Saturday, December 09, 2017

Media Reports Of H5N1 Outbreak In Cambodia


Although largely overshadowed the past couple of years by the globe-trotting dual threat from HPAI H5N8 and H5N6, along with China's ominous array of evolving LPAI and HPAI H7N9 viruses,  venerable H5N1 - the OG of the bird flu world - has been around for two decades, has killed more than 450 people, and remains endemic in several parts of the world.
Today, the sharp-eyed newshounds on FluTrackers (h/t Commonground) have picked up media reports of a fresh H5N1 outbreak in east-central Cambodia (see Cambodia: Bird Flu Returns in Poultry (Media Report)).
The last report out of Cambodia came in January of this year (see OIE Notification), and while bird flu activity has been slow there the past few years, Cambodia has the 4th highest total of H5N1 human infections and deaths (56/37) globally - with the bulk of those cases recorded between 2012 and 2014.
Reporting, testing, and surveillance are limited in this part of the world, and so these numbers are likely under counts. 
First a sample of today's reportage, then I'll be back with a postscript.
December 9, 2017
Bird flu outbreak in Kampong Cham

Ros Chanveasna / Khmer Times Share:
Ducks hang at a farm on the outskirts of Phnom Penh. Thousands of ducks were culled in November 2015 after many became sick from a mysterious illness. Reuters

The Ministry of Agriculture, Forestry and Fisheries has reported that in early December the bird flu (H5N1 virus) appeared in Kampong Cham province. The ministry informed Prime Minister Hun Sen on Friday, of the outbreak.

Prey Chor district’s Trapaeng Preah commune was hardest hit, with some 200 chickens perishing.

After the alert from local authorities, the ministry immediately dispatched experts to inspect the site in Trapaeng Preah, and they took away two dead chickens to be sent to a laboratory in Phnom Penh.
“The tests on Wednesday [Dec. 6] confirmed that those chickens had contracted the avian influenza H5N1,” the lab report said.
(Continue . . .)

This is a seemingly small, probably inconsequential report of a local event in a very remote part of the world - and as such is not the sort of thing most people would even notice.  Like so many other reports we see like this, it will probably fade from memory in a matter of days.
But every so often, a seemingly insignificant news item signals the start of a much bigger event. Often we only realize the significance of these items in retrospect. 
While I try to blog those infectious disease stories I think are important, I can only cover a small percentage of the daily wealth of information that comes over the transom.  For every blog I write, there are probably 10 or 20 potentially newsworthy stories I take a pass on.
Luckily, I'm not alone in this endeavor.
Crof blogs on a variety of infectious disease and societal issues every day while CIDRAP News provides both terrific long form articles and news briefs 5 days each week.

The bulk of the flu news gathering, however, is being done quietly by a group of volunteer newshounds at FluTrackers, who gather and collate infectious disease information - both important and obscure - from every corner of the globe.
Their members are an eclectic group - ranging from knowledgeable lay people to research  professionals - who reside in the United States, Europe, Australia/NZ, and Asia. They speak and write in multiple languages, work in different time zones, and many of them have been doing this unsung work for more than a decade. 
While I hope my blog provides context, and details on the `big' stories of the day - if you want to see the big picture - you really need to be a regular visitor to FluTrackers. Everything you read might not seem important at the time, but in retrospect, those puzzle pieces can often prove to be important tipping points. 
Hopefully, if you are not a regular visitor, I've piqued your interest enough that  you'll make the FT repository a daily stop. Just click the Latest Activity button.
As I've stated before, I couldn't do what I do with this blog if it were not for the efforts of Sharon Sanders and her team at FT.  They not only provide me with leads for many of my daily blogs, they free me up to do the more in-depth style of writing I enjoy.

I strongly suspect, whoever ends up writing the history of the next pandemic, will find everything they need to know about how and when it began had been posted the FluTrackers site before the first official alarms were raised.

Netherlands Bird Flu Identified As Reassorted H5N6


The plot thickens. 

As I alluded to in yesterday's blog, while H5N8 was the `prime suspect' in the bird flu outbreak just reported in the Netherlands, over the past month we've seen the unexpected emergence of a reassorted H5N6 virus in the Far East (Japan, South Korea, Taiwan), and that its arrival in Europe could not be ruled out.
Today, based on a report issued by the Wageningen Bioveterinary Research Institute, we learn that this latest outbreak is indeed due to a reassorted H5N6, which is described much in the same way as the viruses detected in recent weeks more than 9,000 miles to the east.
Some excerpts from the statement, then I'll return with more.

