
Moderna’s SARS-CoV-2 Vaccine Phase I Data - hprotagonist
https://blogs.sciencemag.org/pipeline/archives/2020/07/15/modernas-phase-i-data
======
pen2l
Pasting from linked twitter thread, while this is encouraging, some things are
left to be desired:

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.

~~~
objektif
Which vaccines are more promising in terms of longer term immunity? Bloomberg
reports CanSino one seems to be better than Moderna on that and it only
requires one shot.

~~~
claudeganon
It’s possible that longer term immunity (> 3 months) isn’t even possible.
There’s initial evidence of reinfections in that time frame, which means that
vaccines would only last about that long and “herd immunity” is impossible:

[https://www.vox.com/2020/7/12/21321653/getting-
covid-19-twic...](https://www.vox.com/2020/7/12/21321653/getting-
covid-19-twice-reinfection-antibody-herd-immunity)

~~~
kardos
So do we solve that with 4x a year vaccination?

~~~
greesil
At least until something better comes along.

~~~
tzs
Wouldn't it be sufficient to just keep it up until you reach a point where
you've had a couple weeks with no known active cases in your country?
(Assuming similar for the rest of the world, with travel restrictions or
quarantines on people traveling from places where there are active cases).

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.

~~~
Erlich_Bachman
> up until you reach a point where you've had a couple weeks with no known
> active cases in your country?

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?

~~~
objektif
Is that the same influenza that keeps spreading year over year? Can you please
explain how does the virus stay viable over long periods of time without
spreading from host to host?

~~~
Erlich_Bachman
I would very much like a real explanation for this question from some expert
in virology. But I just assume in some kind of similar way to how measles came
back in Canada among the antivax community in recent years.

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.

------
DrBazza
The author of that article also writes these fascinating articles "Things I
won't work with"

[https://blogs.sciencemag.org/pipeline/archives/category/thin...](https://blogs.sciencemag.org/pipeline/archives/category/things-
i-wont-work-with)

~~~
ethbro
Derek Lowe's base blog is better, and more active, currently:
[https://blogs.sciencemag.org/pipeline/](https://blogs.sciencemag.org/pipeline/)

------
melling
“But one thing that you do notice as you look over the data was that day 43
was the best – there was a further evaluation at day 57, and all three groups
had gone down a bit in just those two weeks.“

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?

~~~
creaghpatr
If enough people take the vaccine with that expected length of protection, it
would certainly tamp down the spread at minimum. So it might still 'work' by
collective standards.

~~~
nugget
40% of vaccine recipients experienced fever after administration. I'm not sure
people would rush to take the vaccine with those odds, if only a few months of
immunity is conveyed. There's a psychological element to this beyond whatever
the science shows.

~~~
raxxorrax
Vaccines aren't completely harmless, but this would be expected. You can do a
self test with a flu vaccine. Your doctor probably will recommend no
exhausting activities for a few days after taking the shot. If you, for
science, ignore that advice, you might feel quite horrible.

~~~
geerlingguy
Every time I get the flu shot it feels like someone punched me hard on the
shoulder where it was administered for a couple days, and I feel generally
unwell (but not 'bad' per-se).

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.

~~~
amyjess
My experience with DTP shots is that one of my arms is a useless-but-painful
dead weight for a week or so. I'd still take that over getting tetanus.

------
jakozaur
AZD1222 vaccine by Oxford and AstraZeneca looks the most promising so far:

\+ 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-...](https://www.nytimes.com/2020/04/27/world/europe/coronavirus-
vaccine-update-oxford.html)

~~~
woofie11
Can you please explain the last bullet or post a link?

"~ 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.

~~~
shorts_theory
The Oxford vaccine (ChAdOx1) uses another vector virus called the adenovirus
to deliver the coronavirus genes which the body can fight against. The issue
is that some people might have pre-existing immunity to the adenovirus, making
the vaccine ineffective. Since ChAdOx1 uses an adenovirus which infects
chimpanzees, it is likely that most people will not have any pre-existing
immunity to the vector virus. I guess the parent comment is referring to the
fact that the body might develop immunity to the chimpanzee vector virus after
two doses, making booster shots ineffective.

~~~
woofie11
Thank you!

------
maxehmookau
I'm currently enrolled in the only currently active phase III trial for a
COVID-19 vaccine developed by Oxford Unviersity.
[https://www.ovg.ox.ac.uk/news/covid-19-vaccine-
development](https://www.ovg.ox.ac.uk/news/covid-19-vaccine-development)

It's supposedly a "front-runner" but also who knows!

~~~
ttul
How frequently do you get tested for the virus?

~~~
maxehmookau
Weekly with a PCR swab. 2-monthly for antibodies via a blood sample.

