Dengue vaccine

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Dengue vaccine
Vaccine description
Target disease Dengue fever
Type various
Identifiers
ChemSpider
  • none

Dengue vaccine is a vaccine to prevent dengue fever in humans. The World Health Organization 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 9 years).[1] 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.[2] This has caused a scandal in the Philippines where more than 733,000 children were vaccinated regardless of serostatus.[3]

The development of vaccine for dengue fever began as early as 1929, but has been hindered first by incomplete knowledge of the disease pathogenesis, and later by the need to simultaneously create a stable immunity against all four dengue serotypes. Several vaccine candidates are in development including live attenuated, inactivated, DNA and subunit vaccines. Live attenuated vaccine candidates are the furthest along in development.[4]

In 2016 a partially effective vaccine for dengue fever (Dengvaxia) became commercially available in 11 countries: Mexico, the Philippines, Indonesia, Brazil, El Salvador, Costa Rica, Paraguay, Guatemala, Peru, Thailand, and Singapore.[5][6][7] In Indonesia it costs about US$207 for the recommended three doses.[7] WHO updated its recommendations regarding the use of Dengvaxia in September 2018 based on the evidence that seronegative vaccine recipients have an excess risk of severe dengue compared to unvaccinated seronegative individuals . It is not clear why the vaccinated sereonegative population have more serious adverse outcomes. A plausible hypothesis is the phenomenon of antibody-dependent enhancement.[8]

CYD-TDV[edit]

CYD-TDV, sold under the brand name Dengvaxia and made by Sanofi Pasteur, is a live attenuated tetravalent 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 four of the five dengue serotypes.[9][10] 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.[2] 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 Philippines government suspended the mass immunization program with the backing of the WHO which began a review of the safety data.[11]

Ongoing phase III trials in Latin America and Asia involve over 31,000 children between the ages of 2 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.[12][13] Efficacy varied by serotype. In both trials vaccine reduced by about 80% the number of severe dengue cases.[14] 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 9 years of age, but considerably greater (81.9%) for children who were seropositive (indicating previous dengue infection) at baseline.[15] The vaccination series consists of three injections at 0, 6 and 12 months.[10] The vaccine was approved in Mexico, Philippines, and Brazil in December 2015, and in El Salvador, Costa Rica, Paraguay, Guatemala, Peru, Indonesia, Thailand and Singapore in 2016.[5] Tradenamed Dengvaxia, it is approved for use for those aged nine and older and can prevent all four serotypes.[16]

In development[edit]

DENVax or TAK-003[edit]

DENVax or TAK-003 is a recombinant chimeric 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 Takeda (TAK-003).[17][18] Phase I and II trials are ongoing in the United States, Colombia, Puerto Rico, Singapore and Thailand.[19] Based on the latest 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.[20]

TetraVax-DV[edit]

TetraVax-DV is a tetravalent admixture of monovalent vaccines that were tested separately for safety and immunogenicity. The vaccine passed phase I trials and is being tested in phase II studies in Thailand and Brazil.[21] In Brazil, the studies are being done in collaboration with the Instituto Butantan.

TDENV PIV[edit]

TDEN PIV is inactivated tetravalent vaccine undergoing phase I trials as part of a collaboration between GSK and the Walter Reed Army Institute of Research. 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.[22]

V180[edit]

Merck is studying recombinant subunit vaccines expressed in Drosophila cells. Studies are in phase I stage as of 2015.[22]

DNA vaccines[edit]

The Naval Medical Research Center attempted to develop a monovalent DNA plasmid vaccine, but early results showed it to be only moderately immunogenic.[19]

Manufacturer in India and Vietnam[edit]

Panacea Biotec and Biological E. Limited have vaccine candidates in the earliest stages of development. A company in Vietnam (VABIOTECH) is conducting safety tests and developing a clinical trial plan.[23] All three companies are involved in studies of a TetraVax-DV vaccine in conjunction with the National Institutes of Health.[24]

Events[edit]

