16 ms·

Messengers of hope: two mRNA Covid-19 vaccines herald a new era for vaccinology

288 points by respinal 6y ago

jcims 6y ago
How do they ensure that antibodies for the spike protein don't interfere with other processes in the body? E.g. if the spike protein bears a sufficient resemblance to part of another protein expressed by healthy human tissue, is there a risk of an immune response? Presumably the Phase 1 trial would sort that out for the most part, just wondering if there is any kind of ability to screen for that ahead of time.
- ch4s3 6y ago
  The viral spike proteins aren’t like other proteins the float around in your body, but the are like the proteins on other viruses. Your immune system also has a baroque system for determining which things in your body belong to you.
  - programmarchy 6y ago
    Do we really know this? Obviously the spike proteins are using an existing mechanism (ACE2) in our bodies to bind to cells. Of primary importance to both viruses and our reproductive system is the membrane fusion function for instance. We must also consider how our bodies developed in the first place; “RNA world” and “virus world” theories predict our genetics evolved from RNA-based processes or even a primordial graveyard of viral RNA. We also don’t fully understand what causes autoimmune disease, but various environmental causes have been explored including bacterial and viral infections. Presumably if a viral infection could trigger an autoimmune response in certain genetically predisposed groups, then so could a vaccine designed to mimic a virus. Unfortunately the incentives in our medical system are not designed to find cures for autoimmune diseases, although they are very much incentivized for palliative care, so progress has been painfully slow in understanding the deeper complexities of the immune system.
    - deleted 6y ago
      [deleted]
    - Exmoor 6y ago
      > Presumably if a viral infection could trigger an autoimmune response in certain genetically predisposed groups, then so could a vaccine designed to mimic a virus. This is true. Some of the extremely rare auto-immune issues that have impacted people who have been vaccinated for specific flu viruses in, IIRC, 1976 and 2009, were thought to occur at even higher rates and severity with people who contracted the virus. So, vaccination might impact you, but likely worse the the virus itself due to the greater amount of virus in your system. I am not a scientist, but I would expect that the mRNA vaccines would have less of a chance of having an auto-immune reaction since they contain only one of the many proteins contained in the actual virus.
      - programmarchy 6y ago
        Yeah, I’m actually very hopeful that mRNA medicine will be able to overcome issues like these in ways traditional vaccines couldn’t. For example, variations could be developed that are more effective for each racial group, rather than a one-size-fits all approach that may be biased. From there, perhaps even individuals who have autoimmune disease markers could have variants developed for them as well.
        axiosgunnar 6y ago
        Are you saying there are genetic differences between races?
        mschuster91 6y ago
        Yes, certain medications have different dosages depending on ethnic groups: https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.107.704023 https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.... There exist even special medicine to account for genetic differences in Black people: https://en.wikipedia.org/wiki/Isosorbide_dinitrate/hydralazine https://en.wikipedia.org/wiki/Isosorbide_dinitrate/hydralazi...
  - tamrix 6y ago
    Yeah, I'm not going first on this technology lol
    - Godel_unicode 6y ago
      That ship sailed months ago, when pfizer ran a clinical trial with 43,538 participants who were willing to go first if it meant helping find a vaccine.
      - amanaplanacanal 6y ago
        And unless you are in a high risk group, there will be millions more that will have gotten the vaccine before you even have the chance to make that choice.
  - super_mario 6y ago
    Apparently, protein (Syncytin-1) present in the spike of SARS-COV2 is also present in human placenta. If the vaccine produces anti-bodies for this protein, it could also lead to infertility in women. I think the answer to this questions would be nice to have. "Several vaccine candidates are expected to induce the formation of humoral antibodies against spike proteins of SARS-CoV-2. Syncytin-1 (see Gallaher, B., “Response to nCoV2019 Against Backdrop of Endogenous Retroviruses” - http://virological.org/t/response-to-ncov2019- http://virological.org/t/response-to-ncov2019- against-backdrop-of-endogenous-retroviruses/396), which is derived from human endogenous retroviruses (HERV) and is responsible for the development of a placenta in mammals and humans and is therefore an essential prerequisite for a successful pregnancy, is also found in homologous form in the spike proteins of SARS viruses. There is no indication whether antibodies against spike proteins of SARS viruses would also act like anti-Syncytin-1 antibodies. However, if this were to be the case this would then also prevent the formation of a placenta which would result in vaccinated women essentially becoming infertile. To my knowledge, Pfizer/BioNTech has yet to release any samples of written materials provided to patients, so it is unclear what, if any, information regarding (potential) fertility-specific risks caused by antibodies is included."
