First malaria vaccine reduces early childhood mortality(science.org)
science.org
First malaria vaccine reduces early childhood mortality
https://www.science.org/content/article/first-malaria-vaccine-slashes-early-childhood-deaths
129 comments
> I guess when you're up against anti-vax fear mongering, you need to fight fire with fire.
That's completely unfair, in this case. The vaccine in question was associated with an increase in deaths in some subgroups (vs control), and overall low effectiveness in the phase 3 clinical trials.
A 13% decrease in mortality in this study is actually quite good given what was expected, but it is in no way "fear mongering" to question the safety/efficacy balance, even now. For example, you'd likely never administer this vaccine outside of high-risk populations. The fact that the safety signals "went away" in this trial is likely more indicative of the baseline risk of the population than any change in the vaccine itself.
Where is this line? Hard to say, but just for the sake of argument: anyone suggesting that we add this to mandatory vaccination schedules in the US would be a total lunatic. Should it be widely used outside of the worst parts of Africa, where malnutrition and preventable childhood illness are rampant? Again, hard to say.
Vaccines are not automatically good, and it isn't "anti-vax fear mongering" to question a particular vaccine. We have to test them, and see if the rewards are greater than the risks in the populations where we intend to use them.
That's completely unfair, in this case. The vaccine in question was associated with an increase in deaths in some subgroups (vs control), and overall low effectiveness in the phase 3 clinical trials.
A 13% decrease in mortality in this study is actually quite good given what was expected, but it is in no way "fear mongering" to question the safety/efficacy balance, even now. For example, you'd likely never administer this vaccine outside of high-risk populations. The fact that the safety signals "went away" in this trial is likely more indicative of the baseline risk of the population than any change in the vaccine itself.
Where is this line? Hard to say, but just for the sake of argument: anyone suggesting that we add this to mandatory vaccination schedules in the US would be a total lunatic. Should it be widely used outside of the worst parts of Africa, where malnutrition and preventable childhood illness are rampant? Again, hard to say.
Vaccines are not automatically good, and it isn't "anti-vax fear mongering" to question a particular vaccine. We have to test them, and see if the rewards are greater than the risks in the populations where we intend to use them.
I think a lot of people simply ignore the basic fact that vaccines aren't safe by nature, they have to be proven to be safe through very very rigorous processes.
Anti-vaxxers might come across as a lunatic but their extreme behaviour does not make opposite is true by default.
An astoundingly level-headed take for HN. We need more science in the science community.
"The fact that the safety signals "went away" in this trial is likely more indicative of the baseline risk of the population than any change in the vaccine itself" - or just the fact that sometimes, a study can give the wrong signal, the same way it can happen you land a coin three times heads in a row and yet the coin isn't biased...
A 13% reduction in all-cause mortality is huge. There are other methodological/reliability concerns, but malaria isn't near 100% of death, even among children.
One way to describe Africa's development in this era is that they're economically 100 years behind the rich world, but catching up 3 years per year.
In that environment, you'd expect child mortality to go down year by year, regardless of this vaccine.
Maybe the study corrects for that, but the complete absence of details in this report isn't promising.
In that environment, you'd expect child mortality to go down year by year, regardless of this vaccine.
Maybe the study corrects for that, but the complete absence of details in this report isn't promising.
It's not regardless of the vaccine, though. You'd expect child mortality to go down year by year because of things like that. There used to be malaria in the UK, I'm sure child mortality dropped when it died off here too.
My point is that you need to compare how much the death rates went down in comparable regions, before attributing this 13% decrease to the vaccine.
It is compared to non-vaccinated regions, if you had bothered to read the article.
> To calculate mortality in the three countries, where death registry statistics are unreliable, the researchers employed tens of thousands of community reporters—more than 14,000 of them in Kenya alone—to conduct household surveys of childhood deaths in 79 areas where the RTS,S vaccine was administered and 79 comparator areas where it was not available.
> To calculate mortality in the three countries, where death registry statistics are unreliable, the researchers employed tens of thousands of community reporters—more than 14,000 of them in Kenya alone—to conduct household surveys of childhood deaths in 79 areas where the RTS,S vaccine was administered and 79 comparator areas where it was not available.
That’s not how these kinds of trials work. The 13% figure comes from comparing the control and intervention groups, which were observed over the same period of time. The change in baseline mortality over time of the entire population isn’t relevant.
You really don’t if it’s controlled. The control group would have any other factors baked in.
If the group that got the vaccine has a 13% lower all cause mortality than the group that didn’t, and it was your standard randomized controlled double blind study, that’s a huge win.
If the group that got the vaccine has a 13% lower all cause mortality than the group that didn’t, and it was your standard randomized controlled double blind study, that’s a huge win.
> but the complete absence of details in this report isn't promising.
We don't have the actual report yet: just reporting on it being presented at a conference. I have not found it in indexes yet, but hopefully soon.
> Maybe the study corrects for that
Yes: the article we're reading makes it clear that it's comparing like-communities where there was and was not vaccine rollout, not looking at time series data.
We don't have the actual report yet: just reporting on it being presented at a conference. I have not found it in indexes yet, but hopefully soon.
> Maybe the study corrects for that
Yes: the article we're reading makes it clear that it's comparing like-communities where there was and was not vaccine rollout, not looking at time series data.
I'm actually surprised we don't have the actual report yet - for large medical conferences and big results like this, there's often a joint Press Release - Conference Presentation - Journal Publication release.
Do you not understand how control groups work?
I do, just wasn't thinking of it when posting :(
Fair enough! Good on you for realizing your error.
Yes, it is clear that they do not.
They look at differences across comparable regions that got the vaccine and regions that didn't with time period controlled for so I'd say they account for that.
OK, I've been convinced that I'm wrong, because the number is of course compared to the control group.
I apologize for any inconvenience!
I apologize for any inconvenience!
Of course, the catching up of '3 years per year' is partially thanks to roll-outs of vaccination.