~~~
ttul
Ouch!

~~~
maxehmookau
It's not that bad. You get used to it pretty quickly!

------
chvid
This NY Times overview of various candidate vaccines is interesting:

[https://www.nytimes.com/interactive/2020/science/coronavirus...](https://www.nytimes.com/interactive/2020/science/coronavirus-
vaccine-tracker.html)

Coronavirus Vaccine Tracker

~~~
EarthIsHome
Oh wow! Thanks for this. I didn't know there were candidates in Phase III
already or that there's already a vaccine that's been approved.

~~~
chvid
It is approved only for use within the Chinese military.

~~~
lbeltrame
It's also unlikely to be very effective due to it using the adenovirus Ad5 as
a vector, which is a human adenovirus that many people have antibodies
against. This means a marked loss of efficacy if you have them.

~~~
sudosysgen
Well, the trials show that is effective in essentially everyone. The use of
the Ad5 vector does not require replication, it's therefore unlikely that
antibodies will be effective at stopping a significant amount of the vector
implantation of a large fraction of the viral particles in cells.

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...](https://www.thelancet.com/journals/lancet/article/PIIS0140-6736\(20\)31208-3/fulltext)

~~~
lbeltrame
Like with Moderna, if I recall (on mobile, so I can't refresh my memory by
rereading it) the highest doses had some Grade 3 level fevers. So probably
medium dose would be used.

~~~
sudosysgen
Yep, side effects seem to be comparable. Medium dose would probably be used,
or likely something between medium dose and high dose.

------
DrScientist
Note Moderna's vaccine is using newish technology in that rather than being
injected with bits of the virus, dead virus or attenuated virus, so your body
can mount an immune response, you are given RNA which encodes the bit of the
virus - so your body makes the virus bit itself, which then leads to the
immune response.

How this compares to the other approaches will be interesting.

~~~
guruz
For the record, other companies are having (early) success with RNA too.

BioNTech [https://investors.biontech.de/news-releases/news-release-
det...](https://investors.biontech.de/news-releases/news-release-
details/pfizer-and-biontech-announce-early-positive-data-ongoing-phase/)

CureVac [https://www.curevac.com/news/curevac-s-optimized-mrna-
platfo...](https://www.curevac.com/news/curevac-s-optimized-mrna-platform-
provides-positive-pre-clinical-results-at-low-dose-for-coronavirus-vaccine-
candidate)

------
The_rationalist
Very interesting but an ELI5 of the implications would be welcome:

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!

~~~
christoph
On the linked Twitter thread from the article there is a link to the AE chart

[https://twitter.com/RNAiAnalyst/status/1283149377427701761/p...](https://twitter.com/RNAiAnalyst/status/1283149377427701761/photo/1)

~~~
The_rationalist
Thanks! I would love to see a similar chart of competing vaccines.

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_

~~~
searine
>So the side effects are huge

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.

------
mchusma
Human challenge studies need to be seriously lined up right now as a part of
phase III work. (Human challenge studies mean giving people the full vaccine
dose, checking for antibodies, then giving a dose of the actual disease).

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/](https://1daysooner.org/) \- no affiliation although
I volunteered).

~~~
ljf
Remember that is just the risk of death.

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.

~~~
steve_adams_86
I had this experience, though with a different virus. It’s no joke. I was in
above average shape, able to run fast and far, lift heavy things, free dive
deep and long, etc. After a two week illness, I couldn’t lift my hands above
my head and I haven’t run more than 10km since, let alone at <5m per km. It
has been 4 years. It wrecked my lungs and I think even caused mild nerve
damage.

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.

~~~
ljf
So sorry to hear that - the more we have read about the post viral issues from
SARs, ebola and the 'spanish flu', the more we see that there are a huge
number of people affected in very different ways. For the first 3 months we
totally felt disbelieved by doctors and even some friends - 'are you sure it
isn't just anxiety?'.

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.

~~~
steve_adams_86
Thank you, and likewise - I hope your wife continues to recover and it doesn’t
impact your family too much.

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.

------
rossdavidh
So, long story short: encouraging first phase, with a whole lot of caveats, it
will need to wait on phase 2 and phase 3 even if everything goes well, there
are some negative reactions (but in this small group nothing too serious), and
it would take at least two doses and the effect starts to fade after a couple
months (which doesn't mean it would go away entirely). Plus we really only
know that there was _some_ response, not that it would protect you in the way
we normally expect a vaccine to.

In other words, long story short, probably not this year.

~~~
The_rationalist
* Plus we really only know that there was _some_ response, not that it would protect you in the way we normally expect a vaccine to.*

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.

~~~
psychometry
Why should only the financially desperate be asked to sacrifice for their
species? What a repugnant stance you've adopted.

~~~
The_rationalist
You can randomize it in an authoritarian way if you reject here the free
market, the way of selection matter far less than the discussion of how much
lives could be saved.

