Seems like a big deal. Dengue is different (and more problematic) than a lot of diseases in that if you've had Dengue even mildly or at least not severely, you're actually far more at risk for serious effects the next time if it's a different one of the four varieties of the disease. The article suggests that the trials so far protect against that effect as well.
[EDIT: As pak notes elsewhere, this trial apparently didn't test against all four varieties although there was some evidence it might protect against multiple.]
While I am of course a huge fan of NIAID and vaccine development against dengue, and I believe that a vaccine that works against dengue will probably be found within our lifetimes and prevent millions of hospitalizations (EDIT: not deaths, sorry) per year, this is a classic example of a downstream news report editorializing the headline and misrepresenting the implications of the original article.
The whole challenge in creating a dengue vaccine is that it has to protect against all four serotypes (called a tetravalent vaccine). Incomplete protection against one of the serotypes could potentially lead to an even worse infection if you are infected, through a process called antibody dependent enhancement: https://en.wikipedia.org/wiki/Antibody-dependent_enhancement This is why vaccine development against dengue has been so painstakingly slow.
The candidates in this trial were only challenged with one serotype, DENV-2. Therefore, we have no way to know if the tetravalence of the vaccine actually achieved efficacy against all four serotypes (although promisingly, antibodies against all serotypes were seen in 92% of the patients). The sample size is also quite small (N = ~20). This is why the original article states its impact conservatively as "This model may serve as an early check for dengue vaccine candidates, limiting the risk of conducting large unsuccessful trials" and furthermore "the true efficacy of TV003 can only be established by performing a phase 3 trial in endemic areas." Here's how you write a more honest headline and summary for lay people: http://www.cnn.com/2016/03/16/health/dengue-vaccine-effectiv...
I don't intend to detract from the achievement here, but I don't like when headlines oversimplify the implications of a clinical trial. It sets unrealistic expectations and decreases the public's trust in proper vaccine research.
Disclaimer: I am doing research with a lab that studies dengue virus, and we have collaborators that are working on a commercial vaccine.
> vaccine that works against dengue will probably be found within our lifetimes and prevent millions of deaths
Are you sure about "millions of deaths" ? Dengue fever fatality rate is lower than 1%. I'm not saying this is not a grave disease, but it's hardly something that kills as much as many other viruses out there.
> This is why the original article states its impact conservatively as "This model may serve as an early check for dengue vaccine candidates, limiting the risk of conducting large unsuccessful trials"
You're obviously much more familiar with this subject, but doesn't the quote from the original article refer to the testing model itself (i.e. "dengue human challenge model"), rather than the efficacy of the actual vaccine?
> this is a classic example of a downstream news report editorializing the headline and misrepresenting the implications of the original article.
To be fair, it doesn't seem like Wired has editorialized/misrepresented at least the headline much relative to the original article ("The live attenuated dengue vaccine TV003 elicits complete protection against dengue in a human challenge model" vs "Dengue fever vaccine proves 100% effective in human trials").
> I believe that a vaccine that works against dengue will probably be found within our lifetimes and prevent millions of deaths per year
I tried finding estimates of infections and deaths per year, but didn't find any that are close to millions/year. Do you have a source for that? The closest I got was from the CDC/WHO: The World Health Organization (WHO) estimates that 50 to 100 million infections occur yearly, including 500,000 DHF cases and 22,000 deaths, mostly among children. [0]
> doesn't the quote from the original article refer to the testing model itself
Yes, it does, precisely because the trial is about a human challenge model that uses an attenuated virus. It may or may not be representative of efficacy against natural infections by wildtype viruses, hence the second statement by the authors that "the true efficacy of TV003 can only be established by performing a phase 3 trial in endemic areas."
> it doesn't seem like Wired has editorialized/misrepresented at least the headline much relative to the original article
I believe the inclusion of "in a human challenge model" in the original title is quite significant to its interpretation, but it's precisely the kind of detail that would get overlooked by people unfamiliar with vaccine trials. A researcher in the field would know that human challenge models may or may not be representative of protection against natural infections, but the Wired title ignores that distinction and instead sows confusion by saying the vaccine simply "proves 100% effective".
> millions/year
You're right, I meant hospitalizations; sorry about that. Dengue hemorrhagic fever is a life-threatening condition that warrants hospitalization, and dengue fever in more vulnerable patients also can result in hospitalization.
The interview with the researcher addressed pretty much all the points you are making and stated that the goal of the trial type was to demonstrate the efficacy against DENV-2 so that they would be able to move forward in a full trial of all four types.