It is a fact that poor/undeveloped countries are currently developing faster than any country ever has at any point in history.
If you have not read it, Factfullness by Hans Rosling is incredible.
If you have not read it, Factfullness by Hans Rosling is incredible.
I hadn’t grasped the all-cause aspect from a skim read.
That’s not all that huge when there’s such a small number of deaths in the given group over that time. This is part of the reason a lot of drugs later prove to be useless…
I also don’t see a citation for the 13% reduction in all cause mortality. To be honest, that’s an insanely weird metric to review for a malaria vaccine. Why not malaria related deaths?
Total in 2015 study [1]:
> 8922 children and 6537 young infants were included in the modified intention-to-treat analyses.
Total deaths: …? Are we talking 8 deaths in the control group and 7 in those injected?
This isn’t clear at all to me
[1] https://pubmed.ncbi.nlm.nih.gov/25913272/
On page 20 of the 2021 report we see 1443 deaths in comparison group and 1421 in implementing group [2]. With a pretty wide margin of error I might add. Is that what they’re reporting…?
[2] https://www.nitag-resource.org/sites/default/files/2022-05/M...
I also don’t see a citation for the 13% reduction in all cause mortality. To be honest, that’s an insanely weird metric to review for a malaria vaccine. Why not malaria related deaths?
Total in 2015 study [1]:
> 8922 children and 6537 young infants were included in the modified intention-to-treat analyses.
Total deaths: …? Are we talking 8 deaths in the control group and 7 in those injected?
This isn’t clear at all to me
[1] https://pubmed.ncbi.nlm.nih.gov/25913272/
On page 20 of the 2021 report we see 1443 deaths in comparison group and 1421 in implementing group [2]. With a pretty wide margin of error I might add. Is that what they’re reporting…?
[2] https://www.nitag-resource.org/sites/default/files/2022-05/M...
All-cause mortality is easier to measure, it also takes into account any deaths caused by the vaccine, and any deaths caused by non-malaria proximate causes that would nevertheless have been averted by the vaccine. Malaria is really bad for you even if you survive it, and probably makes you more vulnerable to dying of other things:
"For instance, clinical malaria is known to exhaust T cells, he says, and vaccination, by preventing infection, might therefore leave T cells readier to combat other pathogens. Such a general survival benefit has been documented for measles and tuberculosis vaccination. Other leading causes of death in the young children in these areas include pneumonia and diarrhea caused by pathogens including Streptococcus pneumoniae and rotavirus."
So, surviving malaria could very easily make it harder to survive your next encounter with rotavirus; vaccinating against malaria would then reduce deaths from rotavirus.
"For instance, clinical malaria is known to exhaust T cells, he says, and vaccination, by preventing infection, might therefore leave T cells readier to combat other pathogens. Such a general survival benefit has been documented for measles and tuberculosis vaccination. Other leading causes of death in the young children in these areas include pneumonia and diarrhea caused by pathogens including Streptococcus pneumoniae and rotavirus."
So, surviving malaria could very easily make it harder to survive your next encounter with rotavirus; vaccinating against malaria would then reduce deaths from rotavirus.
Yeah, but...it's also subject to sample bias. Especially in a place like east Africa, having enough resources (not just money -- time, transport, etc.) to get a crazy expensive new vaccine could easily have co-variates that affect all-cause mortality.
It's great to report it, but you definitely want to see the cause-specific numbers, too.
It's great to report it, but you definitely want to see the cause-specific numbers, too.
They used two sets of controls: 1, an entire set of communities where the vaccination wasn't offered at all, and 2, children who were not eligible due to age. They weren't just comparing children who got the vaccine with children who didn't, they were comparing children who were eligible for the vaccine and those who weren't, and that couldn't have been so easily confounded:
"79 areas where the RTS,S vaccine was administered and 79 comparator areas where it was not available"
"Researchers then compared the death rates of babies whose age made them eligible to receive three doses of the vaccine with those of young children who were not age-eligible for three doses, in both RTS,S areas and unvaccinated areas."
This is obviously not foolproof, but it seems like a substantial bulwark against obvious confounders.
If you can show that 1) the mortality rate in the vaccinated communities was lower in the age-eligible children than not-age-eligible[0] and 2) this effect was absent in unvaccinated communities that seems like it goes quite far towards proving that it's real and not an artifact. It probably even underestimates how protective it is at an individual level.
(communities which had the vaccine offered also had fewer cases of severe malaria recorded in their hospitals, so there's a straightforward reason to think it does something)
[1] okay probably age-ineligible children have a different mortality rate regardless. You'd be taking the difference between those two groups of children and comparing it to the same difference in communities without the vaccination offered. This difference-of-difference would tell you whether the vaccine is doing anything. It wouldn't matter if only the richer children received the vaccine if the communities have basically the same distribution of wealth since you're comparing differences between age cohorts, not between vaccinated and unvaccinated.
"79 areas where the RTS,S vaccine was administered and 79 comparator areas where it was not available"
"Researchers then compared the death rates of babies whose age made them eligible to receive three doses of the vaccine with those of young children who were not age-eligible for three doses, in both RTS,S areas and unvaccinated areas."
This is obviously not foolproof, but it seems like a substantial bulwark against obvious confounders.
If you can show that 1) the mortality rate in the vaccinated communities was lower in the age-eligible children than not-age-eligible[0] and 2) this effect was absent in unvaccinated communities that seems like it goes quite far towards proving that it's real and not an artifact. It probably even underestimates how protective it is at an individual level.
(communities which had the vaccine offered also had fewer cases of severe malaria recorded in their hospitals, so there's a straightforward reason to think it does something)
[1] okay probably age-ineligible children have a different mortality rate regardless. You'd be taking the difference between those two groups of children and comparing it to the same difference in communities without the vaccination offered. This difference-of-difference would tell you whether the vaccine is doing anything. It wouldn't matter if only the richer children received the vaccine if the communities have basically the same distribution of wealth since you're comparing differences between age cohorts, not between vaccinated and unvaccinated.
