Dengue vaccine

Dengue vaccine is a vaccine used to prevent dengue fever in humans.[8] Development of dengue vaccines began in the 1920s, but was hindered by the need to create immunity against all four dengue serotypes.[9] As of 2023, there are two commercially available vaccines, sold under the brand names Dengvaxia and Qdenga.[10]

Dengue vaccine
Vaccine description
TargetDengue fever
Vaccine typeAttenuated
Clinical data
Trade namesDengvaxia, Qdenga
Other namesCYD-TDV
AHFS/Drugs.comMonograph
License data
Routes of
administration
Subcutaneous
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)[1][2]
  • BR: Approved[3]
  • UK: POM (Prescription only)[4]
  • US: Rx-only (Dengvaxia)[5]
  • EU: Rx-only[6][7]
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
DrugBank
ChemSpider
  • none

Dengvaxia is only recommended in those who have previously had dengue fever or populations in which most people have been previously infected.[10] The value of Dengavaxia is limited by the fact that it may increase the risk of severe dengue in those who have not previously been infected.[11][10] In 2017, more than 733,000 children and more than 50,000 adult volunteers were vaccinated with Dengvaxia regardless of serostatus, which led to a controversy.[12] Qdenga is designated for people not previously infected.[13]

There are other vaccine candidates in development including live attenuated, inactivated, DNA and subunit vaccines.[9]

History

In December 2018, Dengvaxia was approved in the European Union.[6]

In May 2019, Dengvaxia was approved in the United States as the first vaccine approved for the prevention of dengue disease caused by all dengue virus serotypes (1, 2, 3 and 4) in people ages nine through 16 who have laboratory-confirmed previous dengue infection and who live in endemic areas.[14][5] Dengue is endemic in the US territories of American Samoa, Guam, Puerto Rico, and the US Virgin Islands.[14]

The safety and effectiveness of the vaccine was determined in three randomized, placebo-controlled studies involving approximately 35,000 individuals in dengue-endemic areas, including Puerto Rico, Latin America and the Asia Pacific region.[14] The vaccine was determined to be approximately 76 percent effective in preventing symptomatic, laboratory-confirmed dengue disease in individuals 9 through 16 years of age who previously had laboratory-confirmed dengue disease.[14]

In March 2021, the European Medicines Agency the filing package for TAK-003 (Qdenga) intended for markets outside of the EU.[13]

In August 2022, the Indonesian FDA approved Qdenga for use in individuals six years to 45 years of age and become the first authority in the world to approve Qdenga.[15][16] Qdenga was approved in the European Union in December 2022.[7]

CYD-TDV (Dengvaxia)

CYD-TDV, sold under the brand name Dengvaxia and made by Sanofi Pasteur, is a live attenuated tetravalent vaccine that is administered as three separate injections, with the initial dose followed by two additional shots given six and twelve months later.[14] The US Food and Drug Administration (FDA) granted the application for Dengvaxia priority review designation and a tropical disease priority review voucher.[14] The approval of Dengvaxia was granted to Sanofi Pasteur.[14]

The vaccine has been approved in 19 countries and the European Union,[14] but it is not approved in the US for use in individuals not previously infected by any dengue virus serotype or for whom this information is unknown.[14][5]

Dengvaxia is a chimeric vaccine made using recombinant DNA technology by replacing the PrM (pre-membrane) and E (envelope) structural genes of the yellow fever attenuated 17D strain vaccine with those from the four dengue serotypes.[17][18] Evidence indicates that CYD-TDV is partially effective in preventing infection, but may lead to a higher risk of severe disease in those who have not been previously infected and then do go on to contract the disease. It is not clear why the vaccinated seronegative population have more serious adverse outcomes. A plausible hypothesis is the phenomenon of antibody-dependent enhancement (ADE).[19] American virologist Scott Halstead was one of the first researchers to identify the ADE phenomenon.[20] Dr. Halstead and his colleague Dr. Phillip Russell proposed that the vaccine only be used after antibody testing, to check for prior dengue exposure and avoid vaccination of sero-negative individuals.[21]