Bird flu in Biddinghuizen

Published on

December 8, 2017

In Biddinghuizen (municipality of Dronten, Flevoland Province) bird flu has been demonstrated by Wageningen Bioveterinary Research (WBVR) at a company with meat ducks on Friday, December 8, 2017. The virus has been classified as a high pathogen H5N6. This company was also one of the first to be infected last year.
High-pathogenic H5N6 virus

A first genetic analysis shows that the virus is not related to the zoonotic H5N6 strain, which circulates in Asia and can also make people ill.

  • The H5 is related to the highly pathogenic H5N8 virus that was found in the Netherlands in 2016.
  • The N6 is related to low-pathogenic viruses previously found in wild birds in Europe.
The H5N6 virus was created by exchange of genetic material, or reassortment. WBVR carries out follow-up research to gain further insight into the origin and genetic composition of this virus.
Measures against the spread of bird flu

To prevent further spread of the virus, the company is cleared by the Dutch Food and Consumer Product Safety Authority (NVWA). In total, about 16,000 meat ducks are involved. In the area of ​​one kilometer around the company in Biddinghuizen there are no other companies that have to be disposed of preventively. In the area of ​​three kilometers around the infected company, there are four other companies. These last poultry farms are sampled and examined by WBVR for avian influenza.

WBVR will determine the characterization of the H5 avian influenza virus in follow-up research.
         (Continue . . . )

Last winter's record setting avian epizootic in Europe was caused by the arrival of an (also recently reassorted) HPAI H5N8 virus, which spread rapidly across Western Europe, into the Middle East, and into Africa.  While 99% of the outbreaks were caused by this H5N8 virus, a small number of reassorted H5N5 viruses were detected; new reassortments spun off from H5N8.
Towards the end of the season, a lone reassorted H5N6 virus (see CIDRAP: Greek H5N6 Virus Appears Distinct From Asian Strain) was also reported.  At the time, this appeared to be an isolated incident.
It now appears this reinvented `European' H5N6 virus was able to thrive and compete successfully with other avian viruses in migratory birds over the summer, and has become a new player in the evolution of HPAI H5.
We'll have to wait for a full analysis to find out just how close this latest virus is to those detected in the Far East, but the preliminary description is very similar.
Since H5N8 still circulates in Italy and Africa, and the Asian version of H5N6 continues to plague Chinese poultry, it is far too soon to declare this new H5N6 virus the new heir apparent in the bird flu world.
But its ability to show up on two continents within a span of 3 weeks is pretty impressive. 
Avian flu continues to evolve at a rapid, and unpredictable rate. Unlike 6 years ago, when we really only had one HPAI avian flu virus (H5N1) to worry about, the roster of new viruses has grown to include H5N8, H5N6 (Asian), H5N6 (European), H5N5, and H7N9.

Given the ability for avian viruses to swap gene segments, and to continually re-invent themselves, the expectation is that we'll see more reassortments emerge in the months and years ahead.

Friday, December 08, 2017

Netherlands Rijksoverheid: H5 Outbreak (Likely HPAI) In Biddinghuizen


Although there have been reports in the media for the past 3 or 4 hours, I've been waiting for an official report to appear on the Netherlands' Rijksoverheid (government) websiteFirst the statement, then I'll return with a bit more.  

Bird flu identified in poultry in Biddinghuizen

release | 08-12-2017 | 12:09

In Biddinghuizen (Dronten) on Friday, December 8th at a company with duck meat bird flu of the H5 type set. It probably involves a highly pathogenic strain of bird flu. To prevent spread of the virus, the company is cleared. In total there are approximately 16,000 meat ducks. The culling is performed by the Dutch Food Safety Authority (NVWA).

In the area of ​​three kilometers around the infected holding in Biddinghuizen are four other poultry farms. These companies are sampled and tested for avian influenza. In the 10-kilometer zone surrounding this company are 23, poultry farms.