> This is obviously not foolproof, but it seems like a substantial bulwark against obvious confounders.
I mean...they had controls? That's good. But otherwise, there's no way you can tell from what is written. Even if the controls are perfect (which I don't grant without more detail), the implementation of the controls can still allow for confounding.
> they were comparing children who were eligible for the vaccine and those who weren't, and that couldn't have been easily confounded
You can trivially get confounding based on that. Just pick the kids who are healthier, and call them "eligible". Or pick the ones who are older (which they did, as you note), and voila...infinite time bias! Kids who make it to age N are more likely to survive to age N+1 than kids who make it to age N-1 (I mostly disregarded the between-group differences based on age, for this exact reason. It's too easily confounded.)
More commonly, bias of this form sneaks into a study. Particularly in a place like sub-saharan Africa, the set of people who are even willing to engage with you, mysterious doctor-magician, are of a fundamentally different nature than the ones you never see. They probably do all sorts of things that make them a little bit healthier, on average.
It's hard to correct for that, and it's a real problem when the primary metric is "community survey of all-cause mortality". For example: are the community surveyors also magical stranger doctor-magicians, or are they just regular people? It matters.
I mean...they had controls? That's good. But otherwise, there's no way you can tell from what is written. Even if the controls are perfect (which I don't grant without more detail), the implementation of the controls can still allow for confounding.
> they were comparing children who were eligible for the vaccine and those who weren't, and that couldn't have been easily confounded
You can trivially get confounding based on that. Just pick the kids who are healthier, and call them "eligible". Or pick the ones who are older (which they did, as you note), and voila...infinite time bias! Kids who make it to age N are more likely to survive to age N+1 than kids who make it to age N-1 (I mostly disregarded the between-group differences based on age, for this exact reason. It's too easily confounded.)
More commonly, bias of this form sneaks into a study. Particularly in a place like sub-saharan Africa, the set of people who are even willing to engage with you, mysterious doctor-magician, are of a fundamentally different nature than the ones you never see. They probably do all sorts of things that make them a little bit healthier, on average.
It's hard to correct for that, and it's a real problem when the primary metric is "community survey of all-cause mortality". For example: are the community surveyors also magical stranger doctor-magicians, or are they just regular people? It matters.
> > This is obviously not foolproof, but it seems like a substantial bulwark against obvious confounders.
> I mean...they had controls? That's good. But otherwise, there's no way you can tell from what is written. Even if the controls are perfect (which I don't grant without more detail), the implementation of the controls can still allow for confounding.
> > they were comparing children who were eligible for the vaccine and those who weren't, and that couldn't have been easily confounded
> You can trivially get confounding based on that. Just pick the kids who are healthier, and call them "eligible". Or pick the ones who are older (which they did, as you note), and voila...infinite time bias! Kids who make it to age N are more likely to survive to age N+1 than kids who make it to age N-1 (I mostly disregarded the between-group differences based on age, for this exact reason. It's too easily confounded.)
They did use two control groups, that's the whole point so you compare the difference between the age groups for the area where they vaccinated and the area where they didn't. That reduces confounding factors, e.g. based on area.
> More commonly, bias of this form sneaks into a study. Particularly in a place like sub-saharan Africa, the set of people who are even willing to engage with you, mysterious doctor-magician, are of a fundamentally different nature than the ones you never see. They probably do all sorts of things that make them a little bit healthier, on average.
And you base that assertion on what? Your prejudice ("mysterious doctor-magician", do you think about what you're implying here?!). In reality based on the studies I have read people in underdeveloped nations are significantly more likely to engage with health professionals and less likely to believe in anti vax or other anti science prkpaganda across all classes than in developed nations. Also one should note that in developed nations the effect is the other way around, anti vax sentiments are strongest (and therefore less likely to get vaccinated) in richer classes, who tend to generally have healthier lifestyles.
> It's hard to correct for that, and it's a real problem when the primary metric is "community survey of all-cause mortality". For example: are the community surveyors also magical stranger doctor-magicians, or are they just regular people? It matters.
It's much easier to look at all cause mortality than cause specific mortality, because you include more confounding factors. It's the much better study.
> I mean...they had controls? That's good. But otherwise, there's no way you can tell from what is written. Even if the controls are perfect (which I don't grant without more detail), the implementation of the controls can still allow for confounding.
> > they were comparing children who were eligible for the vaccine and those who weren't, and that couldn't have been easily confounded
> You can trivially get confounding based on that. Just pick the kids who are healthier, and call them "eligible". Or pick the ones who are older (which they did, as you note), and voila...infinite time bias! Kids who make it to age N are more likely to survive to age N+1 than kids who make it to age N-1 (I mostly disregarded the between-group differences based on age, for this exact reason. It's too easily confounded.)
They did use two control groups, that's the whole point so you compare the difference between the age groups for the area where they vaccinated and the area where they didn't. That reduces confounding factors, e.g. based on area.
> More commonly, bias of this form sneaks into a study. Particularly in a place like sub-saharan Africa, the set of people who are even willing to engage with you, mysterious doctor-magician, are of a fundamentally different nature than the ones you never see. They probably do all sorts of things that make them a little bit healthier, on average.
And you base that assertion on what? Your prejudice ("mysterious doctor-magician", do you think about what you're implying here?!). In reality based on the studies I have read people in underdeveloped nations are significantly more likely to engage with health professionals and less likely to believe in anti vax or other anti science prkpaganda across all classes than in developed nations. Also one should note that in developed nations the effect is the other way around, anti vax sentiments are strongest (and therefore less likely to get vaccinated) in richer classes, who tend to generally have healthier lifestyles.
> It's hard to correct for that, and it's a real problem when the primary metric is "community survey of all-cause mortality". For example: are the community surveyors also magical stranger doctor-magicians, or are they just regular people? It matters.