Common side effects include headache, pain at the site of injection, and general muscle pains.[8] Severe side effects may include anaphylaxis.[8] Use is not recommended in people with poor immune function.[8] Safety of use during pregnancy is unclear.[8] Dengvaxia is a weakened but live vaccine and works by triggering an immune response against four types of dengue virus.[14][8]

Dengvaxia became commercially available in 2016 in 11 countries: Mexico, the Philippines, Indonesia, Brazil, El Salvador, Costa Rica, Paraguay, Guatemala, Peru, Thailand, and Singapore.[22][23][24] In 2019 it was approved for medical use in the United States.[14][25] It is on the World Health Organization's List of Essential Medicines.[26][27] In Indonesia it costs about US$207 for the recommended three doses as of 2016.[24]

In 2017, the manufacturer recommended that the vaccine only be used in people who have previously had a dengue infection, as outcomes may be worsened in those who have not been previously infected.[28] This led to a controversy in the Philippines where more than 733,000 children and more than 50,000 adult volunteers were vaccinated regardless of serostatus.[12]

The World Health Organization (WHO) recommends that countries should consider vaccination with the dengue vaccine CYD-TDV only if the risk of severe dengue in seronegative individuals can be minimized either through pre-vaccination screening or recent documentation of high seroprevalence rates in the area (at least 80% by age nine years).[10]

The WHO updated its recommendations regarding the use of Dengvaxia in 2018, based on long-term safety data stratified by serostatus on 29 November 2017. Seronegative vaccine recipients have an excess risk of severe dengue compared to unvaccinated seronegative individuals. For every 13 hospitalizations prevented in seropositive vaccinees, there would be 1 excess hospitalization in seronegative vaccinees per 1,000 vaccinees. WHO recommends serological testing for past dengue infection [29]

In 2017, the manufacturer recommended that the vaccine only be used in people who have previously had a dengue infection as otherwise there was evidence it may worsen subsequent infections.[28] The initial protocol did not require baseline blood samples prior to vaccination in order to establish an understanding of increased risk of severe dengue in participants who had not been previously exposed. In November 2017, Sanofi acknowledged that some participants were put at risk of severe dengue if they had no prior exposure to the infection; subsequently the Philippine government suspended the mass immunization program with the backing of the WHO which began a review of the safety data.[30]

Phase III trials in Latin America and Asia involved over 31,000 children between the ages of two and 14 years. In the first reports from the trials, vaccine efficacy was 56.5% in the Asian study and 64.7% in the Latin American study in patients who received at least one injection of the vaccine.[31][32] Efficacy varied by serotype. In both trials vaccine reduced by about 80% the number of severe dengue cases.[33] An analysis of both the Latin American and Asian studies at the 3rd year of follow-up showed that the efficacy of the vaccine was 65.6% in preventing hospitalization in children older than nine years of age, but considerably greater (81.9%) for children who were seropositive (indicating previous dengue infection) at baseline.[34] The vaccination series consists of three injections at 0, 6 and 12 months.[18] The vaccine was approved in Mexico, the Philippines, and Brazil in December 2015, and in El Salvador, Costa Rica, Paraguay, Guatemala, Peru, Indonesia, Thailand, and Singapore in 2016.[22] Under the brand name Dengvaxia, it is approved for use for those aged nine years of age and older and can prevent all four serotypes.[35]

TAK-003 (Qdenga)

TAK-003 or DENVax, sold under the brand name Qdenga and made by Takeda,[15] is a recombinant chimeric attenuated vaccine with DENV1, DENV3, and DENV4 components on a dengue virus type 2 (DENV2) backbone originally developed at Mahidol University in Bangkok and now funded by Inviragen (DENVax) and (TAK-003).[36][37] Phase I and II trials were conducted in the United States, Colombia, Puerto Rico, Singapore and Thailand.[37] Based on the 18-month data published in the journal Lancet Infectious Diseases, indicated that TAK-003 produced sustained antibody responses against all four virus strains, regardless of previous dengue exposure and dosing schedule.[38]