    - kypro 6y ago
      Occurring to the AP this is inaccurate, > Jacob Yount, an associate professor of the department of microbial infection and immunity at Ohio State University, College of Medicine, has studied the syncytin proteins as well as SARS-CoV-2. Yount said the COVID vaccines do not contain syncytin-1 protein or mRNA encoding syncytin-1, and thus there is no reason to think that an immune response against syncytin-1 would be developed. > “We don’t see infertility with the flu vaccine and that is also targeting a viral fusion protein in a similar way that the spike is a viral fusion protein of the coronavirus,” he said. https://apnews.com/article/fact-checking-9856420671 https://apnews.com/article/fact-checking-9856420671
      - deleted 6y ago
        [deleted]
      - hajile 6y ago
- abcc8 6y ago
  Those developing the vaccine likely studied which viral epitopes (structural elements of the virus, consisting of multiple amino acids in a specific folded conformation) were recognized by antibodies from previously infected individuals. The frequency with which antibodies from different individuals are specific to any given epitope can indicate which epitopes might be best used in a vaccine.
- flobosg 6y ago
  > Tissue cross-reactivity assay is a standard method based on immunohistochemistry, required prior to phase I human studies for therapeutic antibodies. ―https://en.wikipedia.org/wiki/Cross-reactivity#Applications_in_drug_development https://en.wikipedia.org/wiki/Cross-reactivity#Applications_... EDIT: The mRNA vaccines are obviously not therapeutic antibodies, but they probably checked for cross-reactivity of the engineered spike protein as well as the generated antibodies using similar methods. I’m not 100% sure, though.
  - jcims 6y ago
    This is perfect thank you!!!
  - tn890 6y ago
    > EDIT: The mRNA vaccines are obviously not therapeutic antibodies, but they probably checked for cross-reactivity of the engineered spike protein as well as the generated antibodies using similar methods. I’m not 100% sure, though. There is a study[0] showing cross-reactivity between SARS-CoV-2 antibodies and other human tissues, thus predisposing the host to autoimmune diseases. This should apply even more so to any vaccine since vaccines produce a more robust immune response. Phase 2/3 of Pfizer-BioNTech did, however, include people with autoimmune diseases [1]. Other vaccine trials did not, as far as I am aware. This does not really shine a light on pre-disposition to an autoimmune disease 6-9-12 mo down the road. Reading this comment again before I post made me realize it sounds very gloomy, so I feel obliged to say I'll be getting whatever vaccine I can get my hands on at the soonest possible date. [0] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246018/#__ffn_sectitle https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246018/#__ffn_... [1] https://www.fda.gov/media/144245/download https://www.fda.gov/media/144245/download
    - flobosg 6y ago
      Thank you for the links! Here’s a review about autoimmunity in COVID-19: https://www.sciencedirect.com/science/article/pii/S0896841120301281#sectitle0075 https://www.sciencedirect.com/science/article/pii/S089684112... > There is a study[0] showing cross-reactivity between SARS-CoV-2 antibodies and other human tissues, thus predisposing the host to autoimmune diseases. This should apply even more so to any vaccine since vaccines produce a more robust immune response. Since the antibody tested in the study was a commercial, monoclonal one, this is somewhat hard to assess. But I think you’re right given what they found in the blood tests. > This does not really shine a light on pre-disposition to an autoimmune disease 6-9-12 mo down the road. Autoimmune reactions should happen in the short run, right?
- deleted 6y ago
  [deleted]
- m3kw9 6y ago
  Right, meaning isn’t the generated spike protein supposed to bind to ACE2 receptors? If it binds, wouldn’t that disrupt some thing?
  - arrosenberg 6y ago
    ACE-2 is a popular target for blood-pressure related medications, but I highly doubt the vaccine is creating enough spike proteins to cause a systemic effect. Otherwise you'd see people showing up with oxygenation and other blood/lung related issues, just like actual COVID patients. You just create a little bit of spike protein to give your immune system a benign target to work off of.
    - jcims 6y ago
      One thing I haven't been able to find yet is how many spike proteins are generated per strand of mRNA. Is it 1:1 or is the mRNA reused a few/buncha times before it degrades?