It's much easier to look at all cause mortality than cause specific mortality, because you include more confounding factors. It's the much better study.
> And you base that assertion on what?
Lots and lots of prior research, as well as direct experience talking to people who run these kinds of experiments. It's practically the #1 most common theme you will hear from anyone who has run a public health campaign in a third-world country.
Just for example [1]: "From the onset, Northern Nigeria presented an extreme challenge. The transmission of polio in Northern Nigeria was due to complex health, economic and social issues such as poor demand for and access to health services, low immunization coverage, few available skilled health workers, extreme poverty, low literacy, and community resistance to immunization and government services. Other factors such as the safety of the vaccine, religious factors, and community distrust of government health systems played a major role in increasing transmission. This led to a reemergence of polio in Nigeria, especially in the Northern states. Even in areas where polio immunization was not controversial, failure to engage parents and discuss why a fully vaccinated child may develop polio disease, for instance, reinforced and increased parents’ negative perceptions of the polio program."
> "mysterious doctor-magician", do you think about what you're implying here?!
I'm not implying anything. I'm saying it explicitly. I'm certainly exaggerating for effect, but I'm saying it explicitly: lots of people in poor countries are fearful of medical professionals.
I don't know why that's surprising -- it's true right here in the USA, as well, and one of the reasons why certain ethnic groups have disproportionately bad medical outcomes.
> less likely to believe in anti vax or other anti science prkpaganda across all classes
Oh, stop. Nobody in this discussion is "anti science" -- I have a doctorate, in a biological science. Nor am I "anti-vax".
It's helpful if you don't characterize people who critically analyze research with an entire class of fictional villains. Because that actually is what scientists do.
[1] https://www.ajtmh.org/configurable/content/journals$002ftpmd...
Lots and lots of prior research, as well as direct experience talking to people who run these kinds of experiments. It's practically the #1 most common theme you will hear from anyone who has run a public health campaign in a third-world country.
Just for example [1]: "From the onset, Northern Nigeria presented an extreme challenge. The transmission of polio in Northern Nigeria was due to complex health, economic and social issues such as poor demand for and access to health services, low immunization coverage, few available skilled health workers, extreme poverty, low literacy, and community resistance to immunization and government services. Other factors such as the safety of the vaccine, religious factors, and community distrust of government health systems played a major role in increasing transmission. This led to a reemergence of polio in Nigeria, especially in the Northern states. Even in areas where polio immunization was not controversial, failure to engage parents and discuss why a fully vaccinated child may develop polio disease, for instance, reinforced and increased parents’ negative perceptions of the polio program."
> "mysterious doctor-magician", do you think about what you're implying here?!
I'm not implying anything. I'm saying it explicitly. I'm certainly exaggerating for effect, but I'm saying it explicitly: lots of people in poor countries are fearful of medical professionals.
I don't know why that's surprising -- it's true right here in the USA, as well, and one of the reasons why certain ethnic groups have disproportionately bad medical outcomes.
> less likely to believe in anti vax or other anti science prkpaganda across all classes
Oh, stop. Nobody in this discussion is "anti science" -- I have a doctorate, in a biological science. Nor am I "anti-vax".
It's helpful if you don't characterize people who critically analyze research with an entire class of fictional villains. Because that actually is what scientists do.
[1] https://www.ajtmh.org/configurable/content/journals$002ftpmd...
Just a quick clarification, I was not accusing you of being anti-science or anti-vax. I was using that as a short-hand for people the who don't want to get vaccinated, I'm sorry if I gave you the impression that I'm talking about you.
Regarding the "reaching only people based on certain educational background" I think choosing a citation about northern Nigeria is quite selective. The assertion that people in Africa are more vaccination skeptical seems to be a gross overgeneralisation and is vaccination acceptance rates vary greatly between countries (not surprising as this is the same in the developed world as well).
> I'm not implying anything. I'm saying it explicitly. I'm certainly exaggerating for effect, but I'm saying it explicitly: lots of people in poor countries are fearful of medical professionals.
Well your choice of language certainly makes an association to stereotypes of "superstitious primitives"
> I don't know why that's surprising -- it's true right here in the USA, as well, and one of the reasons why certain ethnic groups have disproportionately bad medical outcomes.
Yes some ethnic groups, would these somehow be more likely to engage with the medical professionals that engage with the control groups, or go to the hospitals while being opposed to the "mysterious doctor-magicians"? Also the modern "health-suspicious" population in the USA (and other developed nations) is primarily composed of well off, well educated socio-economic backgrounds, e.g. just look at where recent measles outbreaks happened.
Regarding the "reaching only people based on certain educational background" I think choosing a citation about northern Nigeria is quite selective. The assertion that people in Africa are more vaccination skeptical seems to be a gross overgeneralisation and is vaccination acceptance rates vary greatly between countries (not surprising as this is the same in the developed world as well).
> I'm not implying anything. I'm saying it explicitly. I'm certainly exaggerating for effect, but I'm saying it explicitly: lots of people in poor countries are fearful of medical professionals.
Well your choice of language certainly makes an association to stereotypes of "superstitious primitives"
> I don't know why that's surprising -- it's true right here in the USA, as well, and one of the reasons why certain ethnic groups have disproportionately bad medical outcomes.
Yes some ethnic groups, would these somehow be more likely to engage with the medical professionals that engage with the control groups, or go to the hospitals while being opposed to the "mysterious doctor-magicians"? Also the modern "health-suspicious" population in the USA (and other developed nations) is primarily composed of well off, well educated socio-economic backgrounds, e.g. just look at where recent measles outbreaks happened.
> Just pick the kids who are healthier, and call them "eligible".
