Considering all the excluded groups on the trial (page 3, kids, 55+, obese, weak immune system, a lot more), it's a lot of exclusions, how does one get from results on a study like this to declaring the vaccine safe for general use?
Generally speaking, experimental drug trials are run first on healthy groups and then in at-risk groups (old, young, those with co-morbidities). From the article, my guess is that they are expediting the sensitive groups trials, but unfortunately there's a lack of technical detail.
Source: My partner is an infectious disease specialist and we talk about this pretty much daily because I'm so curious.
But for this disease that's particularly bad because Covid has shown to be worst in 55+, obese, comorbidities, etc... which means that the trials on healthy groups are proving very little, since the virus itself is so much weaker on healthy groups.
>But for this disease that's particularly bad because...
Doesn't change the fact that, when you're developing a new drug, you want to test it in a way which will cause the least harm. You don't begin trials with those most at risk for obvious reasons. The primary goal of this phase it to asses the safety of the vaccine candidate.
I'm also unaware of any disease that isn't more threatening to people in relatively poor health.
"Spanish" flu was a notorious example: older people are believed to have had some amount of immunity from old strains, and the cytokine storms which made that strain so deadly are actually a consequence of having an active, robust immune system.
For much of 1918, a lot of people in their 20s getting the flu were also experiencing trench warfare, which can't be an optimal situation, both in terms of immediate self-care and co-occurring health conditions.
Older people were less vulnerable in the U.S. as well. The problem was that young healthy people were more likely to have an immune system overreaction. This applied to both genders.
You say it’s “obvious” but it’s the opposite of my intuition. Can you explain the logic a bit more?
I would have thought you’d give a risky new drug to the least healthy, most likely to die without it population, to raise the chance of survival from low to unknown.
Because you may not be raising it at all. The side effects could do more harm than the intended effects do good. So you need to do a large very controlled study with healthy people so you can more easily find side effects. Second, many side effects can be tolerated well by a healthy person but could be very dangerous in an at risk person. A drug that causes hypertension might not be a problem for a healthy person, but could kill someone with a heart condition. If you skipped this step, you could put people at risk of heart attacks and make it harder to detect the drugs effect on the heart vs already increased morbidity in those heart condition patients.
You are also evaluating the intended effects (as opposed to side effects), so you can see if it is actually doing what we want it to do, and how well. We could find out that the vaccine is very effective at preventing covid infections. But we could find out that it does not reduce the rate of covid infections, but does reduce the severity, or we could find out it does not reduce anything for reasons we don’t yet understand.
Once that is done, we will have a good understand of A. the level of benefit and B. the level of harm. From there we can make an educated decision to proceed or not. If we do, then it is approved and given to the general population, including those at risk. It is at this stage that the effects on at risk groups can be studied, during the ongoing monitoring of the approved drug.
Hopefully this answers your question and shows why this is the best way to do it.
There is always a balance of risks, and this is why there are ethics review board.
My intuition on this has become that the more certainty there is that you are to die without treatment, the easier it is to try relatively risky new treatments on you (with your consent). But say having stage IV pancreatic cancer is very different than having a comorbidity for a disease you haven't contracted yet.
Additionally with something like a vaccine, you are very interested in what it will do to the general population, not just the most vulnerable, because it should be rolled out to the general population. Anything screening program, you have to pay attention to the unlikely side effects since the denominator will be large.
Finally, you do these trials in phases because you need to find out if it is safe for humans first, then if it is effective.
Even among the 65+ survival is liable to be 90% even if infected and stand a good chance of avoiding the virus entirely even if they must wait a a few more months. Thus the probability of survival waiting isn't low to start with.
The proper calculation would be probability of infection * probability of death in the intervening months before we collect data on the efficacy of various options vs expected outcome if they just take the oxford vaccine now.
The users chance of survival is already quite high in the intervening period and while the benefits of the oxford vaccine are highly hypothetical they are also largely contingent on vaccinating everyone. People are liable to only see IF it works a 30% - 60% effectiveness, lower for some with worse immune systems. The real benefit is decreasing the spread of the virus until it dies out not merely the individuals benefit which will never happen if it turns out it doesn't work.