Schouten Minister of Agriculture, Nature and Food Quality has immediately announced a ban on transporting poultry in an area of ​​ten kilometers around the infected holding in Biddinghuizen. A movement ban applies to poultry, eggs, poultry manure and used bedding, but also other animals and animal products from companies with commercially farmed poultry.
national measures

Because there is a highly pathogenic variant of the Netherlands set an indoor confinement. This applies to all commercial companies that birds intended for the production of meat, eggs or other products. The indoor confinement also applies to companies that breeding birds are released into the wild. The measure was taken as a precaution to reduce the risk of further infection.

Zoos, petting zoos and owners of hobby birds are obliged to protect their poultry and waterfowl that these animals do not come into contact with wild waterfowl and their droppings. For example, this can be done by keeping the animals in an aviary or for placing in a run. Zoos and petting zoos can be visited.

The existing hygiene protocol for visitors to visit commercial poultry is extensive. This also means that visitors are only allowed to enter the house or yard after taking strict hygiene.

There is a ban on the exhibition of ornamental poultry and waterfowl.
Duck and turkey companies

In addition, some additional measures applicable to duck and turkey companies, these are effective immediately. Firstly, ducks companies should comply with a protocol for hygiene litter, including the covering of the litter storage, and cleaning of the equipment which is used to bring in the barn bedding materials. Second, ducks or turkeys may be transported only after they have been examined by a veterinarian. Finally shipments to or from these companies may only take place directly.
         (Continue. . . )

Despite persistent outbreaks of HPAI H5N8 in Northern Italy, and the occasional report of a dead wild bird in Germany or Switzerland, the expected return of HPAI H5N8 this fall has been slow in coming.
Every year is different, however, and as we saw after the 2014-15 HPAI H5 epizootic, sometimes bird flu doesn't return the following year (see PNAS: The Enigma Of Disappearing HPAI H5 In North American Migratory Waterfowl).
The wrinkle this year, aside from the timing, may be the subtype that shows up in Europe.  While H5N8 is high on the the expected list, reports of a reassorted H5N6 showing up in Japan, South Korea, and Taiwan over the past couple of weeks are a reminder of how quickly the status quo can change.

Stay tuned. 

Nat Sci. Rpts.: Long-Term Outcomes Of H7N9 Survivors



While the number of mild and moderate H7N9 cases that recover are unknown, we know that roughly 40% of those patients who are sick enough to be hospitalized eventually succumb to their infection.

From time to time we get glimpses of their in-hospital course of treatment (see below), but seldom to we hear about their long-term recovery.
CID Journal: Early Administration Of NAIs Improves Survivability Of H7N9 Patients
ISIRV Journal: Predictors For Fatal Infection With H7N9 Over 4 Epidemic Waves - Jiangsu Province

Given the severity of the illness, often requiring ventilation support, and the demographics of infection - skewed heavily towards older men, often with comorbidities (see  A Look At The Demographics Of H7N9) - it would not be unexpected to find long-term sequelae. 
Today we've a new study, published in Nature Scientific Reports, that follows the 2-year post-hospital recovery of 56 H7N9 cases in Zhejiang Province, China.  
Researchers report a substantial number of patients continued to show reduced pulmonary function - and to report a reduced level of health-related quality of life (HRQoL) - at the end of that 24 month follow-up period.

Long term outcomes in survivors of epidemic Influenza A (H7N9) virus infection 

Jiajia Chen, Jie Wu, Shaorui Hao, Meifang Yang, Xiaoqing Lu, Xiaoxiao Chen & Lanjuan Li

Scientific Reports 7, Article number: 17275 (2017)
Published online: 8 December 2017


Patients who survive influenza A (H7N9) virus infection are at risk of physical and psychological complications of lung injury and multi-organ dysfunction. However, there were no prospectively individualized assessments of physiological, functional and quality-of-life measures after hospital discharge. The current study aims to assess the main determinants of functional disability of these patients during the follow-up. 

Fifty-six influenza A (H7N9) survivors were investigated during the 2-year after discharge from the hospital. Results show interstitial change and fibrosis on pulmonary imaging remained 6 months after hospital discharge. Both ventilation and diffusion dysfunction improved, but restrictive and obstructive patterns on ventilation function test persisted throughout the follow-up period. For patients with acute respiratory distress syndrome lung functions improved faster during the first six months.

Role-physical and Role-emotional domains in the 36-Item Short-Form Health Survey were worse than those of a sex- and age-matched general population group. The quality of life of survivors with ARDS was lower than those with no ARDS. Our findings suggest that pulmonary function and imaging findings improved during the first 6 months especially for those with ARDS, however long-term lung disability and psychological impairment in H7N9 survivors persisted at 2 years after discharge from the hospital.