From the article:
"Whitehead and the other researchers said that in the case of dengue, the testing was warranted because they knew that the vaccine appeared to be effective at preventing dengue 1, 3 and 4 viruses through previous testing but needed to learn more about its impact on dengue 2 before proceeding to larger trials that could take three to 10 years and cost tens of millions of dollars."
So, we know people get Dengue fever and what it does to people. Why do you still need the placebo group in a study like this? I'm having a hard time seeing the morality of such a choice when we already have plenty of data on Dengue fever.
Yeah, I know the purpose, but I'm really still having a tough time seeing any actual justification when we know how bad a diseases is. I cannot think of a reason it is worth it. I worked in clinical trials briefly (9 months) and still think its a level of cruel that borders on inhuman. "I'm sorry, we know the disease / condition kills, but we gave your loved one sugar pills".
The dengue fever does not kill most of the time. It makes you paralyzed with high fever for one to two weeks, but usually it does not kill you, unless you are already old and weak. I'm pretty sure that the recruitment for the clinical trial can ensure that only healthy people with appropriate constitution would not die from dengue fever.
Don't we actually have enough data on the dengue fever to tell exactly what will happen to the control group? I don't think this is an actual unknown anymore.
Again, it is probably known - You would need to ask an expert, but I wage there are probably good reasons for having a control group, that we may not be aware of. I think the ethical question you raised is a serious concern in any clinical trial, so I would be very surprised if it is not addressed at any point by the trials's sponsors.
For this trial, the placebo and treatment groups are both composed of healthy volunteers that are exposed to a controlled amount of an attenuated dengue virus (called rDEN2Δ30). All groups in the trial are told the risks of exposure to the virus. Because the virus is attenuated (weakened), the risk of severe sickness is very very low.
The point of using an attenuated virus is that this is a "challenge model" that is supposed to simulate an exposure to the real virus closely enough that one can judge if the vaccine is likely working, without exposing the patients to the risks of infection by the full-strength virus. CNN did a much better job than Wired in explaining this. http://www.cnn.com/2016/03/16/health/dengue-vaccine-effectiv...
Therefore, the fact that the placebo group had certain levels of various symptoms (according to the article, 80% had a rash, 20% had nausea, etc.) is still important data for other scientists who are trying to judge if they should use the rDEN2Δ30 challenge model in their candidate vaccine trials. It's not intended to provide data on what natural dengue fever is like, which I agree would be unethical and unnecessary.
No, there is also an ethical concern behind it. We already know the survival rate per months for most cancers so there is no need to have a placebo group anyway. For cancer patients on trial we only want to offer a potential upside (once the drug is confirmed to be safe for use).
Plus, there are some cancers out there with very few working treatments (so no real SoC) - If SoC is not available you would not consider a placebo group anyway.
Can you give some examples of trials where there wasn't a control arm (e.g. placebo or SOC)? I agree actual placebos are rare since there is always something you can give to a cancer patient, even if it doesn't work well.
What I haven't seen is a clinical trial without a control arm.
In terms of the ethical considers it's not unusual to run a trial for a yeat and then switch every patient over to the new drug.
That's a valid point - I don't now enough about the dengue virus, but one possibility is that some folks are naturally immunized for the dengue fever, and if that is the case you would need to have a baseline to ensure that the vaccination works beyond that level/ratio. Just a guess.
First, and most importantly, the variant of Dengue that they infected the (presumably somewhat healthy) person with was a weaker variant that is highly unlikely to do serious harm, particularly in a hospital environment.
Second, I know you probably know this, but the purpose of the placebo/control group is to understand if the vaccine is actually doing anything, or whether there is another common factor (possibly placebo effect, but possibly environmental, diet, poorly activated dengue virus, etc...) that is preventing Dengue from taking hold.
I.E. if you have two groups one with the Vaccine, and one with just the Placebo, and both are injected with the dengue virus, and the group with the Vaccine and the group with the placebo both don't contract Dengue - then you have to consider the strong possibility that the vaccine didn't help, but some other factor prevented the two groups from getting dengue.
And, it's far, far better that you try this with 10 people, with a relatively weaker version of Dengue, in a controlled hospital environment where the person can be taken care of, in an area where they are very likely to get the more dangerous dengue regardless of the study, than to come to the incorrect conclusion that you have a workable Vaccine, that you then spend many more hundreds of thousands (millions?) of dollars in broader clinical trials - only to discover the vaccine wasn't really doing anything in the first place.