Worse it may be most apt to kill or harm those who are also most vulnerable to covid.
At worst the patient trades a very good chance of survival for a substantial downside with no upside and a future vaccination with a different vaccine they ought to have waited for.
There are a few factors -- one is that the major goal is to measure the side effects and safety of a particular new drug, in relative isolation... someone who is already sick is more likely to be on other drugs, thereby greatly increasing the risk of drug interactions.
Another is that when someone is already sick, they are more likely to not do well with any particular new drug (pretty much nothing is 100% effective for 100% of people), so you'd have to have some way to trying to discern whether the fact they got worse or even died is related to the new drug vs. just a natural progression. This can get complicated to measure.
And specifically for this particular thread, this is a vaccine, not a cure -- so in any case, when we say "least healthy" in this context, we're not talking about giving it to people who are already diagnosed with the virus, but rather to those who are _at most risk of complications_ from the virus, _if they were to contact it_. So it would be giving a drug to people who _don't_ immediately "need" it to survive, but who are still most at risk from any side effects.
You don't want people to drop dead from your experimental vaccine . As a general rule, the people least likely to drop dead from your experimental vaccine are young, fit, healthy people. Start with them. If they drop dead, well shoot. If they nearly drop dead, lucky you didn't start with the people who are one bad day away from the grave already.
In addition to what others said, if you know or suspect the procedure is extremely risky, and no other good options exist, you _do_ start with the least healthy.
As an example, the patient who got the first heart transplant:
“As a result of heart attacks in 1965, approximately only one third of his heart was still functioning. In late October, he went into a diabetic coma, but regained consciousness. […] He was also suffering from kidney and liver failure.”
It’s a vaccine, not a cure once you have it. So the people you would be testing it on wouldn’t be infected yet. Therefore you don’t first test it on unhealthy people when the vaccine might have unrelated nasty side effects.
You have a built in assumption in your statement that you haven't acknowledged: that the drug helps rather than harms. A new drug may help or it may harm.
If the drug turns out to harm people, a healthy person may be able to deal with it and recover. While a person that is barely hanging on to life may be pushed over the edge. There's no data to support a new drug raises the survival rate. It may in fact lower it from low to zero. During testing you generally want to kill as few people as possible.
Once more data has been collected on the drug, then the balance starts to shift toward giving it to at risk groups.
If you did start experiments with those most vulnerable you exposing them to far more risks.
Drug trials always start from learning more about safety of treatment (as opposed to efficacy) and once deemed statistically safe, you move to test for efficacy.
I assume you're thinking about treatments who could give a chance to those who have little hope/time for surviving. There's probably a chance they can benefit from taking experimental drugs but if we know little about it (because they are early in trial phases) we less confident this treatment will be useful and worst, we maybe not learn much from why it failed
Presumably the risks of an unknown response outweigh an as yet unknown benefit when testing is starting. These risks would be amplified for those with already compromised systems.
This is preventative medecine, as far as I know, most vaccines cannot be given to someone who already has the disease.
So it makes sense to target healthy people first, to test out the vaccine side effects, make sure there aren't many or bad ones, and then test out if the vaccine works. And then once you know it has low side effects and works, you can risk testing it on more compromised individuals.
One of the goals of pre trials is to establish that negative effects, if there are any, aren't caused by other factors other than the drug itself.
It's already hard to prove it on healthy candidates, it's pretty much impossible on candidates whose immune system is already weakened by previous conditions.
> I would have thought you’d give a risky new drug to the least healthy
Yes, but at this stage there is no drug. You're in the process of making the drug. And you don't want to test your beta versions on sensitive subjects.
Once nothing obviously bad happens, you can expand the test circle.
The high-risk population introduces statistical complications evaluating the results - were bad outcomes caused by the treatment under investigation or by the preexisting conditions?
But even if only healthy people get the vaccine, it could prevent the virus from spreading as much, thus protecting the people who cannot get the vaccine and saving countless lives.
