Thursday, December 07, 2017

Philippines DOH Threatens To Sue Sanofi Over Dengue Vaccine











#12,952

A week after the news of safety concerns with Sanofi's Dengvaxia® vaccine sent shock waves through the Philippines (see Philippines Halts Dengue Vaccine After Sanofi Issues Warning), the crisis continues to grow with a Senate and House of Representatives investigation promised next week, and threats of legal action by the MOH.

This report from ABS-CBN News:


Philippines to seek refund, sue Sanofi over dengue vaccine: health chief
 
Trishia Billones, ABS-CBN News

Posted at Dec 07 2017 09:54 AM | Updated as of Dec 07 2017 10:30 AM

MANILA - The Philippine government will seek a refund and bring to court pharmaceutical giant Sanofi Pasteur over the dengue vaccine that spurred a health scare in the country, Health Secretary Francisco Duque said Thursday.

The Department of Health last week suspended the vaccination program after the company disclosed that its Dengvaxia vaccine may cause "more cases of severe disease" if given to those who have not had the mosquito-borne illness before.

(SNIP)

Sanofi would be liable if it is found to have withheld material information "that would have changed the outcome of all of these problems and the decision-makers in the Department of Health in the previous administration," said Duque.


(Continue . . . )
 
While all parties appear to be doing their best Claude Rains Captain Renault imitation ('I'm shocked, shocked to find there are suddenly concerns over the dengue vaccine!'), last week's announcement is not completely unexpected, and as you'll see below, serious concerns have been voiced by a number of Dengue researchers for years.

One need look no further than a CIDRAP News report from July of 2016, which eerily presages last week's announcement.

Contrary dengue vaccine response hints at possible problems with Zika

Jul 28, 2016
"It's happened. We have a vaccine that enhances dengue," said Scott B. Halstead, MD, talking about a phenomenon whereby the dengue vaccine sets up dengue-naive recipients for severe disease.

Halstead, the leading figure in dengue research in the past 50 years, is referring to CYD-TDV (Dengvaxia, Sanofi Pasteur), the first dengue vaccine approved by the World Health Organization in April, and now licensed for use in five countries. When Halstead, a former senior advisor of the Dengue Vaccine Initiative and the founder of Children's Vaccine Initiative, first saw the 3-year results of the vaccine published in the New England Journal of Medicine last summer, he immediately saw a problem in the data.
“It's clear as the nose on my face: Vaccine recipients less than 5 years old had five to seven times more rates of hospitalizations for severe dengue virus than placebo controls."
ADE primes subjects for severe illness
Halstead is describing a problem dengue researchers feared for years; the vaccine appears to cause ADE, or antibody-dependent enhancement. In dengue ADE, which Halstead first identified, infection with one of the four strains of the virus produces antibodies to that strain and cross-reactive antibodies to the other dengue strains.

"Over time, you make and keep protective levels of antibody from the initial infection, but you lose the cross-reactive antibodies," said Halstead. "That allows a second dengue infection to cause severe illness, including dengue hemorrhagic fever."

(Continue . . . )

The paper by Halstead and Russell called Protective and immunological behavior of chimeric yellow fever dengue vaccine, published in March of 2016 in the journal Vaccine, featured the following highlights.
  • Children, ages 5 years and younger, given three doses of CYD vaccine were hospitalized five times more frequently with breakthrough dengue virus infections than were placebo controls.
  • Children who were seronegative at the time of CYD vaccination were poorly protected against symptomatic dengue virus infection.•
  • Seronegative children uniformly developed dengue neutralizing antibodies following vaccination.•
  • Symptomatic dengue virus infections in individuals circulating non-protective dengue antibodies suggests disease in vaccinated young children is antibody enhanced.•
  • CYD vaccination protected seropositives from disease, mild or severe, when challenged by a wild-type dengue virus.

In the above CIDRAP interview, Halstead presciently went on to say:
For Halstead, concerns about Zika and ADE are interesting but are so far only projections. He’s more worried about what he sees in Dengvaxia. He said the Philippines just bought 1 million doses of the vaccine, with intentions to begin inoculating 9-year-olds across the country. That could mean thousands of children could be affected by dengue ADE.

"I don't understand why there seems to be some sort of silent majority on this," said Halstead. "Seronegatives are going to be sensitized to dengue virus for the rest of their lives, and it's not going to stop at hospitalizations.

