Moderna’s SARS-CoV-2 Vaccine Phase I Data
blogs.sciencemag.org
blogs.sciencemag.org
1) No data for the most vulnerable older (>55) population
2) Second dose absolutely necessary
3) Safety profile less than desirable
4) Durability of neutralizing Ab not so encouraging (decline from day 43~57)
5) Very low CD8 T-cell responses
Novavas phase I results (NVX-CoV2373), probably due to be out soon, will be interesting.
I think we're at about "vague hunch" certainty on how well these vaccines will work in the field.
https://www.vox.com/2020/7/12/21321653/getting-covid-19-twic...
In places with good contact tracing, they should mostly be able to keep it at near zero after that point by tracing and self-quarantine, occasionally needing to use the vaccine on a whole city if you find that you had a super-spreader event.
In places without good contract tracing, it would be similar except the threshold at which you need to vaccinate the city would be lower.
We’ve had a measles vaccine for three generations, we still have the measles.
We’ve had a polio vaccine for three generations, polio is not eliminated.
Seriously, though, i wonder why would Russia be developing coronavirus vaccine if most people these days die there from "atypical pneumonia" and not from coronavirus ... at least if one is to believe the official info.
This point never came for influenza anywhere, why would you think it will come for COVID19, a much more contagious and invisible in many more cases virus?
They are anti-vaxxers, yes, so no wonder that they could technically get measles, but where did it come from? It was completely irradicated because most people had the immunity. The virus should have died off and disappeared from the face of the planet. And yet here were are. There must mechanisms for viruses to survive this.
It's not even a serious candidate due to lack of efficacy and actually dangerous side effects, so far.
That breaks the site guidelines, and we ban accounts that do that, so please don't. Your comment would be just fine with the link and the second sentence.
The Oxford vaccine is the front runner. They're doing several Phase III trials right now, and people are taking that to be a good sign - that they want to present plenty of evidence of efficacy.
The downside is that it's two doses and you're still going to get COVID-19. It's just that the effects are far less severe.
One person taking the highest dose had a 103+ fever with the second...
If this is happening in healthy young people, what will the side effects look like for older or more vulnerable people who actually need it the most?
May be better on that axis (only way to know is to do the trial). Efficacy, on the other hand, is likely to be lower. Both sides of the same coin: you probably get less of a response from the old.
Even if the vaccine is not suitable for the older groups, high vaccination rates in younger people may be enough to drop the rate of infection significantly below 1.0, eventually conferring herd immunity for the immunocompromised.
Fever is very common in vaccines, especially in children.
Did anyone look at the actual data? [1, Table S1-S3]
At the 100 μg 2nd dose, the most frequent moderate symptoms were fatigue (40%, "some interference with activity"), chills (26.7%, "some interference with activity"), and headache (26.7%, "repeated use of non-narcotic pain reliever > 24 hours or some interference with activity"), with no severe events reported.
In other words, pretty much what you'd expect if you asked your immune system to floor it. I wouldn't characterize these as concerning.
In all probability, we won't see sufficiently numerous cohorts until Phase II is published, Phase III is in process. Remember, this was n=15 for most arms.
> One person taking the highest dose had a 103+ fever with the second...
That's why they standardized on the 100 μg dose for Phase III [2], as a result of Phase I/II safety profile and efficacy.
[1] https://www.nejm.org/doi/suppl/10.1056/NEJMoa2022483/suppl_f...
[2] https://investors.modernatx.com/news-releases/news-release-d...
[1] - https://www.statnews.com/2020/05/26/moderna-vaccine-candidat...
The stock market should be considered because of why?
What in Gods name does the Stock market have to do with anything? This is peoples lives we are talking about, not $company share price.
Do we know if this is actually an issue? A lower CD8 t-cell response might be expected given it's an RNA vaccine.
https://blogs.sciencemag.org/pipeline/archives/category/thin...
Interesting that it was slightly weaker at day 57.
If people don’t gain permanent immunity once they get covid, will this sort of drug still work?
If english has a good way to say this I'm not aware of it.
But the alternative is I could end up in the ICU with pneumonia without it (and have, in the past, from the flu), so the risk/annoyance is worth it.