As far as I know, they don't inject people in the trial with Covid, instead they wait long enough and use statistics to asses how many should have gotten Covid by now and if they didn't attribute it to the vaccine working.
Since healthy young people are more likely to get Covid, it might be this is the fastest avenue to knowing how effective the vaccine is.
But I am not a doctor or infectious disease expert or vaccine researcher.
There's a protective effect of 'herd immunity'. E.g., if we vaccinate all the ordinarily healthy people, then it should slow spread to better protect the at-risk groups. Sort of counter-intuitive, but it buys us time until we can figure out if this vaccine is safe for those groups.
Age and comorbidities (!!) always make a disease worse, obesity is a bit less common perhaps, but there's always something that's a risk factor, and the point is not to do something highly experimental and unknown starting with people who are already at increased risk.
What is the alternative? Skip testing it on healthier groups first? Imagine what would happen if the trial was going awry _with_ healthy people. You certainly wouldn't want to test this on vulnerable populations.
They prove that it is generally safe on a group less likely to throw spurious correlations at you ...because they are at risk Of just about everything not just covid
This phase I/II study's primary objective was to learn about the safety of the vaccine, and about whether it causes an immune response. I'm no expert, but I expect the phase III trials in the US and India will include a broader population.
Ah, thanks for clarifying that you participated in phase 1/2, I had not gotten this from skimming through the document, that makes a lot more sense to me. Thanks for sharing!
Not really qualified to answer this, but I would imagine follow-on rounds of testing. Also, those groups should be protected through herd immunity if everyone else gets the vaccine.
Vaccines often cause a minor cosmetic bump. If you see people with a triangle of bumps on their shoulder for example they have received a common vaccine for healthcare workers.
And the smallpox one can leave an even bigger scar. I suppose they don't want the liability for that which could impact the model's income
Maybe a stupid question, but do we need to vaccinate everyone? I remember reading that heard immunity is 70% or something - so could we get away with leaving the people out that it wasn’t tested on?
THEORY: Assuming 100% efficacy vaccine. In completely homogeneous population if people are randomly vaccinated the threshold where the diseases effective R drops below 1.0 is 1 - 1/R. For example if R = 3.0 you need to vaccinate 66% population until infections start to decline.
REALITY: Assuming 75-90% efficacy vaccine, vaccination is non-random and population is heterogeneous. You want to vaccinate everyone who agrees to take it. Just like with children diseases, there will be clusters of anti-vaxxers, or people just don't bother and they are often clumped together, travel around the world and spread the disease.
It's not a stupid question, and I've heard that some vaccines are aiming to be approved only for adults at first. This would make sense not only because, as you say, you can start to approach herd immunity without vaccinating everyone, but also because children are weaker spreaders.
Obviously "herd immunity" is more of a gradient than a cut-off, and it's much easier to approach it if we can vaccinate everyone, but we can definitely speed up the process (including the months-long process to even get the vaccines to everyone) if we can start vaccinating some people early.
Theoretically the % of people needed to reach herd immunity is a function of how infectious the virus is. They use a number R to represent for each person who gets infected how many people they go on to infect. This changes over time as different measures come into place like lockdowns, masks, and social distancing. The basic reproductive number R0 (R-naught) is how infectious the virus is initially without any of those measures in place. The formula for the % of people needed to reach herd immunity is R0-1/R0. So if R0 is 4 then you need 3/4 of the population. If R0 is 3 then you need 2/3.
The vaccine may itself not be perfectly protective, and the herd immunity threshold only works if the people vaccinated are random. Otherwise any unvaccinated population can have an outbreak.
You should be able to see that Covid-19 is in fact a disease listed in the table on the wikipedia page you reference. You should also be able to see that the percentage required for herd immunity effect to begin (the 'herd immunity threshold') is a function of the R0 level for each disease.