Sure, yeah. Or whatever. But there's no evidence for that in the article, it says it was done based on age, and then matched between comparable communities. You'd have to not only mess with the eligibility, but only do so in the vaccinated communities. Because they compared eligible and ineligible children in the unvaccinated communities, too. And again, the cohorts were split apart by age. Maybe a bunch of unhealthy children didn't get the vaccine for that reason, but they'd be included in the age-cohort anyway.
Of course they could maliciously juice the study but the "what if richer, healthier children were the ones that got the vaccine" just doesn't seem a reasonable criticism at least as described. It seems like a perfectly good design to avoid being confounded that sort of thing.
Sure, yeah. Or whatever. But there's no evidence for that in the article, it says it was done based on age, and then matched between comparable communities. You'd have to not only mess with the eligibility, but only do so in the vaccinated communities. Because they compared eligible and ineligible children in the unvaccinated communities, too. And again, the cohorts were split apart by age. Maybe a bunch of unhealthy children didn't get the vaccine for that reason, but they'd be included in the age-cohort anyway.
Of course they could maliciously juice the study but the "what if richer, healthier children were the ones that got the vaccine" just doesn't seem a reasonable criticism at least as described. It seems like a perfectly good design to avoid being confounded that sort of thing.
> You'd have to not only mess with the eligibility, but only do so in the vaccinated communities. Because they compared eligible and ineligible children in the unvaccinated communities, too.
Yes, I get that. I'm not suggesting malfeasance here [1]. I'm just saying controls are hard, and these problems pop up in the best studies.
The difference between the clinical trials and this was that the clinical trials were an actual RCT, and this is an observational study. Observational studies almost always have confounding issues.
[1] I do think the immortal time bias is real, however. Whether or not the bias was consistent between groups is a separate question, but I almost don't really care. The fact that they're reporting that older children survive a bit longer than younger children, and not mentioning this issue, is sketchy to me. They either don't understand the problem (bad), or are exaggerating (typical, but still bad), or they're hiding something (really bad).
Honestly stuff like this just makes me exhausted for the state of medical science. You spent a crapload of money on this. Immortal time bias is confounding 101. We know how to avoid it. Do the damned RCT!
Yes, I get that. I'm not suggesting malfeasance here [1]. I'm just saying controls are hard, and these problems pop up in the best studies.
The difference between the clinical trials and this was that the clinical trials were an actual RCT, and this is an observational study. Observational studies almost always have confounding issues.
[1] I do think the immortal time bias is real, however. Whether or not the bias was consistent between groups is a separate question, but I almost don't really care. The fact that they're reporting that older children survive a bit longer than younger children, and not mentioning this issue, is sketchy to me. They either don't understand the problem (bad), or are exaggerating (typical, but still bad), or they're hiding something (really bad).
Honestly stuff like this just makes me exhausted for the state of medical science. You spent a crapload of money on this. Immortal time bias is confounding 101. We know how to avoid it. Do the damned RCT!
> Kids who make it to age N are more likely to survive to age N+1 than kids who make it to age N-1
Look, maybe I'm just giving them credit because this is filtered through journalism, but isn't that the point of the control communities? You can subtract out this bias using the control community. It's all down to picking comparable controls, obviously. If I had to point to a place you could screw up it would be picking the wrong control communities. Ideally you'd probably pair communities and then assign them at random to get the vaccines or not.
I'm not objecting to the idea that there could be confounders, just that it's probably not sampling bias along the lines of "richer and healthier children probably got the vaccine." If all you're saying is, "it's not an RCT" then... yeah, it's not?
Look, maybe I'm just giving them credit because this is filtered through journalism, but isn't that the point of the control communities? You can subtract out this bias using the control community. It's all down to picking comparable controls, obviously. If I had to point to a place you could screw up it would be picking the wrong control communities. Ideally you'd probably pair communities and then assign them at random to get the vaccines or not.
I'm not objecting to the idea that there could be confounders, just that it's probably not sampling bias along the lines of "richer and healthier children probably got the vaccine." If all you're saying is, "it's not an RCT" then... yeah, it's not?
The question is how hard is to pick good control communities. During the pandemic I've read a lot of preprints about cures for covid-19 (like Ivermectin) and many of them used a similar aproach. It looks very hard. I've seen too many bad results with this kind of controls. Double blind randomized controled trial or it didn't happen.
We already did the RCT and saw that the incidence of severe malaria was reduced.
Now we've done an actual rollout, and have seen in observational data a bigger reduction in all-cause mortality than we expected. It's relatively high quality observational data, but of course the risk of confounds is larger than the RCT.
Now we've done an actual rollout, and have seen in observational data a bigger reduction in all-cause mortality than we expected. It's relatively high quality observational data, but of course the risk of confounds is larger than the RCT.
[deleted]
Actually, all cause is the right metric. Let's say the vaccine stops 100% of malaria but causes severe heart attacks. You'd probably want to know that. I didn't review _this_ study, so I won't comment on the quality of analysis, but what you want to know about a vaccine is "effectivity" does it stop contraction and spread of the illness and "safety" does it not cause any other problems that in aggregate are worse than the illness (all cause mortality is one metric here).
And indeed there are a number of trials that show a decrease in all cause mortality (mass childhood administration of azithromycin comes to mind) that we'd miss if we were just looking at already known endpoints.
Here is the relevant text from the article
> The comparison, covering 46 months, revealed the 13% decline in mortality—excluding accidental deaths—attributed to RTS,S.
Thats a 13% decline in all cause morality, excluding accidental deaths. The 13% number isn't just in deaths from malaria, its in deaths including all diseases.
> The comparison, covering 46 months, revealed the 13% decline in mortality—excluding accidental deaths—attributed to RTS,S.
Thats a 13% decline in all cause morality, excluding accidental deaths. The 13% number isn't just in deaths from malaria, its in deaths including all diseases.
From the article, yes. Where's the report?
"I guess when you're up against anti-vax fear mongering, you need to fight fire with fire."
That's seems like a dubious strategy likely to backfire. I hope you're not serious.
That's seems like a dubious strategy likely to backfire. I hope you're not serious.
