different Pregnancy Stages: Anatomopathological Findings, Target Cells and Viral Persistence in Placental Tissues. Front. Microbiol. 2018, 9, 2266.
  7. Faria, N.R.; Quick, J.; Claro, I.M.; Thézé, J.; de Jesus, J.G.; Giovanetti, M.; Kraemer, M.U.G.; Hill, S.C.; Black, A.; da Costa, A.C.; et al. Establishment and Cryptic Transmission of Zika Virus in Brazil and the Americas. Nature 2017, 546, 406–410.
  8. Zanluca, C.; de Melo, V.C.A.; Mosimann, A.L.P.; dos Santos, G.I.V.; dos Santos, C.N.D.; Luz, K. First Report of Autochthonous Transmission of Zika Virus in Brazil. Mem. Inst. Oswaldo Cruz 2015, 110, 569–572.
  9. BRAZIL. Brazil’s Ministry of Health. Health Surveillance Department. Monitoring of Arbovirus Cases until Epidemiological Week 35 of 2022. Epidemiological Bulletin. ISSN 9352–7864. Vol 53, No.34.2022. Available online:,per%C3%ADodo%20analisado%20(Figura%201) (accessed on 9 September 2021).
  10. BRAZIL. Brazil’s Ministry of Health. Health Surveillance Department. Monitoring of Arbovirus Cases until Epidemiological Week 1–51 of 2021. Vol 52—No. 48. 2021. Available online: (accessed on 9 September 2021).
  11. Brazil’s Ministry of Health Brazil. Ministry of Health. Secretary of Health Surveillance. Portaria n.° 1.813, 11 November 2015. Available online: (accessed on 9 September 2021).
  12. World Health Organization. WHO Statement on the First Meeting of the International Health Regulations (2005) (IHR 2005) Emergency Committee on Zika Virus and Observed Increase in Neurological Disorders and Neonatal Malformations. 2016. Available online: (accessed on 9 September 2021).
  13. Dyer Montreal, O. Zika Virus Spreads across Americas as Concerns Mount over Birth Defects. BMJ 2015, 351, h6983.
  14. del Campo, M.; Feitosa, I.M.L.; Ribeiro, E.M.; Horovitz, D.D.G.; Pessoa, A.L.S.; França, G.V.A.; García-Alix, A.; Doriqui, M.J.R.; Wanderley, H.Y.C.; Sanseverino, M.V.T.; et al. The Phenotypic Spectrum of Congenital Zika Syndrome. Am. J. Med. Genet. A 2017, 173, 841–857.
  15. Brazil’s Ministry of Health. Epidemiological Situation of Congenital Syndrome Associated with Zika Virus Infection: Brazil, 2015 to 2022, by SE 31. Epidemiological Bulletin. Vol 53, No. 35. 2022. Available online:–2022.pdf (accessed on 9 September 2021).
  16. Faye, O.; Freire, C.C.M.; Iamarino, A.; Faye, O.; de Oliveira, J.V.C.; Diallo, M.; Zanotto, P.M.A.; Sall, A.A. Molecular Evolution of Zika Virus during Its Emergence in the 20th Century. PLoS Negl. Trop. Dis. 2014, 8, e2636.
  17. Lanciotti, R.S.; Kosoy, O.L.; Laven, J.J.; Velez, J.O.; Lambert, A.J.; Johnson, A.J.; Stanfield, S.M.; Duffy, M.R. Genetic and Serologic Properties of Zika Virus Associated with an Epidemic, Yap State, Micronesia, 2007. Emerg. Infect. Dis. 2008, 14, 1232–1239.
  18. Haddow, A.D.; Schuh, A.J.; Yasuda, C.Y.; Kasper, M.R.; Heang, V.; Huy, R.; Guzman, H.; Tesh, R.B.; Weaver, S.C. Genetic Characterization of Zika Virus Strains: Geographic Expansion of the Asian Lineage. PLoS Negl. Trop. Dis. 2012, 6, e1477.
  19. Hayes, E.B. Zika Virus outside Africa. Emerg. Infect. Dis. 2009, 15, 1347–1350.
  20. Sharma, A.; Gupta, S.P. Fundamentals of Viruses and Their Proteases. In Viral Proteases and Their Inhibitors; Elsevier: Amsterdam, The Netherlands, 2017; pp. 1–24. ISBN 9780128097120.
  21. Sevvana, M.; Rogers, T.F.; Miller, A.S.; Long, F.; Klose, T.; Beutler, N.; Lai, Y.C.; Parren, M.; Walker, L.M.; Buda, G.; et al. Structural Basis of Zika Virus Specific Neutralization in Subsequent Flavivirus Infections. Viruses 2020, 12, 1346.