In addition, to question of "can anyone really say for covid-19", I suppose the answer is 'No, but I would trust that the consensus of the scientific community of infectious disease experts is the best estimation we can get.'
i haven't read through all the questions asked here, but yours is perhaps the least stupid
i suspect you may already know the answer to your question; of course not everyone needs to be vaccinated - that's the job of any reasonably healthy immune system and this virus, which has not been properly isolated by the way, and that comes directly from the CDC, is not particularly dangerous, and that comes directly from the WHO
any thinking human being knows that masks are, at best, largely ineffective at preventing transmission, as is "social distancing" - the way governments are handling this "pandemic", which by definition is not a pandemic, is killing far more people and ruining far more lives that the virus ever will
the question then becomes, why? why are we being asked, and compelled in many case, to wear ineffective masks? why are being threatened and arrested in some cases for not distancing when there is no creditable scientific evidence to support that distancing works?
furthermore, the rt-PCR "test" that is used by many labs to diagnose COVID-19 is not a test - it is a procedure designed to amplify a tiny amount of RNA or DNA - it was never designed to test for this or any other virus and it does not produce a binary result, so in the end , we have NO idea how many cases there are, and it gets worse than that because apparently PCR is looking for any corona virus, alive or dead! that means that anyone that's ever had a cold can test positive (along with people that died in motorcycle accidents, fallen down stairs, or got shot in the face apparently)
the number of 'cases' is meaningless and the survival rate is exceedingly high, and if we make an adjustment for the radically inflated number of deaths, it becomes very questionable whether there even is a "novel" corona virus or whether it's the flu
lastly, even if one is not reasonably healthy, or just doesn't wish to spend a lot of time being sick, all that required is high-dose vitamin C along with D3 (and zinc wouldn't hurt) - what's a high dosage? 4 grams+ / hr. for an adult, not that it's critical because no one has ever died from vitamins (minerals is a different story)
> this "pandemic", which by definition is not a pandemic
> any thinking human being knows that masks are, at best, largely ineffective at preventing transmission, as is "social distancing"
> it becomes very questionable whether there even is a "novel" corona virus or whether it's the flu
You know, I live in Adelaide, where we haven't had a single locally-acquired case in several months. I've been wondering how almost every other city on the planet has been screwing things up so badly when we've not really done all that much apart from having a quick reaction and social distancing appropriately.
My question is now answered: those cities have people like you, willing to spout even the most blatantly abject conspiratorial nonsense for the sake of advertising your own website.
Please show some responsibility for the lives of those around you.
As someone living in Melbourne it's been frustrating to see this same nonsense spread locally by a very vocal minority, followed by "lockdowns don't work".
I'm celebrating that following the science here has taken us from > 700 new cases per day, to our second consecutive day of zero (and lockdown ending less than 3 hours from now)
The control group will not be given the vaccine, but a placebo.
Clinical trials are phased. Typically you start with a very small group of people to evaluate toxicity (e.g. below treatment levels of a drug), then a slightly larger group looking for side effect, then a significantly larger group looking for desired effects, and finally a broad group looking for safety and efficacy.
That phase 3 study for the Oxford vaccine is already underway, and its initial findings are what the article is referring to. It was one of the first (possibly the first, I'm not entirely sure) to enter phase 3.
Extrapolation. Is there a scientific rationale as to why the vaccine would NOT be safe and effective in a new population? If not, approve it for that population. If there is rationale why it wouldn’t be, ask for more data.
Noise in the data - you want as clean a population as you can get. If you start including people with chronic conditions, as soon as someone in your trial dies you get to play a game called "prove that it wasn't the vaccine that killed them".
Same with people over 55 years old - they are known to respond differently to vaccines. The worst thing in the world would be showing a 49.4% reduction in Covid infection rate (the FDA wants 50% minimum) and then being forced to do a bunch of handwaving about how your results were skewed by the 55+ patients in your study and "by gosh, I swear it would be over 50% if we adjust for them using this methodology we just made up". Nobody will believe you and you'll be relegated to "that vaccine that almost works".
Ethics - Kids aren't (well, very rarely) dying from Covid, but they could die after getting your experimental vaccine. Kids sickened by experimental drugs makes for bad press, not only you, but also the FDA. Easier to just exclude them for now.