 _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/#...](https://www.worldometers.info/coronavirus/worldwide-
graphs/#total-deaths)

This give us 277,145 human deaths in this trial period. According to
[https://en.wikipedia.org/wiki/Mortality_due_to_COVID-19#Mort...](https://en.wikipedia.org/wiki/Mortality_due_to_COVID-19#Mortality_by_age)
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.

~~~
simiones
What is the error rate of the immune system response currently used, compared
to actual immune response? If it is small, then the value of infecting humans
directly goes way down. Further, what is the probability that the control
group and the vaccine groups will not be exposed naturally and accidentally to
Covid19 during the Phase II, Phase III studies? If they are likely to be
accidentally exposed, then purposefully exposing them has even less value.
Given the current infection rates in the US, this likelihood seems pretty
good.

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.

------
lymeeducator
Our immune systems are very complex and unique! If you want to apply
scientific method and improve outcomes (safety, efficacy), then there is a lot
more data to collect. Sharing that data and allowing recipients to own their
data, would go a long way towards improving vaccine safety and allow for
customization as needed. My children have had ~minor/moderate reactions to the
varicella vaccine (fluid on my son's hip joint ~2" from injection site at 23
days--ER doctors just shrug), my daughter a moderate rash. How could these be
improved? Guillain-Barre is very real side effect as well. How can it be
avoided? I accumulate metals easily, so Al, a potent neurotoxin hangs out in
my system much longer than others (possible/probable HLA variant). Shouldn't
the adjuvant for my vaccines exclude Al?

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).

~~~
wyattpeak
Spending a bunch more time collecting data to convince people who reflexively
put their fingers in their ears when presented with evidence seems a decidedly
wrong-headed approach.

~~~
lymeeducator
Spending time collecting data is for improving our understanding of an
individual's immune system. Sharing that data helps educate those who are
unfamiliar with, but have complete ownership of their body.

~~~
jbob2000
Data needs a narrative attached, otherwise it's just noise. There is a point
where adding more data doesn't change the narrative, so it's pointless to
continue gathering data.

~~~
lymeeducator
Are the immune responses to the vaccine identical across the trial group? No.
Is everyone's response to sars-cov-2 identical? No. Is everyone's immune
system unique in its signaling and adaptive behavior? Yes. How is it possible
to correlate immune responses by measuring 0.000x percent of the available
data? We do not have complete understanding of our immune systems, thus we
need more data and most of it can be relevant.

~~~
jbob2000
Ok, you can sit in a corner for the next 1000 years while all of that data is
gathered for you. A glimpse at your username suggests you have intense bias
with regards to the human body and its immune system.

------
dharma1
this is encouraging - hope the side effects at those lower doses don't turn
out to be significant.

How does the Moderna mRNA vaccine differ from the other mRNA vaccine in Phase
1/2 trials - BioNTech/Pfizer?

~~~
snapetom
Derek Lowe's last blog post was about Pfizer/BioNTech. He discussed Pfizer's
CEO comments and their Phase I data. Lowe seems optimistic.
[https://blogs.sciencemag.org/pipeline/archives/2020/07/14/pf...](https://blogs.sciencemag.org/pipeline/archives/2020/07/14/pfizers-
progress)

~~~
dharma1
nice. Looking forward to his Moderna results blog post.

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

~~~
snapetom
Oh, good. Sooner than I thought for Chaddox.

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.

------
tayebhid
Nice

------
AprilArcus
I'm very nervous about the safety of any vaccine based on a complete spike
protein, and worried that if one is rushed to market it will have such
disastrous side effects that it will be an antivaxxer talking point for the
next century.

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.

~~~
addictedcs
Very thoughtful point. I was concerned about it as well. Rushing a half-backed
vaccine that has serious side-effects will fuel antivaxxers for decades.

~~~
hannob
Frankly I don't buy that.

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.

~~~
objektif
I also happen to agree with you it is very unlikely that more people will
become anti-vaxer just because covid vaccine was not effective.

------
niccolop
How does this compare to the Oxford/AZ vaccine?

------
Trias11
Taking relatively healthy aged population group and feeding them placebo could
achieve similar outcome?

~~~
sp332
Phase 1 trials are primarily to demonstrate safety. Data about efficacy is a
nice bonus, but a Phase 2 trial should be large enough to show more clearly
whether it's effective.

~~~
mxcrossb
But they already are testing their blood for effectiveness. I have to say, if
a placebo can cause your blood cells to fight off a disease better even when
removed from your body, that would be something.

------
mathdev
It's quite incredible. This chemical appears to have a safety profile
comparable with the coronavirus itself, and yet the stock market appears to
anticipate a possibility that people will get injected with it en masse.

~~~
snapetom
That's because the one thing certainly Moderna has been good at is hype. Many
biologists have been pretty skeptical about an mRNA vaccine and yet Moderna
has been riding high.