Following the attempt by the dengue vaccination maker Sanofi Pasteur on November 29, 2017,[25] the Philippine Department of Health (DOH) suspended the vaccination program based in schools owing to the concern that it worsens the disease in some cases where the recipient had no previous exposure.[26] DOH Secretary Francisco Duque III said "In the light of this new analysis, the DOH will place the dengue vaccination on hold while review and consultation is ongoing with experts, key stakeholders and the World Health Organization."[citation needed] On December 2, 2017, the government of Makati immediately suspended its anti-dengue vaccination drive following its statement.[27]

In its statement, pharmaceutical company Sanofi Pasteur reported concerns that Filipinos, mostly schoolchildren, could be potentially be at risk of a more severe disease, where the recipient of the vaccine had not had a previous dengue infection. On December 4, 2017, Sanofi denied that they made Filipinos into “guinea pigs”, explaining that the vaccine program was conducted by the DOH, not Sanofi.[28][29] Dr Ruby Dizon, a medical director of Sanofi, said that the dengue vaccination would not cause "severe dengue".[30] Senator JV Ejercito, chair of the Senate Committee on Health and Demography, is seeking to identify by January 2018 whether there was an irregularity in the procurement of the vaccine.[31] Senator Risa Hontiveros urged the government to address the health threats posed by the vaccine.[32] The Food and Drug Administration of the Philippines ordered Sanofi to stop distributing of Dengvaxia into the country.[33][34] Former Health Secretary Janette Garin said she welcomed the investigation which will be conducted by the Philippine Department of Justice.[35] Presidential spokesperson Harry Roque told the media that 10 percent of the 733,000 schoolchildren[note 1] were at risk of dengue infection.[38] Since then, the Philippine Department of Education has closely monitored the students who have been injected by the vaccine.[39] Hontiveros said that Sanofi should take liability for the medical expenses of those who contracted severe dengue fever after receiving doses of the vaccine.[40]

Sanofi representative Thomas Triomphe "was forced to apologize" during the House of Representatives hearing on the Dengvaxia dengue vaccine.[41] Former President Benigno Aquino III, who approved the vaccination program in 2016, expressed interest on attending the Senate hearing.[42] On December 16, Aquino told reporters that "With the announcement of Sanofi and the reactions to it, there has been a lot of tension building up and I think it is incumbent upon me even as a citizen to try and allay certain fears, to put it in the proper perspective, to put it on the proper level".[43]

Secretary Duque reminded the public, especially parents, that "the vaccine is not a 'standalone' preventive measure against dengue."[44] On December 15, 2017, former Education and Skills Development chief Augusto Syjuco Jr filed "mass murder and plunder" complaints against Aquino and former health secretary Janette Garin over the controversial vaccination program.[45] Former health secretary Enrique Ona blamed his successor Janette Garin, who advised former president Benigno Aquino lll to purchase the Dengvaxia.[46]

On February 2, 2018, the University of the Philippines-Philippine General Hospital (UP-PGH) issued a report stating that three out of 14 children who died after receiving Dengvaxia had an indication of dengue despite immunization.[47] On February 3, a group of doctors, including former health secretary Esperanza Cabral, urged the Public Attorney's Office (PAO) to stop conducting autopsies.[48] On February 21, Senator Richard Gordon said that the DOH must be liable for the controversy.[49] On March 13, Senator Gordon formally terminated the investigation of the controversy.[50] On February 26, Aquino appeared for the first time at House inquiry about the controversy; he said that the controversy has been "politicized",[51] but the Malacañang Palace distanced itself from Aquino's allegations.[52] On February 27, the opposition Representatives such as Gary Alejano of Magdalo and Edcel Lagman of Albay urged President Rodrigo Duterte to intervene about the dispute between the PAO and DOH.[53] On March 3, about 200 families of Dengvaxia vacinees joined the advocacy run held in Quezon Memorial Circle.[54]

Sanofi stated that they will make a decision on seeking regulatory approval for dengue vaccine Dengvaxia in the United States, despite the health scare in the country, after they have had a meeting with the US Food and Drug Administration.[55]

Charges[edit]

On April 5, Public Attorney’s Office filed the criminal charges (reckless imprudence resulting in homicide under Article 365 of the Revised Penal Code and violation of Republic Act No. 9745 (Anti-Torture Act) and torture) against the Former Health Secretary Janette Garin and other former officials.[56][57] However, Garin said that the charges have no basis and vowed to file a counter-charge against PAO.[58] The families of four children — Aejay Bautista (11), Lenard Baldonado (10), Zandro Colite (11), and Angelica Pestilos (10), whose deaths had been linked to Dengvaxia — also filed the charges.[59]