Just to be clear I do HIIT, strength training, and (my favorite) lots of yard work regularly and the flu vaccine doesn't interfere with any of that.
I don't know how common it is to experience this, as I would say I have a subpar immune system (frequently sick as a kid, history of food allergies, etc.). But when I've discussed it with doctors they do say my reaction is unsurprising, however the benefits outweigh the "costs".
In January, this would have felt like a terrible deal. Right now, it feels like you're telling me that - should I socially isolate for a few weeks a year after vaccine shots - I can largely go back to living a normal life. That feels great.
As long as it's not a Grade 3 fever, I don't see a problem: many vaccines can cause (transient) fevers. (Part of that is due to the adjuvants used to prime the immune system by causing a localized inflammation).
I got a shot for the yellow fever a few years ago and I felt quite bad for a couple of days. When I was asked for a booster shot for measles, I was warned of the possibility of developing fever for a couple of days as well.
Discomfort is totally expected with vaccines.
The other would be whether it helps with partial immunity: it doesn’t need to be lifelong immunity to be worth using if, say, it shifted the serious case rate down by a fair margin.
Now if it isn’t close to 100% effective then you’ll probably still need people to quarantine, so, good luck with that.
+ already in late-stage trials
+ they are pre-producing it at large capacity
+ verified safe, no side-effects
~ may be very efficient in preventing diseases, but not enough to prevent spread, just slows it
~ may need second shoot after 4 months
~ long-term immunity is questionable for covid and you can get only two shoots of this type of vaccine in lifetime while maintaining it efficiency
https://www.nytimes.com/2020/04/27/world/europe/coronavirus-...
"~ long-term immunity is questionable for covid and you can get only two shoots of this type of vaccine in lifetime while maintaining it efficiency"
This suggests some fundamental misunderstanding in how I think about the immune system (which is unsurprising given I have no formal background there), and I think I'd learn a lot of important things from understanding why or how this works.
If it's hard or deep, I'm glad to do long-form reading if you have a link.
I'm not a doctor and there's a good chance I'm missing something, but this seems crazy to me. How could this be known already? I could understand if it just means that short term side-effects are rare to nonexistent, but what about long term issues or rare catastrophic ones?
It's supposedly a "front-runner" but also who knows!
I suffered standard vaccine side-effects. Flu-like symptoms for a couple of hours, muscle aches, that sort of thing. All resolved within 3 days but I had to self-isolate for those 3 days as having a fever in the UK means you must stay at home.
I wear a mask in crowded places and shops.
I go out in public, as normal but I work from home. I'm an otherwise healthy volunteer, so my risk of being severely unwell is _relatively_ low.
It's worth bearing in mind that the control group got an active vaccine for Meningitis, so it's impossible to know if I'm protected, and even if I was vaccinated with the experimental vaccine, if it even works!
Happy to answer other questions too :)
https://www.nytimes.com/interactive/2020/science/coronavirus...
Coronavirus Vaccine Tracker
If you read the study, it states that even in recipients with high Ad5 immunity, as long as the dose is sufficient (high-dose or medium dose) long-term seroconversion is high - 84% to 100% in medium or high dose after 28 days for recipients with strong antibodies against Ad5, and for high-dose seroconversion and interferon gamma response was indistinguishable from those without strong Ad5 immunity. [0, fig 1 - Specific T-cell response measured by ELISpot].
So I don't really think it will be an issue. You just need the proper dose. : https://www.thelancet.com/journals/lancet/article/PIIS0140-6...
How this compares to the other approaches will be interesting.
BioNTech https://investors.biontech.de/news-releases/news-release-det...
CureVac https://www.curevac.com/news/curevac-s-optimized-mrna-platfo...
Okay it needs 2 injection. Do they need to be spaced by 42 days? If so that would induce nuisible inertia.
How many percents of the patients recovered from the covid thanks to to the injection? I see 80% of response but I don't know how that translate into chance de of curing. Also how fast did they recover? The second injection has an adverse response, how bad is it? Too much for mainstream?
It's always fascinated me, this paradox of reporting: The author has made a lot of researchs and a great write-up but fail to answer the most pressing questions that both mainstream people and shareholders wants!
https://twitter.com/RNAiAnalyst/status/1283149377427701761/p...