The significance seems to be that it shows real-world results from a malaria vaccine that’s only moderately effective:
> In clinical trial results published in 2015, RTS,S showed 36.3% efficacy against clinical malaria a median of 4 years after toddlers were vaccinated.
Some possible side-effects seem to be ruled out:
> Giving RTS,S to 5-month-olds to 24-month-olds did not hurt the uptake of other childhood vaccines, which had been a concern. And it didn’t cause a decline in bed net use due to a false sense of security.
> In clinical trial results published in 2015, RTS,S showed 36.3% efficacy against clinical malaria a median of 4 years after toddlers were vaccinated.
Some possible side-effects seem to be ruled out:
> Giving RTS,S to 5-month-olds to 24-month-olds did not hurt the uptake of other childhood vaccines, which had been a concern. And it didn’t cause a decline in bed net use due to a false sense of security.
13% of all toddler deaths by any (non-accident) cause. That's very substantial.
Quick googling says that there are around 3.4 million child (<5 years) deaths in the region; 450k malaria deaths would be about 13% of that.
I would expect that approach fuels it.
What would fight it is honesty, not rushing to markets with sensationalism.
> What would fight it is honesty
To a degree. After a certain point, people have freedom to choose and society natural selection to benefit from.
To a degree. After a certain point, people have freedom to choose and society natural selection to benefit from.
Society pays a huge cost from premature death.
The article doesn't say but my understanding is this was a 13% reduction in all-cause mortality as in they measured the number of children who died during the time period and that went down by 13%. Not that 87% of malaria related deaths still occurred. A 13% reduction in all-cause mortality is quite large. To know how effective the vaccine is at stopping malaria related deaths you'd need to know what % of those who were dying were dying to malaria. If it was 14% then the vaccine is performing insanely well if it was 50% more work needs to be done.
> I guess when you're up against anti-vax fear mongering, you need to fight fire with fire.
You do know the vax is associated with a myriad of side effects including clots, strokes, reduced fertility and increase in turbo cancers, contains dna contaminants and was not properly tested don't you ?
You do know the vax is associated with a myriad of side effects including clots, strokes, reduced fertility and increase in turbo cancers, contains dna contaminants and was not properly tested don't you ?
> I guess when you're up against anti-vax fear mongering, you need to fight fire with fire.
Comment was great until this. Rent-free. Don't start fires and you won't have to fight them.
Comment was great until this. Rent-free. Don't start fires and you won't have to fight them.
People are opposed to being forced into injections of experimental mRNA.
Very few people were ever opposed to the standard-type vaccines we have been using for 100 years.
That is why the vast majority of people are happy to vaccinate themselves against polio and tetanus, but only 2% of people were interested in the latest Pfizer booooster experiment.
I would suggest against making up imaginary enemies.
Very few people were ever opposed to the standard-type vaccines we have been using for 100 years.
That is why the vast majority of people are happy to vaccinate themselves against polio and tetanus, but only 2% of people were interested in the latest Pfizer booooster experiment.
I would suggest against making up imaginary enemies.
The problem with your assessment is that you aren't being injected with experimental mRNA, it is well tested and proven on billions of people. It's fine to not want to be a part of that, but saying it is experimental is misinformation.
Seems inaccurate where vaccines were correlated to autism in a 2016 GOP debate. (And the doctor on stage said nothing to rebut, and turned out to be anti mRNA as well)
Don't make it partisan. Remember, for decades prior to covid, antivax had been more predominate on the left. Both parties have plenty of ignorant members.
It wasn’t so much a question of skew but visibility: people saw celebrities opposing vaccination a lot more than, say, the Christian homeschoolers who were doing the same things but not holding press conferences back then.
This is a readily citable nationally televised recent singular event with many elected officials on stage, ~3 years before mRNA was rolled out for a major event
Decades and smaller advocacy groups are less distinct.
Decades and smaller advocacy groups are less distinct.
Wow I thought there already was a Malaria vaccine and that that was what the Gates foundation had been deploying to eradicate the disease, but they've only so far been able to (go to great lengths to) mess with mosquitos, protect people from symptoms, remove people from conditions, etc. to otherwise prevent it by conventional means. A vaccine is huge!
It is indeed huge. It might be coming as a shock that there was no vaccine for this, but it would make sense if you look at the demographics and geography that gets affected by malaria, dengue. And that truly makes it huge. Hope this is accessible as well. Now I hope my country gets an approved dengue vaccine. I had it once, won’t wish to my enemies. I’d rather take covid any day.
Beyond demographics and geography, malaria is just hard. It's not a virus with fairly stable antigenic targets - it's a parasite that readily develops resistance to things.
This is indeed huge, even if the effect is only modest on a per-person basis, because we're still talking about a tremendous number of the world's population being protected.
This is indeed huge, even if the effect is only modest on a per-person basis, because we're still talking about a tremendous number of the world's population being protected.
I find these results extremely promising. If I understand the numbers correctly, about 450,000 children die of malaria alone every year. That means a 13% reduction in deaths would save over 50,000 children per year. This is a lower bound estimate as well, as there are other sources of child mortality and the 13% figure is for all deaths.
I think some of the other commenters were expecting higher numbers. It has been very difficult to produce a malaria vaccine in the past, and we already knew this particular one was not very effective. If you had this as a prior, you should be able to see this as the breakthrough it ultimately is.
I think some of the other commenters were expecting higher numbers. It has been very difficult to produce a malaria vaccine in the past, and we already knew this particular one was not very effective. If you had this as a prior, you should be able to see this as the breakthrough it ultimately is.
13% is the reduction in all-cause mortality — ie, if every death this prevented was a death from malaria, this reduced deaths from malaria by over 99%.
This would mean that a lot of malaria related deaths are unaccounted for or that the vaccine is helping in another way.
One hypothesis is that some people who caught malaria but did not die from malaria, did die more frequently to another cause where having had malaria was a contributing factor to that death.