      - usrusr 6y ago
        I don't know, but I think that if it was just 1:1 it would be far easier to get the protein manufactured by cells living in a petri dish (that can be subjected to much more drastic changes) and inject those protein copies directly instead of mRNA wrapped in some fancy vector molecules.
        tachyonbeam 6y ago
        The fancy vector molecules are just oils. AFAIK the reason they use mRNA is precisely because it's easy to make lots of it quickly through simple chemical processes. Proteins are much more complex, and harder to synthesize using traditional chemical processes.
      - tachyonbeam 6y ago
        Not all the mRNA makes it into your cells, but for the mRNA that does, it probably produces thousands of spike proteins before degrading.
- deleted 6y ago
  [deleted]
- AntiImperialis3 6y ago
  The same way they ensured that DDT doesn't have any long-term adverse environmental side-effects. The same way they did with antibiotics.
- shawnz 6y ago
  Wouldn't a real infection carry the same risks? Why would an mRNA vaccine be worse in that way?
  - flavius29663 6y ago
    It depends how different the response to the vaccine vs the virus is. e.g. the vaccine immune response is based on the spike, while the virus could trigger an immune response based on some detail on the virus, but not the spike
    - shawnz 6y ago
      But there would still be a period of time where the spike protein was present in the body. Are you saying introducing other markers as well would make the presence of the spike protein less risky? Why would that be the case?
      - flavius29663 6y ago
        I didn't say that. I said that the antibodies might behave differently (this is purely theoretical, I have no idea) when presented with a spike vs a spike attached to a corona. That different behavior might cause different long term effects. It might be that the virus causes the worse long term effects and an auto immune attack... In fact, I personally know someone who got an auto-immune induced arthritis from getting a virus infection in central America.
        deleted 6y ago
        [deleted]
- aquadrop 6y ago
  Considering that the original virus has this protein as well, I think getting the illness still will be worse. And in vaccine they can control amount of proteins produced. And they can check a lot of things before even hitting human trials, so risk should be minimal.
- zilian 6y ago
  Our bodies ard entirely capable of doing that without external mRNA. Im also interested in potential side effects when we already have an autoimmune disorder.
iridium_core 6y ago
Should I get vaccinated if I have already been infected with COVID?
- ch4s3 6y ago
  I think that depends on your risk factors and where you are « in line ». IMNADB, talk to your doctor
- SamBam 6y ago
  The current recommendation is yes, you should get vaccinated. (If we continue at the incredibly slow pace of vaccinations we're going, though, I wouldn't be surprised if experts start recommending people who have had Covid get lower priority. An expert recently shared that, at this rate, it will take ten years to get to herd immunity in the US. [1]) 1. https://twitter.com/DrLeanaWen/status/1343920976854196225 https://twitter.com/DrLeanaWen/status/1343920976854196225
  - Ericson2314 6y ago
    Well hopefully they approve the Oxford-AstraZeneca vaccine too, which should be much easier to roll out are greater scale.
    - grawprog 6y ago
      I'm probably going to be downvoted for this...pointing out any issues in any measures towards covid seems to have this effect. But how is astrazeneca's methodology reasonable? https://www.astrazeneca.com/media-centre/press-releases/2020/azd1222hlr.html https://www.astrazeneca.com/media-centre/press-releases/2020... >Over 23,000 participants are being assessed following two doses of either a half-dose/full-dose regimen or a regimen of two full doses of AZD1222 or a comparator, meningococcal conjugate vaccine called MenACWY. The placebo in the study was a meningitis vaccine that actually caused issues that halted the study and because astrazeneca's vaccine was deemed more effective than that, the vaccine was deemed a success. In what way is that anywhere near a reasonable clinical study?
biotico 6y ago
> Unlike DNA vaccines, mRNA vaccines do not have to cross the nuclear envelope, they pose no risk of genomic integration, and they work in both dividing and non-dividing cells. This reads too much like a whitepaper / marketing material. Of course mRNA doesn’t cross the nuclear envelope. It doesn’t mean that it’s not a potential danger to the cells, though. I’m not anti-vax. But, I don’t want to gloss over the danger with vaccines that were fast-tracked and now will be given to a few billion people. What could go wrong? Lots, but if we don’t take it, that could be much worse.
- xiphias2 6y ago
  They are so fragile that the risk of danger is much lower than with DNA based therapy. It's not just marketing: there was a COVID DNA vaccine competitor and it lost.