"Someone is going to die. Once that happens there's enough lawyers that are going to do something about it."
A pretty apt prediction of what we've seen transpire in the Philippines over the past week. Another study published just last month in the Journal of Clinical Epidemiology, provides a similarly bluntly worded assessment, which calls into question the methodology of safety trial meta-analyses used for the vaccine.
Review of a licensed dengue vaccine: Inappropriate subgroup analyses and selective reporting may cause harm in mass vaccination programs
Antonio L. Dans, MD, MSc1,Leonila F. Dans, MD, MSc1,Mary Ann D. Lansang, MD, MMedSc1,Maria Asuncion A. Silvestre, MD2,Gordon H. Guyatt, MD, MSc3
https://doi.org/10.1016/j.jclinepi.2017.11.019

Highlights:

1. The possibility that dengue vaccines can cause severe dengue has led to serious concern regarding the safety of mass vaccination programs.

2. This paper points out problems in the analyses of a published meta-analysis addressing this safety issue for a new vaccine against dengue fever - Dengvaxia ™.
3. Although the authors of the meta-analysis show a 7-fold rise in hospitalization for dengue fever in children < 5 years old, they fail to point out two signals of harm for another outcome – hospitalization for severe dengue fever in children younger than 9 years, the relative risk was 8.5 [95% CI 0.5, 146.8], and in the overall study group, the relative risk was 5.5 [95% CI: 0.9, 33].

4. The selective reporting and inappropriate subgroup claims mask the potential harm of dengue mass vaccination programs.

5. Countries planning public use of the vaccine must conduct diligent post-marketing surveillance, secure informed consent from parents of potential recipients and closely monitor the results of ongoing long-term follow-up of

clinical trial participants.

Abstract

Severe life-threateni
ng dengue fever usually occurs when a child is infected by dengue virus a 2nd time. This is caused by a phenomenon called antibody dependent enhancement or ADE. Since dengue vaccines can mimic a first infection in seronegative children (those with no previous infection), a natural infection later in life could lead to severe disease. The possibility that dengue vaccines can cause severe dengue through ADE has led to serious concern regarding the safety of mass vaccination programs.
A published meta-analysis addressed this safety issue for a new vaccine against dengue fever - Dengvaxia ™. The trials in this meta-analysis have been used to campaign for mass vaccination programs in developing countries. We discuss the results of this paper and point out problems in the analyses.

Reporting the findings in an Asian trial (CYD14), the authors show a 7-fold rise in one outcome – hospitalization for dengue fever in children < 5 years old. However, they fail to point out two signals of harm for another outcome – hospitalization for severe dengue fever (as confirmed by an independent data monitoring committee):
1. in children younger than 9 years, the relative risk was 8.5 [95% CI 0.5, 146.8], and
2. in the overall study group, the relative risk was 5.5 [95% CI: 0.9, 33]
The authors conduct a subgroup analysis to support claims that the vaccine is probably safe among children aged 9 years or more. This subgroup analysis has limited credibility because: 1) it was a post-hoc analysis; 2) it was one of a large number of subgroup analyses; 3) the test of interaction was not reported; but was insignificant (p=0.14); and 4) there is no biological basis for a threshold age of 9 years. The more likely explanation for the higher risk in younger children is ADE, that is, more frequent seronegativity, rather than age itself.

The selective reporting and inappropriate subgroup claims mask the potential harm of dengue mass vaccination programs. Countries planning public use of the vaccine must conduct diligent post-marketing surveillance, secure informed consent from parents of potential recipients and closely monitor the results of ongoing long-term follow-up of clinical trial participants.

There's no doubt that dengue is a devastating public health threat, that the world desperately needs a safe and effective vaccine, and that we've known for a very long time just how daunting a task making one would be. All reasons why this week's developments are so disappointing.
Hopefully the health risks to seronegative children vaccinated in the Philippines will prove to be minor - as suggested earlier this week by Sanofi -  but it may take years before its impact can be fully evaluated. 
Meanwhile, the big question is why - in light of concerns published more than 18 months ago - the mass vaccination of children went ahead anyway.  A question that appears destined to be settled by the courts, with the lawyers being the only guaranteed winners.

Undoubtedly, the biggest blow has been dealt to the public's perception of the safety of vaccines, and reputation of `Big Pharma' - both of which can ill afford the hit.
Regardless of culpability or fault, this very public debacle has handed the anti-vaccine crowd just the sort of hammer they need to pound away at all vaccines, not just Dengvaxia ™.
Sadly, this kind of negative publicity could easily result in a loss of faith in science and medicine that might cost millions of lives in the years ahead, and may seriously hinder the bringing to market of new, vitally needed, life-saving vaccines in the future.

In which case, we may all find ourselves on the losing side. 

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