Data from the phase III trial, which began in September 2016, show that TAK-003 was efficacious against symptomatic dengue.[39] TAK-003 appears to not lack efficacy in seronegative people or potentially cause them harm, unlike CYD-TDV. The data appear to show only moderate efficacy in other dengue serotypes than DENV2.[40]

Qdenga received approval for use in the European Union in 2022 for people aged 4 and above,[41][42][43] and is also approved in the United Kingdom, Brazil, Argentina, Indonesia, and Thailand. Takeda voluntarily withdrew their application for the vaccination's approval in the United States in July 2023 after the FDA sought further data from the firm, which the company stated could not be addressed during the current review cycle.[43][44]

In development

TV-003/005

TV-003/005 is a tetravalent admixture of monovalent vaccines, that was developed by NIAID, that were tested separately for safety and immunogenicity. The vaccine passed phase I trials and phase II studies in the US, Thailand, Bangladesh, India, and Brazil.[45]

NIH has conducted phase I and phase II studies in over 1,000 participants in the US. It has also conducted human challenge studies[46] while having conducted NHP model studies successfully.[47]

NIH has licensed their technology for further development and commercial scale manufacturing to Panacea Biotec,[48] Serum Institute of India,[48] Instituto Butantan,[48] Vabiotech,[48] Merck,[49] and Medigen.[50]

In Brazil, phase III studies are being conducted by Instituto Butantan in-collaboration with NIH. Panacea Biotec has conducted phase II clinical studies in India.[51]

A company in Vietnam (Vabiotech) is conducting safety tests and developing a clinical trial plan.[52] All four companies are involved in studies of a TetraVax-DV vaccine in conjunction with the US National Institutes of Health.[53]

TDENV PIV

TDENV PIV (tetravalent dengue virus purified inactivated vaccine) is undergoing phase I trials as part of a collaboration between GlaxoSmithKline (GSK) and the Walter Reed Army Institute of Research (WRAIR). A synergistic formulation with another live attenuated candidate vaccine (prime-boost strategy) is also being evaluated in a phase II study. In prime-boosting, one type of vaccine is followed by a boost with another type in an attempt to improve immunogenicity.[9]

V180

Merck is studying recombinant subunit vaccines expressed in Drosophila cells. As of 2019, it had completed phase I stage and V180 formulations found to be generally well tolerated.[54]

DNA vaccines

In 2011, the Naval Medical Research Center attempted to develop a monovalent DNA plasmid vaccine, but early results showed it to be only moderately immunogenic.[37]

Society and culture

On 13 October 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Qdenga, intended for prophylaxis against dengue disease.[55][42] The applicant for this medicinal product is Takeda GmbH.[42] The active substance of Qdenga is dengue tetravalent vaccine (live, attenuated), a viral vaccine containing live attenuated dengue viruses which replicate locally and elicit humoral and cellular immune responses against the four dengue virus serotypes.[42] Qdenga was approved for medical use in the European Union in December 2022.[7][56][57]

In February 2023, Qdenga was approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for people aged four years and older.[58]

In July 2023, Takeda withdrew its application for Qdenga before the FDA, citing the FDA's requirement for additional data not captured in the phase III studies.[43][44]

Economics

In Indonesia, Dengvaxia cost about US$207 for the recommended three doses as of 2016.[24] Indonesia was the first country to approve Qdenga, in late 2022.[59]

Philippines

The 2017 dengue vaccine controversy in the Philippines involved a vaccination program run by the Philippines Department of Health (DOH).[23] The DOH vaccinated schoolchildren with Sanofi Pasteur's CYD-TDV (Dengvaxia) dengue vaccine. Some of the children who received the vaccine had never been infected by the dengue virus before. The program was stopped when Sanofi Pasteur advised the government that the vaccine could put previously uninfected people at a somewhat higher risk of a severe case of dengue fever.[28] A political controversy erupted over whether the program was run with sufficient care and who should be held responsible for the alleged harm to the vaccinated children.[30]