- arcticbull 6y ago
  The "vaccine was rushed" thing is really all too common, and not at all a fair assessment of what happened. We got here a lot faster in many different ways. 1. Moderna only took 2 days to develop this COVID vaccine. [1] That was thanks to major advancements in vaccine development over many, many years. It wasn't just Moderna, other vaccine candidates were developed extra quick too thanks to advancements in science. 2. This vaccine was developed taking advantage of research done on very similar human coronaviruses over decades, starting from SARS in 2002. 3. Most diseases just aren't very prevalent in the population. For instance, if you created an ebola vaccine, there were a total of 14,000 cases globally between 2014 and 2016. Determining the efficacy would take years. On the other hand there have been 82 million cases of COVID since March. 19.2M in the US alone -- that's a prevalence of 5% (!!). It doesn't take long to prove the vaccine works when 1 in 20 people in the US have or have had COVID. 4. Most of the time human and animal trials are done back-to-back to reduce risk. With the government footing the bill and high confidence you can do them both at the same time. All in all the result is a vaccine much faster but with all the usual rigor. [1] https://www.businessinsider.com/moderna-designed-coronavirus-vaccine-in-2-days-2020-11 https://www.businessinsider.com/moderna-designed-coronavirus...
  - 6y ago
supernova87a 6y ago
I think the incredibly historic accomplishments of these vaccines are unfortunately dulled quite a bit in this moment by the practical issues of how badly the US government and states are still bumbling the distribution of the vaccines. I'm not talking the mundane details of the logistics of shipping, etc. getting those boxes out. That's well understood. I'm talking strategy of who gets vaccinated, how they find out, how they get in line to receive the vaccine. How government tracks and ensures that the population is getting to an effective level of immunity. I have not seen a whiff of that information and management system being put in place. We're still random walking our way through this crisis. CVS has more information on the vaccination status of people in the country than the government does, for fuck's sake. It's almost as if we're leaving it to everyone to figure it out themselves, or on a voluntary basis. Do you know how you're supposed to get the vaccine? Has anyone contacted you or given you information? Have you seen any information on when you specifically are to sign up to receive the vaccine? A more contagious/virulent variant of the virus was just detected in Colorado, today. And we're still letting a patchwork of counties figure it out as it comes.
- packetlost 6y ago
  Each state is handling the logistics themselves, but overall it seems that healthcare and state/government employees will have appointments set up through their employers. For the next several months, it's going to be elderly and then those whose jobs are deemed 'more important', which means communication will likely come from employers first for most people until general availability.
  - supernova87a 6y ago
    Employers are now responsible for ensuring the general public's health? Just for this initial stage? How frightening that is to realize. And for the rest of the population later? A massive abdication of responsibility / competence by the government.
    - packetlost 6y ago
      No, that is not at all what is happening. The government is deciding what occupations constitute early access to the vaccine. For now, they are prioritizing medical workers and government employees, especially those providing essential public services. The only possible way for that to work is through the employer themselves. This has always been the case, and has been publicly stated as such (frontline medical workers, assisted living workers, etc.). It was always going to be based on occupation initially. Once there's enough for general availability, individuals will likely be able to schedule vaccinations themselves or be contacted by their PCP to schedule one. Just because you have not seen any communication does not mean it is not happening.
biotico 6y ago
> For both products, adverse events elevated in the vaccine arm of the trial included ..., lymphadenopathy, nausea, erythema, Bell’s palsy and appendicitis. If those are the bad side effects of the two vaccines that didn’t make the cut yet, what about the two that did?
- krallja 6y ago
  Adverse events are not side effects. Side effects are included in adverse events. Other events, which are completely uncorrelated, are also included.
wpietri 6y ago
This is the part I find especially exciting: > What is perhaps most exciting is the potential for mRNA as a rapid and generic platform for any desired immunogen(s). As upstream computational design and downstream processing and manufacture are standardized, custom work will mostly involve optimizing specific mRNA constructs to express efficiently in cells of interest. It's always interesting to me when we shorten feedback loops like this. For example, could this significantly improve flu vaccines by allowing them to be more up-to-date? How much more quickly can we squash the next pandemic? Could we respond rapidly enough to help with common colds?
- xiphias2 6y ago
  Yes, Moderna announced a few month ago that they are developing a few vaccine. But I'm personally much more excited about the personalized cancer vaccines that they are developing by designing the vaccine for the specific tumor and human genome.
  - tachyonbeam 6y ago
    How would that work?