On April 19, PAO filed criminal complaints before the Department of Justice (DOJ), including the incumbent Health Secretary Francisco Duque III, following the death of the 13-year-old girl after receiving Dengvaxia on November 17, 2017.[60] Duque fires back by describing the charges against him as "malicious and oppressive" and he also said that he has nothing to do with the implementation of the dengue immunization program since he was seated as the secretary last October 2017.[61]

Gordon's draft report[edit]

On April 11, Gordon released his draft report, stating that Aquino is guilty of "malfeasance, misfeasance and nonfeasance" in connection to that controversy.[62] The blue ribbon committee also told Aquino for "simply not caring" because the lives of Filipino children in grave danger.[62] Gordon said that Aquino, former Budget Secretary Florencio Abad, Garin and other conspirators must be prosecuted for the Dengvaxia mess.[62][63] Gordon slammed Aquino by saying that "he's insensitive and lacks compassion."[64] However, left-wing figures called Gordon’s report “one-sided,”[65] and Senator Antonio Trillanes IV defends Aquino by saying that Gordon's report was "black propaganda".[66] Aquino reacted by saying, “What should we expect from the Dick Gordon show?”.[67] Also, Senator Ejercito said that while Aquino is "guilty of negligence", Garin and Abad are the ones who should be held liable.[65]

On April 15, Gordon said he expected at least 10 senators to sign his report holding former President Benigno Aquino III and other officials liable.[68] Senator Panfilo Lacson will not sign the report due to "unreasonable comments" about him.[69] On April 17, Aside from Gordon, who already signed the report, Senators Ralph Recto, Manny Pacquiao, Sherwin Gatchalian, Tito Sotto, Gregorio Honasan, Juan Miguel Zubiri, JV Ejercito, Nancy Binay, and Grace Poe have signed.[70] On April 20, Senator Sonny Angara also signed.[71]

Casualties[edit]

Since the announcement by Sanofi, at least 65 children have died as of early July 2018, allegedly after receiving a vaccination. The victims' parents blamed the dengue vaccine for the deaths of their children.[72] Most of the deaths are caused by internal bleedings in heart, lungs, and brain based on the autopsy conducted by PAO.[73][74][75] Duque angrily confronted the summoned hospital officials after he learned that four hospitals in Cavite allegedly refused to admit the Dengvaxia vaccinees because "there is no room for the patient".[76]

Reactions[edit]

Netizens, as well as Senator Ejercito, expressed frustration on February 5, blaming the PAO for panic in dengue vaccination.[77] Attorney Persida Acosta of the PAO said that the PAO should not be blamed for that panic but Sanofi Pasteur itself.[77]

Notes[edit]

  1. ^ Some sources say 700,000[36] or 830,000[37]

References[edit]