> To calculate mortality in the three countries, where death registry statistics are unreliable, the researchers employed tens of thousands of community reporters—more than 14,000 of them in Kenya alone—to conduct household surveys of childhood deaths in 79 areas where the RTS,S vaccine was administered and 79 comparator areas where it was not available.
That doesn't sound remotely close to reliable.
> The mortality benefit was documented even in the areas with the lowest RTS,S coverage
The report doesn't provide any actual data, so it's impossible to make sense of this statement.
That doesn't sound remotely close to reliable.
> The mortality benefit was documented even in the areas with the lowest RTS,S coverage
The report doesn't provide any actual data, so it's impossible to make sense of this statement.
13% is a large effect size, you'd have to presuppose a systematic bias in the unreliability between the comparator districts.
Also, this is the case where research needs to be conducted but reality makes it hard but you can't just +not+ do the research. Field tests are always messy, and I'd posit that community reporting is probably more reliable thn politically motivated reporting from some governments.
> 13% is a large effect size,
You can't just say that. Depends on what you're measuring, how you measure it, and how big the denominator is.
The fact that they saw the same effect size in groups that didn't get the vaccine is a reason to doubt the results, regardless of effect size. It was weird/credulous that they called it out as some kind of mysterious woo-woo advantage ("maybe it helps their immune system somehow!"). When you see stuff like that in a paper, it makes you scrutinize the results. When you hear it in a conference talk, it makes you reserve judgment until you see the paper.
You can't just say that. Depends on what you're measuring, how you measure it, and how big the denominator is.
The fact that they saw the same effect size in groups that didn't get the vaccine is a reason to doubt the results, regardless of effect size. It was weird/credulous that they called it out as some kind of mysterious woo-woo advantage ("maybe it helps their immune system somehow!"). When you see stuff like that in a paper, it makes you scrutinize the results. When you hear it in a conference talk, it makes you reserve judgment until you see the paper.
> The fact that they saw the same effect size in groups that didn't get the vaccine is a reason to doubt the result
Where does it say that in the article? The closest it gets is "The mortality benefit was documented even in the areas with the lowest RTS,S coverage" but the lowest coverage was 62% (the highest was 75%).
Where does it say that in the article? The closest it gets is "The mortality benefit was documented even in the areas with the lowest RTS,S coverage" but the lowest coverage was 62% (the highest was 75%).
Yep, but then they go on to make the credulous woo-woo argument. None of us know what the actual results are here (since this is a conference talk, translated by a reporter), so I can only work with what they say.
In any well-done study with an effective treatment, you'd expect, a priori, that a reduction in intervention produces a reduction in effect. In other words, you don't benefit if you don't get the drug.
In any well-done study with an effective treatment, you'd expect, a priori, that a reduction in intervention produces a reduction in effect. In other words, you don't benefit if you don't get the drug.
The article is actually silent on whether the mortality effect was reduced, or whether the study was powerful enough to reliably detect that the mortality effect was reduced in lower-vaccinated communities. It just says the effect "was documented" in those communities, not whether it was exactly as strong.
Randomised placebo controlled trials are the only way to determine the reliability of a product.
The manufacturers know this. When they are doing something different it is not a good sign.
The manufacturers know this. When they are doing something different it is not a good sign.
BS , all there problems are becauseof Bill Gays needles ,there life style is natural and healthy they don't need any help , just leave them alone and stop using them like lab mice
Would love to see independent research, not the company presenting their own.
It’s insane to me that we let people with massive financial incentives run their own trials.
It’s insane to me that we let people with massive financial incentives run their own trials.
Who'd pay to run a trial if they didn't have an interest in the outcome?
A company running their own trial doesn't preclude other trials later on. Would you feel better if the African Union nations bucked up for a trial? Because they have a massive financial incentive too, though it's based on efficacy rather than sales.
A company running their own trial doesn't preclude other trials later on. Would you feel better if the African Union nations bucked up for a trial? Because they have a massive financial incentive too, though it's based on efficacy rather than sales.
Imo most trials should have two parts (1) do a blind bid so competitors can conduct trial (2) fund trial yourself as well. Hide names of both people conducting trial.
Keep results hidden and send both results to FDA for review. Publish both results after review. Only attach names of entities who conducted the trial at the end.
This enables for a full replication and evaluation without anyone knowing who did anything. And at the very least reduces risk of corruption.
Keep results hidden and send both results to FDA for review. Publish both results after review. Only attach names of entities who conducted the trial at the end.
This enables for a full replication and evaluation without anyone knowing who did anything. And at the very least reduces risk of corruption.
Drug trials are already double-blind and highly regulated, particularly stage 3, so further controlling for the corruption you are suggesting doesn't seem necessary. If there is evidence (hard evidence not hearsay or conspiracy theories) of that sort of corruption, then I think what you suggest is a good improvement.
When lots of money is on the line, all kinds of people involved find ways to subvert the blinding process.
Without hard evidence, that's a great example of a conspiracy theory.
Do you have a more recent example than Vioxx in mind where your approach might have made enough of a difference to be worth the longer review process?
> It’s insane to me that we let people with massive financial incentives run their own trials.
The alternative is for some other organization to be on the hook for the HUGE costs a large scale trial. And then the incentives to not run useless expensive trials goes away.
The alternative is for some other organization to be on the hook for the HUGE costs a large scale trial. And then the incentives to not run useless expensive trials goes away.
Consider your argument and opioids, where nearly 1000 people a week overdosed on at the peak?
Also consider "a scientist is as easy to buy as a politician".
Cigarette were considered to not cause cancer backed by science.
On top of that, the replication crisis in even chemistry and physics is seeing 30% of results can't be replicated.
The system is far more busted than people think.
Also consider "a scientist is as easy to buy as a politician".
Cigarette were considered to not cause cancer backed by science.