    - adolph 6y ago
      As I understand it mRNA is one of the latter steps before a cell produces proteins that make up cells. The mRNA in the COVID vaccines is a precursor to immune system cells that can recognize COVID and deal with it. This represents a new way of training an immune system. The classical method is to put some dead or weakened disease cells in your body for your immune system to learn and practice defeating. One method of approaching a cancer treatment might be to train the immune system to recognize cancer cells as something to be defeated. This on its own isn't new. What's new is the approach toward making a pipeline that can be tested for efficacy/safety/etc. The Bio Eats World podcast linked below has an explainer. https://en.wikipedia.org/wiki/Messenger_RNA https://en.wikipedia.org/wiki/Messenger_RNA https://bio-eats-world.simplecast.com/episodes/moderna-covid-vaccine-mrna-technology https://bio-eats-world.simplecast.com/episodes/moderna-covid...
elif 6y ago
Can someone with a good understanding of virology and a passable understanding of code explain to me how mRNA vaccines are not a regex, and don't have the hazards of a regex? What I mean is if the mRNA vaccine causes antigens that respond to a partial match of c-19 dna segments, which is how it is effective against even yet-to-be-developed spike proteins, isn't it necessarily associated with the hazards of fuzzy matching we have with regexes?
- cmrdporcupine 6y ago
  The antigens don't match on DNA segments. They match on proteins that the virus has on it. The mRNA sequence is specific to produce that very particular pattern. Not a wildcard.
  - BurningFrog 6y ago
    To be extra clear, antigens match on the physical shape of the proteins resulting from the mRNA programming. They have no way to access the underlying DNA.
    - ashtonkem 6y ago
      And proteins have two major parts; the sequence of amino acids that they’re composed of, and how they’re folded. This folding detail is no small thing, as proteins don’t do the right thing when they’re folded wrong.
      - LarvaFX 6y ago
        And then there's a fourth stage, where different proteins come together to from a complex. The BioNtech-Vaccine accounts for this afaik, to prevent the spike-proteins from clumping.
        SamBam 6y ago
        Actually, my understanding [1] is that the spike proteins are expected to come together to form a full spike, and that this is what the antibodies match off of. So, even further from regex. The RNA gets turned into a sequence of amino acids, which folds in an extremely complex 3D shape, which bind together with two other proteins to form a large structure, the full shape of which is matched by antibodies. 1. https://www.nytimes.com/interactive/2020/health/pfizer-biontech-covid-19-vaccine.html https://www.nytimes.com/interactive/2020/health/pfizer-biont...
StavrosK 6y ago
> The new vaccines were 90 percent and 94.5 percent effective, said Mr. Paul, Republican of Kentucky and a trained ophthalmologist. And “naturally acquired” Covid-19 was 99.9982 percent effective, he claimed. This is a good point, since you can't get COVID a second time if you're dead.
- arcticbull 6y ago
  Yeah, or in the 99% of people who recover either. A vaccine is obviously preferable though.
  - StavrosK 6y ago
    The issue is that you don't know whether you're going to be in the "recovered" group before you get COVID (which is why the vaccine is preferable, you get good immunity without the pesky dying).
    - deleted 6y ago
      [deleted]
    - nytgop77 6y ago
      In theory: vaccine could work only on people who would anyway not die. Do they test for vaccine innefectiveness corelation with virus lethality and/or complications?
      - rswail 6y ago
        Why would the vaccine only work on people that wouldn't die? The vaccine trains the body to kill the virus (SARS-Cov-2) when it enters, not deal with the symptoms of the virus using the body to replicate (COVID-19). Vaccines stop infection. Therapeutics stop disease. The map is not the territory.
        nytgop77 6y ago
        my (laymans) model/hipothesis how this could work. There are two groups of people. Latent antibody bombs (on slitghest signal antibodies go from zero to hero) and antibody deserts (where even at late stages of desease only low antibody counts are produced). Those which easily make antibodies, kill off the virus quick enough to get significantly less side effects compared to the other group. IF such model would hold, then it would be natural that antibody deserts dont produce much antibodies when reacting to vaccine, so there would be corellation between succeptible to covid mortality and vaccine innefectiveness.
purple_ferret 6y ago
It's ok. If you start to suffer from a persistent autoimmune reaction, I'm sure there's a therapeutic you can take for the rest of your life that only costs about 30k a month.
- djsumdog 6y ago
  And you'll have to pay for it yourself since pharma companies are immune from any vaccine related liability.