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  27. ^ "Makati suspends anti-dengue vaccination program". Philippine Canadian Inquirer.
  28. ^ "Sanofi, DOH allay dengue vaccine fears". The Philippine Star.
  29. ^ "Sanofi denies Pinoys became 'guinea pigs,' says no reported Dengvaxia deaths in PH". News5.
  30. ^ "Ex-DOH chief ready to face probe over Dengvaxia mess". ABS-CBN News.
  31. ^ "Senate to probe dengue vaccine in January". The Philippine Star.
  32. ^ "Risa says Sanofi must pay over Dengvaxia mess; DOJ orders probe of PNoy gov't's P3.5-B vaccination drive". News5.
  33. ^ "PH gov't orders Sanofi to stop sale, distribution of Dengvaxia". News5.
  34. ^ "FDA Advisory No. 2017-318 || Suspension of Sale/Marketing/Distribution of Sanofi Pasteur, Inc.’s Tetravalent Vaccine (Live, Attenuated)(Dengvaxia)". Archived from the original. Food and Drug Administration.
  35. ^ "WATCH | Garin ready to face govt's Dengvaxia probe". News5.
  36. ^ "LIVE: Senate hearing on Dengvaxia". Rappler.
  37. ^ "DOJ wants right expert to look into alleged Dengvaxia deaths". ABS-CBN News.
  38. ^ "Filipinos not made guinea pigs – Sanofi". Philippine Daily Inquirer.
  39. ^ "DepEd monitors students administered with Dengvaxia". Manila Bulletin.
  40. ^ "Hontiveros: Sanofi should take on medical expenses of those who were vaccinated". Manila Bulletin.
  41. ^ "Sanofi exec forced to apologize during Dengvaxia inquiry". Philippine Daily Inquirer.
  42. ^ "Aquino ready to face Dengvaxia probe at Senate".
  43. ^ "Aquino: It's my duty to explain". Philippine Daily Inquirer .
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  57. ^ "Garin: Raps filed by parents of alleged Dengvaxia victims 'have no scientific basis'". Philippine Daily Inquirer.
  58. ^ "Raps filed vs. Garin, 34 others over alleged Dengvaxia deaths". GMA News.
  59. ^ "Dengvaxia victims' kin file complaint vs DOH, Sanofi, Zuellig execs". Rappler.
  60. ^ "Duque, other DOH officials face criminal raps over Dengvaxia mess". ABS-CBN News.
  61. ^ "Duque blasts PAO chief for 'malicious' Dengvaxia rap". ABS-CBN News.
  62. ^ a b c "Senate blue ribbon on Dengvaxia mess: Aquino simply did not care". The Philippine Star.
  63. ^ "Aquino, Abad, Garin 'caused' Dengvaxia 'tragedy' – draft report". Philippine Daily Inquirer.
  64. ^ "Former President Aquino is responsible because he caused the purchase of Dengvaxia and in the process caused irreversible damage, possibly death, to children, [and] anxiety, sleepless nights, unnecessary expense on the part of the parents and guardians. The greatest sin and transgression of Aquino was to put the lives of Filipino children in grave peril. He simply did not care. Manhid siya at walang malasakit (He's insensitive and lacks compassion)."" ("Gordon report: File criminal charges vs Aquino, Garin, Abad over Dengvaxia mess") — Rappler
  65. ^ a b "Senators cool to Gordon report on Dengvaxia". The Philippine Star.
  66. ^ "Gordon draft report 'black propaganda', won't pass Senate scrutiny - Trillanes". ABS-CBN News.
  67. ^ "Clearly it's 'Dick Gordon show,' says Aquino on Dengvaxia draft report". Philippine Daily Inquirer.
  68. ^ "Gordon: 10 senators to sign committee report on Dengvaxia probe". Philippine Daily Inquirer.
  69. ^ "Lacson won't sign Dengvaxia report due to Gordon's 'unreasonable' remark". Philippine Daily Inquirer.
  70. ^ "9 senators have signed report seeking charges vs former President Aquino". Philippine Daily Inquirer.
  71. ^ "Angara signs blue ribbon Dengvaxia report with 'reservations', too". Philippine Daily Inquirer.
  72. ^ "Anak namin namatay sa Dengvaxia" (in Tagalog). Archived from the original. Pilipino Star Ngayon. Retrieved December 20, 2017.
  73. ^ "Bakit namamaga ang internal organs ng mga namatay umano sa Dengvaxia?". ABS-CBN News (in Tagalog).
  74. ^ "TV Patrol: Bangkay ng binatilyong 3 beses tinurukan ng Dengvaxia, sinuri" ABS-CBN News – via YouTube.
  75. ^ "TV Patrol: Nasuri ng PAO na naturukan umano ng Dengvaxia, umabot na sa 41". ABS-CBN News – via YouTube.
  76. ^ "TV Patrol: Duque, sinugod ang mga ospital na 'tumanggi' sa naturukan ng Dengvaxia" ABS-CBN News – via YouTube.
    (1:41-1:47) ...Hindi naman pala puno ang hospital pero wala lang daw bakanteng kwarto noon para sa kaso ng bata.
  77. ^ a b "Bandila: PAO, binabatikos dahil sa 'panic' sa Dengvaxia" (in Tagalog). ABS-CBN News — via YouTube.

External links[edit]