  22. Chambers, T.J.; Hahn, C.S.; Galler, R.; Rice, C.M. Flavivirus Genome Organization, Expression and Replication. Rev. Microbiol. 1990, 44, 649–688.
  23. Filgueirasid, I.S.; Torrentes de Carvalho, A.; Cunha, D.P.; Mathias da Fonseca, D.L.; el Khawanky, N.; Freire, P.P.; Cabral-Miranda, G.; Schimke, L.F.; Camara, N.O.S.; Ochs, H.D.; et al. The Clinical Spectrum and Immunopathological Mechanisms Underlying Zikv-Induced Neurological Manifestations. PLoS Negl. Trop. Dis. 2021, 15, e0009575.
  24. Badolato-Corr, J.; Camilo anchez-Arcila, J.S.; Manuele Alves de Souza, T.; Santos Barbosa, L.; Conrado Guerra Nunes, P.; da Rocha Queiroz Lima, M.; Gandini, M.; Maria Bispo de Filippis, A.; Ven, R.; da Cunha, A.; et al. Human T Cell Responses to Dengue and Zika Virus Infection Compared to Dengue/Zika Coinfection. Immun. Inflamm. Dis. 2018, 6, 194–206.
  25. Grard, G.; Caron, L.; Mombo, I.M.; Nkoghe, D.; Ondo, S.M.; Jiolle, D.; Fontenille, D.; Paupy, C.; Leroy, E.M. Zika Virus in Gabon (Central Africa)-2007: A New Threat from Aedes Albopictus? PLoS Negl. Trop. Dis. 2014, 8, e2681.
  26. Gatherer, D.; Kohl, A. Zika Virus: A Previously Slow Pandemic Spreads Rapidly through the Americas. J. Gen. Virol. 2016, 97, 269–273.
  27. Lazear, H.M.; Diamond, M.S. Zika Virus: New Clinical Syndromes and Its Emergence in the Western Hemisphere. J. Virol. 2016, 90, 4864–4875.
  28. Baud, D.; Gubler, D.J.; Schaub, B.; Lanteri, M.C.; Musso, D. An Update on Zika Virus Infection. Lancet 2017, 390, 2099–2109.
  29. Baud, D.; Musso, D.; Vouga, M.; Alves, M.P.; Vulliemoz, N. Zika Virus: A New Threat to Human Reproduction. Am. J. Reprod. Immunol. 2017, 77, e12614.
  30. Pielnaa, P.; Al-Saadawe, M.; Saro, A.; Dama, M.F.; Zhou, M.; Huang, Y.; Huang, J.; Xia, Z. Zika Virus-Spread, Epidemiology, Genome, Transmission Cycle, Clinical Manifestation, Associated Challenges, Vaccine and Antiviral Drug Development. Virology 2020, 543, 34–42.
  31. Kuck, K.-H.; Brugada, J.; Albenque, J.P. Evidence for Transmission of Zika Virus by Platelet Transfusion. N. Engl. J. Med. 2016, 375, 1099–1101.
  32. Colt, S.; Garcia-Casal, M.N.; Peña-Rosas, J.P.; Finkelstein, J.L.; Rayco-Solon, P.; Weise Prinzo, Z.C.; Mehta, S. Transmission of Zika Virus through Breast Milk and Other Breastfeeding-Related Bodily-Fluids: A Systematic Review. PLoS Negl. Trop. Dis. 2017, 11, e0005528.
  33. Costa, F.; Sarno, M.; Khouri, R.; de Paula Freitas, B.; Siqueira, I.; Ribeiro, G.S.; Ribeiro, H.C.; Campos, G.S.; Alcântara, L.C.; Reis, M.G.; et al. Emergence of Congenital Zika Syndrome: Viewpoint from the Front Lines HHS Public Access. Ann. Intern. Med. 2016, 164, 689–691.
  34. de Barros Miranda-Filho, D.; Turchi Martelli, C.M.; Arraes De Alencar Ximenes, R.; Velho, T.; Araújo, B.; Angela, M.; Rocha, W.; Coeli, R.; Ramos, F.; Dhalia, R.; et al. Initial Description of the Presumed Congenital Zika Syndrome. Public Health 2016, 106, 598–600.
  35. Victora, C.G.; Schuler-Faccini, L.; Matijasevich, A.; Ribeiro, E.; Pessoa, A.; Barros, F.C. Microcephaly in Brazil: How to Interpret Reported Numbers? Lancet 2016, 387, 621–624.
  36. Bayer, A.; Lennemann, N.J.; Ouyang, Y.; Bramley, J.C.; Morosky, S.; Marques, E.T.D.A.; Cherry, S.; Sadovsky, Y.; Coyne, C.B. Type III Interferons Produced by Human Placental Trophoblasts Confer Protection against Zika Virus Infection. Cell Host Microbe 2016, 19, 705–712.