So the side effects are huge relative to standard vaccines but rationally, if it works everybody should still take it. This will need to be enforced by politicians as I doubt people would have the maturity to take it voluntarily. It's the kind of wicked problem where we want that everybody take it except ourselves
Those side effects are very mild. Headache. Myalgia. etc.
How many times in your life has your arm been sore after a flu shot? These need to be measured but are not 'huge side effects'. No observed adverse event met the pre-defined cutoffs for stopping the trial.
The consensus seems to be "they are not ethical", which is an extreme, beaucratic, twisted set of ethics.
Small challenge studies of 100 people, who have a low risk profile, who volunteer to help their friends, family, and humanity will give us a lot of confidence to move forward.
The fatality rate of a soldier volunteering in the US for world war Ii was about 2%. For young healthy volunteers, we are talking something like 2 orders of magnitude less risk, for more clear marginal benefit than being one extra soldier in a war.
I feel that this isn't being lined up is negligent insanity.
(If you want to volunteer without any commitment https://1daysooner.org/ - no affiliation although I volunteered).
My wife is young (40 yo) fit and healthy, and 115 days after contracting covid she is still ill with post covid symptoms - there is no way she could work still and cannot look after or even play with our kids.
On her post covid support group it mainly seems to be women over 40 and men from 20 to 50 - though only about 7000 people who self selected to join the group so that might not be representative.
Just saying that while risk of death are low, there are other risks - though as yet poorly understood and researched.
If COVID is doing similar things to people, it’s very serious. It’s potentially life altering. I genuinely suspect I will never be as healthy or as strong as I was. I didn’t believe this could happen to healthy people in their 20s, especially not someone who could run a half marathon on a whim, but humans simply aren’t invulnerable.
Slowly doctors are realising that while the majority do recover, a not insignificant group will be affected for a lager period of time. Total guess but even if the number of long term cases is the same as those that die, and if on average they can't work for 6 months (conservative) then the economic impacts on those people and their families can be huge.
I really hope you see light at the end of the tunnel and take it easy.
I think the reality of sickness is often a revelation once it happens. It’s hard to believe what an impact it can have, seemingly arbitrarily. But with the right support and the right state of mind, recovery is often possible despite being difficult. After a point it just doesn’t happen on its own. It’s another part of life, something to learn from I suppose.
In other words, long story short, probably not this year.
I don't understand, did the tested patients recovered from covid? They did not inject on them the virus in order to test the vaccine? So many people die and we're too shy to test volunteers? So many humans on earth would risk their lives for a few hundred dollars, it is the reality where we live in. Let's take advantage of this reality, give them more than they would expect + glory and so much more lives would be saved. By doing heuristic guessing of if the vaccin works without really testing it we're going to do order of magnitude more harm to humanity.
tl;dr (the blog in general is a great resource though):
* We're not at a point where we need to deliberately expose people, as there's enough people being exposed in their communities.
* The normal standard for those deliberate tests also only recommend it if there's known effective for treatments for the diseases, which (obviously) there is not for COVID-19. Hell, we're still figuring out what exactly it's doing in the body.
* As a sibling comment brings up, history is riddled with unethical medical experimentation. We don't want to repeat those mistakes.
0: https://blogs.sciencemag.org/pipeline/archives/2020/07/02/ch...
What a repugnant stance you've adopted. Thinking like you think is consenting to mass murder, do you realize it ?
Here's my calculus: The phase I trial has approximately lasted 2 months. I checked the number of total deaths from 01 may to 01 July -> https://www.worldometers.info/coronavirus/worldwide-graphs/#...
This give us 277,145 human deaths in this trial period. According to https://en.wikipedia.org/wiki/Mortality_due_to_COVID-19#Mort... mortality rate for a ~20 years old should be at least lower than 0.1%.