On top of that, the replication crisis in even chemistry and physics is seeing 30% of results can't be replicated.
The system is far more busted than people think.
> Consider your argument and opioids, where nearly 1000 people a week overdosed on at the peak?
What does that have to do, at all, with the process for getting medications approved?
These drugs were clearly being oversubscribed, intentionally and for profit, and people should have been sent to jail for this.
> Also consider "a scientist is as easy to buy as a politician".
What does this have to do with anything at all? This is why the FDA has fairly strict guidelines for approvals.
> Cigarette were considered to not cause cancer backed by science.
Cigarette's were never approved in a clinical trial.
> On top of that, the replication crisis in even chemistry and physics is seeing 30% of results can't be replicated.
Clinical trials are not "chemistry and physics" papers.
> The system is far more busted than people think.
I agree, but you are talking about a bunch of unrelated "systems", not clinical trials.
What does that have to do, at all, with the process for getting medications approved?
These drugs were clearly being oversubscribed, intentionally and for profit, and people should have been sent to jail for this.
> Also consider "a scientist is as easy to buy as a politician".
What does this have to do with anything at all? This is why the FDA has fairly strict guidelines for approvals.
> Cigarette were considered to not cause cancer backed by science.
Cigarette's were never approved in a clinical trial.
> On top of that, the replication crisis in even chemistry and physics is seeing 30% of results can't be replicated.
Clinical trials are not "chemistry and physics" papers.
> The system is far more busted than people think.
I agree, but you are talking about a bunch of unrelated "systems", not clinical trials.
if 30% of chemistry and physics papers can't be replicated, and something more like 70% of sociology and phycology papers can't be replicated, do you think that clinic trials might have a less than 100% trustworthy due to the possible monetary gains from the company conducting them?
opioids went through clinical trials, no?
opioids went through clinical trials, no?
Opioids didn’t cause harm because they should have failed their clinical trials.
To add to your point, this erodes trust in science too. Public perception of complex topics is very, very important. People effectively have to "trust" science. When it's corrupted there are ripples of distrust sown through the populace. Vaccine deniers, climate deniers, etcetc - distrust is just one of the fuels that fan these flames.
The people sowing distrust ARE the vaccine deniers and climate deniers. People comparing vaccine trials to cigarettes, like the person you are agreeing with here, ARE the problem; they were not created by "corporate funded vaccine trials".
You don't think perverse incentivized trials/studies/etc do damage to public perception? I'm not well versed in this subject (or versed at all), but if anything i feel like i am the public we're speaking about. Pro science, but scared of bad faith science.
For example, my perception is that the push for pro-sugar doctrine "back in the day" has caused significant health problems and a distrust in the process.
Do you view this as not the case?
For example, my perception is that the push for pro-sugar doctrine "back in the day" has caused significant health problems and a distrust in the process.
Do you view this as not the case?
I have a Ph.D. in a hard science, so I guess I'm not totally unaware of how science works. Let's say, I have lived experience as to why 30% of physics and chemistry research can't be replicated.
Putting 100% faith and trust in a "corporate funded vaccine trials" is something I would suggest against given the potential monetary gains from those conducting it.
Putting 100% faith and trust in a "corporate funded vaccine trials" is something I would suggest against given the potential monetary gains from those conducting it.
I've been part of teams that have put products through FDA clinical trials.
I can assure it was a somewhat different process than what ever process your "hard science Ph.D" requires for publishing papers.
I can assure it was a somewhat different process than what ever process your "hard science Ph.D" requires for publishing papers.
They don't run their own trial. Hundreds of doctors and clinics sign up to run trials on the companies behalf.
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interesting article, many things left me skeptical throughout but I’m glad they’re doing it
it seems like a nice stride is occurring in the cheap malaria vaccine market
the actual malaria part seems to have limited efficacy - which is what was studied initially - while simply having preventative healthcare at all is improving everything, with this vaccine being a useful component on its own in boosting the immune system
it seems like a nice stride is occurring in the cheap malaria vaccine market
the actual malaria part seems to have limited efficacy - which is what was studied initially - while simply having preventative healthcare at all is improving everything, with this vaccine being a useful component on its own in boosting the immune system
fwungy(1)
tiahura(6)
13% over 4 years sounds pretty weak.
FTA: “the first vaccine approved to fight malaria cut deaths among young children by 13% over nearly 4 years”
I read that as 13% of all young children deaths.
https://www.sciencedirect.com/science/article/pii/S240584402...:
“Malaria was the fourth highest cause of mortality in Sub-Saharan Africa, accounting for 10% of children's deaths”
“In 2013, malaria in Malawi was the leading cause of hospital admissions and death in children under five years of age and pregnant women. The disease accounted for 20% of all deaths of children under five”
⇒ I guesstimate this decreased mortality by malaria in those regions by 50-ish percent.
I read that as 13% of all young children deaths.
https://www.sciencedirect.com/science/article/pii/S240584402...:
“Malaria was the fourth highest cause of mortality in Sub-Saharan Africa, accounting for 10% of children's deaths”
“In 2013, malaria in Malawi was the leading cause of hospital admissions and death in children under five years of age and pregnant women. The disease accounted for 20% of all deaths of children under five”
⇒ I guesstimate this decreased mortality by malaria in those regions by 50-ish percent.
It's presumably all-cause mortality. So deaths solely attributed to malaria might have seen a far larger drop.
13% over 4 years for a novel vaccine against a disease we have been trying and failing to eradicate for the better part of several centuries sounds like a pretty significant step forward to me.
What numbers would your layman mind cosider acceptable?
Thanks—we've s/slash/reduc/'d the title above to make this point clearer.
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But regardless, I found "slashing" to be a bit exaggerated when the fatality reduction was 13% in a small pilot program. Very promising, but sensationalistic. I guess when you're up against anti-vax fear mongering, you need to fight fire with fire.
[0] https://pubmed.ncbi.nlm.nih.gov/25913272/