Wow this is great news. I was the type of person to not even give thought to these types of diseases, thinking they only applied to poorer populations in less-developed nations. When I went to a destination wedding in Jamaica two years ago, I laughed at all my friends who I thought were being excessively paranoid in constantly applying bug spray for fear of mosquito born viruses. You can imagine what happened next: I was infected with one of those viruses - Chikungunya more specifically - and it was one of the worst year and a half experiences of my life. I've just recently completely gotten over it, but man has the experience changed my outlook on these kids of things.
I caught Dengue in Bali a couple years ago. In retrospect I wasn't as careful about mosquitos as I should have been because I hadn't really noticed any. Fortunately it was "mild" in that I "only" spiked a 104 degree or so fever and was out flat for a week. (And had my doctor send me to the ER after I got some blood work done.) I was OK after a few weeks but now I'm rather paranoid about the (increasing) number of places where the disease can happen. I do like to travel and I'd really like to be able to get a vaccine (although I expect it will be a while) given the risk of re-exposure to a different variety.
It's hard to understand what it's like to live in fear of mosquitos.
Having lived in tropical areas where this is prevalent, and having suffered from dengue, this is incredible news. The people who are most affected by this are those who don't have resources to repel these tiny, common insects. They also don't have resources to properly treat this incredibly agonizing, and sometimes fatal, disease.
Lasers, sprays, genetics, and everything else under the sun has been proposed to control mosquitos. Something that controls the thing they spread, which causes so much suffering, is much more exciting.
It's worth to note this is one of a couple of promising vaccines, one of them is already approved in a couple of countries, as of December 2015: https://en.wikipedia.org/wiki/Dengue_vaccine#CYD .
Not "100% efficient" but nothing really is, nor is that really needed, it's not a boolean thing but a continuum and having any kind of antibody response is better than none; it reduces the chances of more severe disease at least, if not prevent disease all-together.
Whats with Figure 1? It looks like they didn't remove/replace template text: Lost to follow up (give reasons)... Discontinued intervention (give reasons)
Is this normal or does it indicate a problem with the peer review at this journal?
33 comments
[ 3.2 ms ] story [ 64.3 ms ] thread[EDIT: As pak notes elsewhere, this trial apparently didn't test against all four varieties although there was some evidence it might protect against multiple.]
The whole challenge in creating a dengue vaccine is that it has to protect against all four serotypes (called a tetravalent vaccine). Incomplete protection against one of the serotypes could potentially lead to an even worse infection if you are infected, through a process called antibody dependent enhancement: https://en.wikipedia.org/wiki/Antibody-dependent_enhancement This is why vaccine development against dengue has been so painstakingly slow.
The candidates in this trial were only challenged with one serotype, DENV-2. Therefore, we have no way to know if the tetravalence of the vaccine actually achieved efficacy against all four serotypes (although promisingly, antibodies against all serotypes were seen in 92% of the patients). The sample size is also quite small (N = ~20). This is why the original article states its impact conservatively as "This model may serve as an early check for dengue vaccine candidates, limiting the risk of conducting large unsuccessful trials" and furthermore "the true efficacy of TV003 can only be established by performing a phase 3 trial in endemic areas." Here's how you write a more honest headline and summary for lay people: http://www.cnn.com/2016/03/16/health/dengue-vaccine-effectiv...
I don't intend to detract from the achievement here, but I don't like when headlines oversimplify the implications of a clinical trial. It sets unrealistic expectations and decreases the public's trust in proper vaccine research.
Disclaimer: I am doing research with a lab that studies dengue virus, and we have collaborators that are working on a commercial vaccine.
Are you sure about "millions of deaths" ? Dengue fever fatality rate is lower than 1%. I'm not saying this is not a grave disease, but it's hardly something that kills as much as many other viruses out there.
You're obviously much more familiar with this subject, but doesn't the quote from the original article refer to the testing model itself (i.e. "dengue human challenge model"), rather than the efficacy of the actual vaccine?
> this is a classic example of a downstream news report editorializing the headline and misrepresenting the implications of the original article.
To be fair, it doesn't seem like Wired has editorialized/misrepresented at least the headline much relative to the original article ("The live attenuated dengue vaccine TV003 elicits complete protection against dengue in a human challenge model" vs "Dengue fever vaccine proves 100% effective in human trials").