References

  1. "Dengvaxia dengue tetravalent vaccine (live, attenuated), powder and diluent for suspension for injection (275964)". Therapeutic Goods Administration (TGA). 26 May 2022. Retrieved 9 April 2023.
  2. "Prescription medicines: registration of new chemical entities in Australia, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 9 April 2023.
  3. "Vacina contra a dengue: aplicação começa nesta semana em clínicas particulares" [Dengue vaccine: administration starts this week in private clinics]. CNN Brazil (in Portuguese). 26 June 2023. Retrieved 29 June 2023.
  4. "Qdenga powder and solvent for solution for injection in pre-filled syringe - Summary of Product Characteristics (SmPC)". (emc). 22 March 2023. Retrieved 9 April 2023.
  5. "Dengvaxia- dengue tetravalent vaccine, live kit". DailyMed. 9 August 2019. Retrieved 17 May 2020.
  6. "Dengvaxia EPAR". European Medicines Agency (EMA). 23 October 2019. Archived from the original on 6 December 2019. Retrieved 6 December 2019.
  7. "Qdenga EPAR". European Medicines Agency (EMA). 16 December 2022. Retrieved 28 December 2022.
  8. "Dengue Vaccine Live Monograph for Professionals". Drugs.com. 23 August 2023. Retrieved 14 November 2019.
  9. McArthur MA, Sztein MB, Edelman R (August 2013). "Dengue vaccines: recent developments, ongoing challenges and current candidates". Expert Review of Vaccines. 12 (8): 933–953. doi:10.1586/14760584.2013.815412. PMC 3773977. PMID 23984962.
  10. World Health Organization (September 2018). "Dengue vaccine: WHO position paper – September 2018". Weekly Epidemiological Record. 93 (36): 457–76. hdl:10665/274316.
  11. Redoni M, Yacoub S, Rivino L, Giacobbe DR, Luzzati R, Di Bella S (July 2020). "Dengue: Status of current and under-development vaccines". Reviews in Medical Virology. 30 (4): e2101. doi:10.1002/rmv.2101. hdl:1983/6d38d9b6-8e1b-4a84-85e3-edab4fc41957. PMID 32101634. S2CID 211536962.
  12. Lopez V (4 December 2017). "DOJ orders NBI to investigate P3.5-B dengue vaccine scandal". STAT. Retrieved 14 December 2017.
  13. "Takeda Begins Regulatory Submissions for Dengue Vaccine Candidate in EU and Dengue-Endemic Countries" (Press release). Takeda Pharmaceutical Company Limited. 25 March 2021. Retrieved 28 March 2021.
  14. "First FDA-approved vaccine for the prevention of dengue disease in endemic regions". U.S. Food and Drug Administration (FDA) (Press release). 1 May 2019. Archived from the original on 6 December 2019. Retrieved 14 November 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  15. "Takeda's Qdenga (Dengue Tetravalent Vaccine [Live, Attenuated]) Approved in Indonesia for Use Regardless of Prior Dengue Exposure" (Press release). Takeda. 22 August 2022. Retrieved 25 November 2022.
  16. Becker Z (22 August 2022). "Takeda's dengue fever vaccine picks up first global nod in Indonesia". Fierce Pharma. Retrieved 25 November 2022.
  17. Thisyakorn U, Thisyakorn C (January 2014). "Latest developments and future directions in dengue vaccines". Therapeutic Advances in Vaccines. 2 (1): 3–9. doi:10.1177/2051013613507862. PMC 3991153. PMID 24757522.
  18. Yauch LE, Shresta S (2014). "Dengue virus vaccine development". Advances in Virus Research. 88: 315–372. doi:10.1016/B978-0-12-800098-4.00007-6. ISBN 9780128000984. PMID 24373316.
  19. "Caution on new dengue vaccine: In some countries, harm outweighs benefit". STAT. 1 September 2016. Retrieved 13 August 2017.
  20. "Dengue Vaccine Maker Struggles to Find a Diagnostic That Will Make Its Product Safe to Use". Scientific American. 17 June 2018. Retrieved 20 September 2020.
  21. "Sanofi restricts dengue vaccine but downplays antibody enhancement". CIDRAP. 1 December 2017. Retrieved 20 September 2020.