During the spring of 2013, a novel avian-origin influenza virus emerged. This new virus had a genome similar phylogenetically to that of a chicken A(H7N9) virus isolated from an epidemiologically linked live poultry market1 and was thus identified as an avian (H7N9) virus1,2,3. H7N9 viruses can cause severe illnesses in persons with contact to poultry, including pneumonia and acute respiratory distress syndrome (ARDS) with high case fatality rates2,4. 

As of August 31, 2016, a total of 795 laboratory-confirmed cases of human infection with avian influenza A(H7N9) virus had been reported in China4. The infections were also detected in the travelers of Canada (two) and Malaysia (one) to China4. Although the clinical features of hospitalized patients with H7N9 virus infection are generally similar to those of patients with severe pandemic H1N15 or H5N1 virus infections6, the mortality rates of H7N9 and H5N1 have been reported to be 37.1% and 53.2%, respectively7, whereas that of H1N1 was < 1%5.

Patients who survive influenza A (H7N9) virus infection are at risk of physical and psychological complications of lung injury and multi-organ dysfunction. However, previous studies have not included prospectively individualized assessments of physiological, functional and quality-of-life measures after hospital discharge to assess the main determinants of functional disability. Therefore, the goal of this study was to assess the long-term changes in pulmonary function and quality of life among patients recovering from H7N9 infection. 

In summary, long-term lung disability and psychological impairment in H7N9 survivors persisted at 2 years after discharge from the hospital. Pulmonary function and imaging findings improved during the first 6 months especially for those with ARDS.
Most survivors returned to work, but at the 2-year follow-up, more than half of survivors still had ventilation and blood-gas diffusion dysfunction. The H7N9 survivors had impaired HRQoL scores that were lower than those of a sex- and age-matched control population, and ARDS substantially influenced these scores.
The good news here - at least so far - is that H7N9 has not produced the kind of reports of severe neurological impairment that we've occasionally seen with H5N1 (see CJ ID & MM: Case Study Of A Neurotropic H5N1 Infection - Canada). 

But even without that component, the potential impact of a prolonged, often incomplete, recovery on patients and their loved ones, and - in the event of a pandemic - to society in general, cannot be overstated.
No matter how you slice it, should H7N9 ever acquire the ability to transmit efficiently from human-to-human, the world would be be facing a formidable public health threat. 

Thursday, December 07, 2017

Nature: Pandemic H1N1 Flu Viruses Suppress Dendritic Immune Reponse


Although it is hardly light reading, there's a fascinating study published this week in Nature Communications that sheds new light on why some pandemic viruses are so much more virulent than seasonal flu.
Before we get to that study, some (extremely) basic background is probably in order. I'll have to keep it simple, because I'm far from being an expert on the subject.
If you are already familiar with DAMPs, PAMPs, and the function of dendritic cells in the immune system, feel free to skip ahead.  Apologies in advance to any real scientists who stick around to read my humble attempt at explaining the basics of the immune system.

The human immune system is extremely complex, multifaceted, and far from completely understood. But in the simplest of terms, we have two basic types of immune defense systems: 

First, we have natural immunity – so called `innate immunity’ – that can detect, and launch a generic defense against a wide variety of invading pathogens.
Were it not for this built-in immunity, none of us would survive past the first few hours or days of life as we'd be quickly overrun by opportunistic infections.
For our innate immunity to work, it must have a way to recognize an infective agent, even one it has never seen before. Toll-like receptors (TLRs) are a type of protein that are able to recognize molecules that are broadly shared by infectious agents called PAMPs (Pathogen-Associated Molecular Patterns). 
In other words, PAMPs are an easily recognizable molecular signature that tells our innate immune system that we have been infected with . . . something.
Our immune systems have cells designed to recognize, and react to these signatures, that include:
  • phagocytic cells (neutrophils, monocytes, and macrophages);
  • cells that release inflammatory mediators (basophils, mast cells, and eosinophils);
  • natural killer cells (NK cells); and
  • molecules such as complement proteins, acute phase proteins, and cytokines.
In other words, our innate immune system throws just about everything but the kitchen sink at an unrecognized infection in order to buy enough time for the second part of our immune system - our Adaptive Immune System - to learn to recognize and fight specific pathogens.
The adaptive immune system produces pathogen-specific antibodies after exposure to a virus that can provide us with varying degrees of acquired immunity. This acquired immunity explains why we rarely get the same virus twice, and why vaccines work.
While PAMPs are easily recognizable traits of many pathogens, when certain types of cells die (necroptosis) - they release intracellular components called DAMPs (danger associated molecular patterns), which can also alert the immune system of an infection and help rally the troops.