With all those data in mind, here's the reasoning: The metric of effectiveness for this Moderna vaccine candidate is epistemologically LOW. They use fuzzy heuristics of matching approximately the immune response of naturally recovering patients as a claim of being effective. So firstly this reasoning is simplistic especially since researchers do not understand precisely how the working immune response work. So there is a risk of the vaccine to be a disappointment. If it is, those 277,145 human lifes would have been wasted and far more will die until we find the true vaccin. But what you need to understand is that researchers are condemned to match the existing immune response as otherwise, without testing on infected young humans, they cannot predict the vaccine expected performance. This alone is far enough for defending that they should have tested on a few dozen of infected patients the effectiveness. If they did: two possible scenarios: (lets suppose they tested 30 humans in their twenties that would make 0.3% of chance of deaths (comparatively to 277,145 human deaths) and the likelihood would be actually far lower as they would be actively monitored) scenario A) the vaccine doesn't work and it shows empirically, it save them weeks of evidence and therefore make them reconsider another paradigm for the virus. That alone would save at the very least thousands of lives by allowing the true vaccine to be found earlier. So you must realize that your "repugnant stance" of inaction is responsible in this likely scenario of far more deaths, sadly numbers quickly become unproportional to the emotional empathic response for a homo sapiens, this kind of brain failure honestly give a taste of vomit in my mouth, but yeah everybody is victim of this cognitive bias, even myself so no offense. In the second scenario, the empiricism would show them that their vaccine works: here again it would accelerate the delivery, and crucially the data would give them insights and allow for far better fine tuning of how the vaccine works and the optimal dosage. Is is not unreasonable to think that such speedup would allow to save a similar order of magnitude than 277,145 human deaths but could actually be far more (imagine 6 months of work saved y avoiding empirically invalidated or fine tuned research directions ? Even if it were to be lower, even if the data sped up the research by only one day (an insanely pessimistic view that I only show to defend your reasoning to the extreme, to its limit) would still save more than 5000 lives which is indeed far bigger than the likely lower than 0.3% of death rate for ~30 persons, so even in the ridiculous limit we talk about 5000+ vs 0.3 death.
The 277,145 number is meaningless. The vaccine was not known to help in any way 2 months ago. For all we knew at the time, if we had started giving this to people on mass 2 months ago, we would have had 300k deaths from the vaccine by now.
Then, the vaccine is not yet known to be effective. We only have proof that it is safe, but we don't have rigorous control studies showing that it is effective yet (we need the Phase II & III trials for that). Before that, there is only a "hunch" that it will help at all, so taking death numbers for the next few months is also going to be meaningless.
Finally, your "even if the data sped up the research by only one day" calculation is pure sophism. Why not assume that the data could slow down the research? What if one of the patients dies because of complications after being infected, and that affects team morale, slowing down the research? What if one of the researchers accidentally gets sick themselves because of improper handling of the live virus, again slowing down the research?
The final point is: we are already rushing this. There are good reasons we have stopped testing drugs on volunteers, we have a horrible history behind us of the effects, often without much better results (and often much worse results) than current methods. There methods we have for estimating actual immunity based on immune system response have been studied for some time and are considered good. Putting people's lives in danger is needless complication, more likely to slow everything down than to speed it up.
Phase II is where you start looking at if it works ( while still looking at safety- always looking at safety ), here you are also trying to typically work out what is the right dosing regime ( how much, how often ).
Phase III is large enough numbers to get population level stats for safety and efficacy, given the treatment regime you have decided on.
Also you don't just need willing people to take the vaccine to do a proper trial, you need the medical infrastructure around it.
People to administer it, keep track of the patients - monitoring them for any signs of adverse reaction - reliable people to take blood samples and handle them properly, proper note and record keeping etc.
The other thing to consider in trials is that roughly half your patients don't get anything ( more accurately a placebo ) - and in the case of vaccine trials, you need to control group to get infected!!! Otherwise you can't see any protective value.
You'd need to choose you control group to carefully reflect the test group - if you had your vaccine test group in New Zealand and your control group in the US - nobody would believe your result.
At the moment people doing trials in America have an advantage in that the virus is still infecting lots of people, so you can more easily demonstrate protection. If you are trying to trials in China - pretty hard.
I don't think lack of volunteers is the problem. If you want to do it ethically, you have to do it incrementally.