  22. Vidalon D (4 October 2016). "Sanofi's dengue vaccine approved in 11 countries". Reuters. Retrieved 13 August 2017.
  23. East S (6 April 2016). "World's first dengue fever vaccine launched in the Philippines". CNN. Retrieved 17 October 2016.
  24. "Dengue Fever Vaccine Available in Indonesia". 17 October 2016.
  25. "Dengvaxia". U.S. Food and Drug Administration (FDA). 21 May 2019. STN 125682. Archived from the original on 6 December 2019. Retrieved 6 December 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  26. World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  27. World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
  28. "Sanofi restricts dengue vaccine but downplays antibody enhancement". CIDRAP. December 2017. Retrieved 2 December 2017.
  29. "Vaccines and immunization: Dengue". World Health Organization (WHO). Retrieved 5 October 2021.
  30. Steenhuysen J, Hirschler B (12 December 2017). "Did Sanofi, WHO ignore warning signals on dengue vaccine?". Reuters. Retrieved 13 December 2017.
  31. Capeding MR, Tran NH, Hadinegoro SR, Ismail HI, Chotpitayasunondh T, Chua MN, et al. (October 2014). "Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial". Lancet. 384 (9951): 1358–1365. doi:10.1016/s0140-6736(14)61060-6. PMID 25018116. S2CID 42841451.{{cite journal}}: CS1 maint: overridden setting (link)
  32. Villar L, Dayan GH, Arredondo-García JL, Rivera DM, Cunha R, Deseda C, et al. (January 2015). "Efficacy of a tetravalent dengue vaccine in children in Latin America". The New England Journal of Medicine. 372 (2): 113–123. doi:10.1056/nejmoa1411037. PMID 25365753. S2CID 2839926.{{cite journal}}: CS1 maint: overridden setting (link)
  33. "The Lancet: World's Most Advanced Dengue Vaccine Candidate Shows Promise in Phase 3 Trial". Science Newsline medicine. 10 July 2014. Archived from the original on 15 July 2014. Retrieved 13 July 2014.
  34. Hadinegoro SR, Arredondo-García JL, Capeding MR, Deseda C, Chotpitayasunondh T, Dietze R, et al. (September 2015). "Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease". The New England Journal of Medicine. 373 (13): 1195–1206. doi:10.1056/NEJMoa1506223. PMID 26214039.{{cite journal}}: CS1 maint: overridden setting (link)
  35. Palmer, Eric (9 December 2015). "Sanofi gets first approval for long-anticipated vaccine against dengue fever". FiercePharma. Archived from the original on 16 March 2016. Retrieved 10 December 2015.
  36. Osorio JE, Huang CY, Kinney RM, Stinchcomb DT (September 2011). "Development of DENVax: a chimeric dengue-2 PDK-53-based tetravalent vaccine for protection against dengue fever". Vaccine. 29 (42): 7251–7260. doi:10.1016/j.vaccine.2011.07.020. PMC 4592106. PMID 21777638.
  37. Schwartz LM, Halloran ME, Durbin AP, Longini IM (June 2015). "The dengue vaccine pipeline: Implications for the future of dengue control". Vaccine. 33 (29): 3293–3298. doi:10.1016/j.vaccine.2015.05.010. PMC 4470297. PMID 25989449.
  38. Liu A (7 November 2017). "With interim phase 2 data, Takeda's dengue vaccine casts shadow on Sanofi". Reuters. Retrieved 18 February 2018.
  39. Biswal S, Reynales H, Saez-Llorens X, Lopez P, Borja-Tabora C, Kosalaraksa P, et al. (November 2019). "Efficacy of a Tetravalent Dengue Vaccine in Healthy Children and Adolescents". The New England Journal of Medicine. 381 (21): 2009–2019. doi:10.1056/NEJMoa1903869. PMID 31693803. S2CID 207952783.{{cite journal}}: CS1 maint: overridden setting (link)
  40. Armstrong M (7 November 2019). "Takeda's dengue data spell more bad news for Sanofi". Evaluate Ltd. Retrieved 11 November 2019.