Dendritic cells are a special type of immune cell, most commonly found in tissues that are exposed to the outside environment (skin, lungs, digestive tract), that boosts immune responses by showing antigens on its surface to other cells of the immune system.

Reduced to terms that even I can understand, dendritic cells help `teach' the adaptive immune system how to recognize a virus, are key in the creation of pathogen-specific antibodies, and are involved in signaling other parts of the immune system.
They also tend to die within hours of being infected by seasonal influenza viruses, and when they do, they release DAMPs. 
Eighteen months ago, a study appeared in the Journal of Immunology, that described the suppression of dendritic cell death with pandemic influenza virus infection, which they suggested contributed to the pathogenicity of these viruses. 

Suppression of dendritic cell necroptosis by pandemic influenza virus 
Boris M. Hartmann, Randy A Albrecht, Nada Marjanovic and Stuart C Sealfon
J Immunol May 1, 2016, 196 (1 Supplement) 78.11;

Necroptosis leads to the release of intracellular components which serve as danger associated molecular patterns (DAMP), making this a highly immunogenic cell death mechanism. Consistent with this view, we find that the suppression of virus-induced necroptosis by the pandemic IAV reduces T cell activation.
These studies show that pandemic viruses are unique in suppressing a key immunological danger signal. The suppression of the generation of DAMPs from infected immune cells may contribute to the pathogenicity of pandemic H1N1 IAV viruses.
         (Continue . . . )

These same authors are back this week with a new study, which identifies the HA genomic segment that serves as the mediator of cell death inhibition, thereby increasing the virulence of pandemic H1N1 infection.

Pandemic H1N1 influenza A viruses suppress immunogenic RIPK3-driven dendritic cell death
Boris M. Hartmann,Randy A. Albrecht, Elena Zaslavsky,German Nudelman, Hanna Pincas, Nada Marjanovic, Michael Schotsaert, Carles Martínez-Romero, Rafael Fenutria, Justin P. Ingram, Irene Ramos, Ana Fernandez-Sesma, Siddharth Balachandran, Adolfo García-Sastre & Stuart C. Sealfon


The risk of emerging pandemic influenza A viruses (IAVs) that approach the devastating 1918 strain motivates finding strain-specific host–pathogen mechanisms. During infection, dendritic cells (DC) mature into antigen-presenting cells that activate T cells, linking innate to adaptive immunity.

DC infection with seasonal IAVs, but not with the 1918 and 2009 pandemic strains, induces global RNA degradation. Here, we show that DC infection with seasonal IAV causes immunogenic RIPK3-mediated cell death. Pandemic IAV suppresses this immunogenic DC cell death.

Only DC infected with seasonal IAV, but not with pandemic IAV, enhance maturation of uninfected DC and T cell proliferation. In vivo, circulating T cell levels are reduced after pandemic, but not seasonal, IAV infection. Using recombinant viruses, we identify the HA genomic segment as the mediator of cell death inhibition. These results show how pandemic influenza viruses subvert the immune response.

(Continue . . . )

Simply put, regular seasonal influenza kills dendritic cells, which serve in multiple capacities on the front lines of our immune system, while pandemic H1N1 does not.  By continuing to live, dendritic cells fail to release DAMPs, and so a weaker immune response is mounted.

Highlights of this research shows that:
  • Seasonal but not pandemic IAVs induce human dendritic cell death
  • Pandemic IAV inhibits RIPK3-mediated cell death
  • RIPK3-mediated cell death activates T cell proliferation
  • Viral genomic segment HA mediates necroptosis inhibition
  • And that Pandemic IAV reduces T cell proliferation in humans

This is just a simplistic, and heavily truncated, summary of their findings. Those with a reasonably good grasp of the science and an hour or five to spare will certainly want to follow the link and read this study in its entirety.

Philippines DOH Threatens To Sue Sanofi Over Dengue Vaccine


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.


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


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.


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.