> I believe that a vaccine that works against dengue will probably be found within our lifetimes and prevent millions of deaths per year
I tried finding estimates of infections and deaths per year, but didn't find any that are close to millions/year. Do you have a source for that? The closest I got was from the CDC/WHO: The World Health Organization (WHO) estimates that 50 to 100 million infections occur yearly, including 500,000 DHF cases and 22,000 deaths, mostly among children. [0]
[0] http://www.cdc.gov/dengue/epidemiology/
Yes, it does, precisely because the trial is about a human challenge model that uses an attenuated virus. It may or may not be representative of efficacy against natural infections by wildtype viruses, hence the second statement by the authors that "the true efficacy of TV003 can only be established by performing a phase 3 trial in endemic areas."
> it doesn't seem like Wired has editorialized/misrepresented at least the headline much relative to the original article
I believe the inclusion of "in a human challenge model" in the original title is quite significant to its interpretation, but it's precisely the kind of detail that would get overlooked by people unfamiliar with vaccine trials. A researcher in the field would know that human challenge models may or may not be representative of protection against natural infections, but the Wired title ignores that distinction and instead sows confusion by saying the vaccine simply "proves 100% effective".
> millions/year
You're right, I meant hospitalizations; sorry about that. Dengue hemorrhagic fever is a life-threatening condition that warrants hospitalization, and dengue fever in more vulnerable patients also can result in hospitalization.
The interview with the researcher addressed pretty much all the points you are making and stated that the goal of the trial type was to demonstrate the efficacy against DENV-2 so that they would be able to move forward in a full trial of all four types.
From the article:
"Whitehead and the other researchers said that in the case of dengue, the testing was warranted because they knew that the vaccine appeared to be effective at preventing dengue 1, 3 and 4 viruses through previous testing but needed to learn more about its impact on dengue 2 before proceeding to larger trials that could take three to 10 years and cost tens of millions of dollars."
https://en.wikipedia.org/wiki/Placebo-controlled_study
The point of using an attenuated virus is that this is a "challenge model" that is supposed to simulate an exposure to the real virus closely enough that one can judge if the vaccine is likely working, without exposing the patients to the risks of infection by the full-strength virus. CNN did a much better job than Wired in explaining this. http://www.cnn.com/2016/03/16/health/dengue-vaccine-effectiv...
Therefore, the fact that the placebo group had certain levels of various symptoms (according to the article, 80% had a rash, 20% had nausea, etc.) is still important data for other scientists who are trying to judge if they should use the rDEN2Δ30 challenge model in their candidate vaccine trials. It's not intended to provide data on what natural dengue fever is like, which I agree would be unethical and unnecessary.
In a cancer trial you'd typically compare standard of care with the new drug.
Plus, there are some cancers out there with very few working treatments (so no real SoC) - If SoC is not available you would not consider a placebo group anyway.
What I haven't seen is a clinical trial without a control arm.
In terms of the ethical considers it's not unusual to run a trial for a yeat and then switch every patient over to the new drug.
Second, I know you probably know this, but the purpose of the placebo/control group is to understand if the vaccine is actually doing anything, or whether there is another common factor (possibly placebo effect, but possibly environmental, diet, poorly activated dengue virus, etc...) that is preventing Dengue from taking hold.
I.E. if you have two groups one with the Vaccine, and one with just the Placebo, and both are injected with the dengue virus, and the group with the Vaccine and the group with the placebo both don't contract Dengue - then you have to consider the strong possibility that the vaccine didn't help, but some other factor prevented the two groups from getting dengue.
And, it's far, far better that you try this with 10 people, with a relatively weaker version of Dengue, in a controlled hospital environment where the person can be taken care of, in an area where they are very likely to get the more dangerous dengue regardless of the study, than to come to the incorrect conclusion that you have a workable Vaccine, that you then spend many more hundreds of thousands (millions?) of dollars in broader clinical trials - only to discover the vaccine wasn't really doing anything in the first place.
Having lived in tropical areas where this is prevalent, and having suffered from dengue, this is incredible news. The people who are most affected by this are those who don't have resources to repel these tiny, common insects. They also don't have resources to properly treat this incredibly agonizing, and sometimes fatal, disease.
Lasers, sprays, genetics, and everything else under the sun has been proposed to control mosquitos. Something that controls the thing they spread, which causes so much suffering, is much more exciting.
Not "100% efficient" but nothing really is, nor is that really needed, it's not a boolean thing but a continuum and having any kind of antibody response is better than none; it reduces the chances of more severe disease at least, if not prevent disease all-together.
Is this normal or does it indicate a problem with the peer review at this journal?