  41. "New vaccine to protect people in the EU and worldwide against dengue". European Medicines Agency (EMA) (Press release). 14 October 2022. Retrieved 14 October 2022.
  42. "Qdenga: Pending EC decision". European Medicines Agency (EMA). 14 October 2022. Archived from the original on 14 October 2022. Retrieved 14 October 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  43. "Takeda withdraws US application for dengue vaccine candidate". Reuters. 11 July 2023. Retrieved 3 October 2023.
  44. Angus L (11 July 2023). "UPDATED: Takeda yanks FDA filing for dengue vaccine, citing data disagreement with regulator". Fierce Pharma. Retrieved 14 July 2023.
  45. "NIH-Developed Candidate Dengue Vaccine Shows Promise in Early-Stage Trial". National Institute of Allergy and Infectious Diseases. 23 January 2013. Retrieved 30 July 2015.
  46. Kirkpatrick BD, Whitehead SS, Pierce KK, Tibery CM, Grier PL, Hynes NA, et al. (March 2016). "The live attenuated dengue vaccine TV003 elicits complete protection against dengue in a human challenge model". Science Translational Medicine. 8 (330): 330ra36. doi:10.1126/scitranslmed.aaf1517. PMID 27089205. S2CID 206690615.{{cite journal}}: CS1 maint: overridden setting (link)
  47. Whitehead SS (2016). "Development of TV003/TV005, a single dose, highly immunogenic live attenuated dengue vaccine; what makes this vaccine different from the Sanofi-Pasteur CYD™ vaccine?". Expert Review of Vaccines. 15 (4): 509–517. doi:10.1586/14760584.2016.1115727. PMC 4956407. PMID 26559731.
  48. Khetarpal N, Khanna I (2016). "Dengue Fever: Causes, Complications, and Vaccine Strategies". Journal of Immunology Research. 2016: 6803098. doi:10.1155/2016/6803098. PMC 4971387. PMID 27525287.
  49. "Merck and Instituto Butantan Announce Collaboration Agreement to Develop Vaccines to Protect Against Dengue Infections". Merck. 12 December 2018. Retrieved 26 October 2021.
  50. "MVC Obtains US NIH's Authorization to Develop Dengue Vaccine in 17 Countries". Medigen. 9 December 2016. Retrieved 26 October 2021.
  51. "Panacea Biotec completes Phase I/II study of DengiAlI vaccine". India Times. 24 September 2020. Retrieved 26 October 2021.
  52. "Vaccine Development. Dengue Vaccine Initiative". Archived from the original on 21 August 2019. Retrieved 31 July 2015.
  53. Roehrig JT (April 2013). "Current Status of Dengue Vaccine Development" (PDF). Archived from the original (PDF) on 11 December 2015. Retrieved 31 July 2015.
  54. Manoff SB, Sausser M, Falk Russell A, Martin J, Radley D, Hyatt D, et al. (3 June 2019). "Immunogenicity and safety of an investigational tetravalent recombinant subunit vaccine for dengue: results of a Phase I randomized clinical trial in flavivirus-naïve adults". Human Vaccines & Immunotherapeutics. 15 (9): 2195–2204. doi:10.1080/21645515.2018.1546523. PMC 6773383. PMID 30427741.{{cite journal}}: CS1 maint: overridden setting (link)
  55. "New vaccine to protect people in the EU and worldwide against dengue". European Medicines Agency (EMA) (Press release). 14 October 2022. Retrieved 14 October 2022.
  56. "Takeda's Dengue Vaccine Approved for Use in European Union". Takeda (Press release). 8 December 2022. Retrieved 10 February 2023.
  57. "Qdenga Product information". Union Register of medicinal products. Retrieved 3 March 2023.
  58. "Takeda UK Ltd. announces MHRA approval for dengue virus vaccine candidate Qdenga". Bloomberg.com (Press release). 6 February 2023. Retrieved 9 February 2023.
  59. Becker Z (21 March 2023). "As approvals roll in, Takeda details pricing strategy for dengue vaccine launch". Fierce Pharma. Retrieved 14 July 2023.
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