There are a lot more ways to get it wrong, than to get it right, and we want the quickest, good result, not just the quickest result. Aside from the ethical consequences of experimenting on poor people (and I don't think those are something we should put aside), coming up with a new process on the spot is not even probably the best way to get a good result fast. Would the people who step forward to do that be unusually healthy (hence willing to take the risk), and so throw off the results? Would they be disproportionately people who have already had Covid-19, for the same reason? Would they be different in some other way? Let's not try to wing this. We've got a time-and-battle-tested method for developing a vaccine. I would prefer we use that.
Moderna aims at an emergency use authorization for health personnel in October or during the autumn in general if the interim data from Phase II / III is good enough.
Measuring temperature & physical symptoms is a good start. It would be great if these trials would measure each recipients HLA SNPs (see GSK MERS 2009 fiasco and others), T-cells (CD4/8/57/etc), inflammation markers like C3a,C4a,TGF-b, MMP-9, and cytokines like TNF-a -- before and after each vaccine dose. Measuring for all ingredients pre-post each dose is also important because the metabolization for each component is not uniform. Stop using 2010+ technology to make vaccines & medications and then evaluating the applied result with 1990s (or earlier) methods.
So if you want to shut up 'anti-vaxxers' than collect/share the data from everyone who receives a vaccine and improve the process instead of shrouding results or conducting half-assed studies (AstraZeneca using meningitis vaccine as control instead of true placebo).
For example, galvanic skin response was used for very bullshit purposes, which led to research on it essentially stopping for over a decade. But recently it has been rebranded as "electrodermal activity", and turns out to have use for studying Epilepsy as well as other promising potential use cases (such as improving sleep staging without EEG).
I am less aware of literature on side effects for current vaccines, so I don't know if this same phenomenon has happened. But I wouldn't be surprised if certain lines of thinking are reflexively stomped down right now.
Maybe this just needs to be the natural life cycle of science though, it might be for the greater good to let anti-vax die down before doing anything which could stoke their flames.
AFAICR, this was done on purpose to prevent people from figuring out they got a vaccine shot, because an inert placebo wouldn't cause any side effects.
One big question about this for me is wondering if any group is looking for why this happened. I feel that either the pharmaceutical company or the government should be spending significant research dollars understanding what happened in this case.
It also shows that vaccines are not 100% safe, which seems to be the general narrative. When the truth maybe something more like you have a 1 in 10 million chance of living the rest of your life in agony, but you are required to accept the risk for the good of everyone.
So maybe collecting the blood markers suggested by the parent poster would be a step in understanding why things go so badly for some people.
How does the Moderna mRNA vaccine differ from the other mRNA vaccine in Phase 1/2 trials - BioNTech/Pfizer?
Oxford/AstraZeneca paper being published tomorrow too in Lancet I think.
Fingers crossed one of these will pan out quick! Winter wave would be ruthless
Chaddox has its downsides, but I think it'll be an effective band aid solution. As far as mRNA vaccines, I read that blog post and think Lowe, (and other biologists) have more hope for Pfizer than they do for Moderna. However, Pfizer's vaccine needs more time.
The only vaccines I'm really excited about are the ones based on S1 Receptor Binding Domain (RBD), none of which are yet in stage 1.
There has actually been something like this during the swine flu pandemic. There was a vaccine that is believed to have caused some cases of narcolepsy. This was a real, bad sideeffect with a vaccine that was rushed to market.
Surprisingly this isn't a big talking point in antivaccine circles. Yeah you'll hear about it sometimes, but compare it to the number of times you hear "somethingsomething MMR aluminium autism" which is all debunked bullshit - you'll hear that far more often.
What I want to say is: Antivaccine people largely don't care about real issues with vaccines. They're happy with their pseudoscientific nonsense, that's good enough for them to reject every vaccine ever made.
S1 Receptor Binding Domain (RBD), What make one more worrying than the other? I have not the expertise to make such inferences
What they think these side effects might be, I have no idea.
* T Cell mediated inflammatory cascade (Cytokine storm) caused by off-target cross-reactivity with IL-11: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092895/
* Autoimmune responses: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1809466/ and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246018/
* Antibody-Dependent Enhancement of viral entry: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4018502/
Not much is known about the humans immunological response to covid or this vaccine. Derek Lowe is rightly pointing out that it's way too early to say if this is even effective against COVID. The safety and dose-dependency is just the first step in the process.