  37. Marbán-Castro, E.; Goncé, A.; Fumadó, V.; Romero-Acevedo, L.; Bardají, A. Zika Virus Infection in Pregnant Women and Their Children: A Review. Eur. J. Obstet. Gynecol. Reprod. Biol. 2021, 265, 162–168.
  38. Zimmerman, M.G.; Quicke, K.M.; O’Neal, J.T.; Arora, N.; Machiah, D.; Priyamvada, L.; Kauffman, R.C.; Register, E.; Adekunle, O.; Swieboda, D.; et al. Cross-Reactive Dengue Virus Antibodies Augment Zika Virus Infection of Human Placental Macrophages. Cell Host Microbe 2018, 24, 731–742.e6.
  39. Driggers, R.W.; Ho, C.-Y.; Korhonen, E.M.; Kuivanen, S.; Jaaskelainen, A.J.; Smura, T.; Rosenberg, A.; Hill, D.A.; DeBiasi, R.L.; Vezina, G.; et al. Zika Virus Infection with Prolonged Maternal Viremia and Fetal Brain Abnormalities. N. Engl. J. Med. 2016, 374, 2142–2151.
  40. Calvet, G.; Aguiar, R.S.; Melo, A.S.O.; Sampaio, S.A.; de Filippis, I.; Fabri, A.; Araujo, E.S.M.; de Sequeira, P.C.; de Mendonça, M.C.L.; de Oliveira, L.; et al. Detection and Sequencing of Zika Virus from Amniotic Fluid of Fetuses with Microcephaly in Brazil: A Case Study. Lancet Infect. Dis. 2016, 16, 653–660.
  41. Brasil, P.; Pereira, J.P., Jr.; Moreira, M.E.; Ribeiro Nogueira, R.M.; Damasceno, L.; Wakimoto, M.; Rabello, R.S.; Valderramos, S.G.; Halai, U.A.; Salles, T.S.; et al. Zika Virus Infection in Pregnant Women in Rio de Janeiro. N. Engl. J. Med. 2016, 375, 2321–2334.
  42. Sisman, J.; Jaleel, M.A.; Moreno, W.; Rajaram, V.; Collins, R.R.J.; Savani, R.C.; Rakheja, D.; Evans, A.S. Intrauterine Transmission of SARS-COV-2 Infection in a Preterm Infant. Pediatr. Infect. Dis. J. 2020, 265–267.
  43. Rice, M.E.; Galang, R.R.; Roth, N.M.; Ellington, S.R.; Moore, C.A.; Valencia-Prado, M.; Ellis, E.M.; John Tufa, A.; Taulung, L.A.; Alfred, J.M.; et al. Morbidity and Mortality Weekly Report Vital Signs: Zika-Associated Birth Defects and Neurodevelopmental Abnormalities Possibly Associated with Congenital Zika Virus Infection-U.S. Territories and Freely Associated States, 2018. Morb. Mortal. Wkly. Rep. 2018, 67, 858.
  44. Rabelo, K.; Souza, L.J.; Salomão, N.G.; Oliveira, E.R.A.; Sentinelli, L.d.P.; Lacerda, M.S.; Saraquino, P.B.; Rosman, F.C.; Basílio-de-Oliveira, R.; Carvalho, J.J.; et al. Placental Inflammation and Fetal Injury in a Rare Zika Case Associated with Guillain-Barré Syndrome and Abortion. Front. Microbiol. 2018, 9, 1018.
  45. Song, B.H.; Yun, S.I.; Woolley, M.; Lee, Y.M. Zika Virus: History, Epidemiology, Transmission, and Clinical Presentation. J. Neuroimmunol. 2017, 308, 50–64.
  46. Grosmark, A.D.; Mizuseki, K.; Pastalkova, E.; Diba, K.; Buzsáki, G. Zika Virus Impairs Growth in Human Neurospheres and Brain Organoids. Electroencephalogr. Clin. Neurophysiol. 2004, 44, 1301–1315.
  47. Uncini, A.; Shahrizaila, N.; Kuwabara, S. Zika Virus Infection and Guillain-Barré Syndrome: A Review Focused on Clinical and Electrophysiological Subtypes. J. Neurol. Neurosurg. Psychiatry 2017, 88, 266–271.
  48. Simmons, D.G.; Fortier, A.L.; Cross, J.C. Diverse Subtypes and Developmental Origins of Trophoblast Giant Cells in the Mouse Placenta. Dev. Biol. 2007, 304, 567–578.
Subjects: Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to : , , ,
View Times: 235
Revisions: 2 times (View History)
Update Date: 09 Dec 2022