  - rswail 6y ago
    For good reason. If they were liable, they wouldn't put it into production. See: https://www.ncbi.nlm.nih.gov/books/n/nap599/ddd00075/#ddd00081 https://www.ncbi.nlm.nih.gov/books/n/nap599/ddd00075/#ddd000... and the entire article for the problem. which is why, in the US, there is a "no-fault" fund: https://www.hrsa.gov/vaccine-compensation/index.html https://www.hrsa.gov/vaccine-compensation/index.html
JohnD95658 6y ago
I don't believe coivid-19 it's real. I think that some unknown people have made it up to have people from the fake vaccine
JohnD95658 6y ago
people have made up covid-19
aazaa 6y ago
> The new nucleoside-modified mRNA vaccines are chemicals that have been almost fully disclosed. They incorporate a trinucleotide cap 1 analog ((m27,3′-O)Gppp(m2′-O)ApG), contain N1-methylpseudouridine instead of uridine, and encode an optimized (P2-mutated) full-length S glycoprotein encapsulated in lipid nanoparticles (LNPs) containing polyethylene glycol and cholesterol. The BNT162b2 LNP also contains (4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate) and 1,2-distearoyl-sn-glycero-3-phosphocholine, whereas Moderna’s LNP contains SM-102 (most likely heptadecan-9-yl 8-((2-hydroxyethyl)(6-oxo-6-(undecyloxy)hexyl)amino)octanoate) and 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (PEG). ... I'll disagree here. Imagine I tell you a white powder of pure molecular composition is made up of just four elements: carbon; hydrogen; nitrogen; and oxygen. Would you ingest it? It could be strychnine (poison) or glycine (an amino acid). You have no way of knowing. Likewise, the physiological effects lipid nanoparticles (LNPs) are still mysterious. First, the exact composition isn't known or even revealed in the FDA filing (thus the "most likely" above). Second, even given known composition, there's no way to know how large, how stable, or how aggregated these particles are or what any of that means. The model for LNPs that gets most widely discussed is an artificial cell membrane. There's a water-filled center surrounded by a bilayer of lipid (grease). These particles may show variable sensitivity to degradation depending on how administered, composition, size, shape, trace impurities, and so on. For example, Moderna's vaccine contains cholesterol, presumably for the same reason our cells do - to modulate membrane fluidity. It's not clear just yet how persistent LNPs might be and what effects they might show, separate from the RNA payload.
- maxerickson 6y ago
  Haven't the companies producing them been studying things like stability? You say 'there's no way to know how large, how stable, or how aggregated these particles are or what any of that means', but they have been working with them for years. Of course they could be lying or hiding information, but it seems like researching them is a way to know things about them.
  - aazaa 6y ago
    > ... but they have been working with them for years. True - in vitro and in limited human studies. But not at scale in human subjects. That's just this year. Studying this kind of thing is new as far as therapeutics go.
JohnD95658 6y ago
I'll be very happy if the vaccination decrease number
fatlasp 6y ago
correct me if I'm wrong but haven't all the mRNA vaccines skipped human studies / have 'emergency use' certification
- karmelapple 6y ago
  Human trials of both the Pfizer and Moderna vaccines were conducted, with tens of thousands participating. Your statement is wrong, and I’m glad you welcomed being corrected. Have a nice day. https://www.cbsnews.com/news/covid-vaccine-pfizer-phase-3-human-trial-united-states/ https://www.cbsnews.com/news/covid-vaccine-pfizer-phase-3-hu...
  - adolph 6y ago
    August 21, 2020, 11:30 AM Two U.S. pharmaceutical giants, Pfizer and Moderna, are in the final phase of coronavirus vaccine development, and Oxford University is expected to start large-scale human trials of its vaccine in the U.S. this month.
    - em500 6y ago
      https://www.fda.gov/media/144245/download https://www.fda.gov/media/144245/download https://fda.report/media/144673/Moderna+COVID-19+Vaccine+review+memo.pdf https://fda.report/media/144673/Moderna+COVID-19+Vaccine+rev...
      - adolph 6y ago
        The initial numbers look awesome: Pfizer: 8/18,198 vaccine, 162/18,325 placebo; Moderna: 5/13,934 vaccine, 90/13,883 placebo for 7 and 14 days respectively after the second dose.
  - tiziniano 6y ago
    How long were the trials? I recall a famous drug that was given in the 70s and it produced birth malformations. Took years for doctors to realize the cause and ban its use in pregnant women. Is there a possibility of unforeseen consequences from using RNA? What if someone has for XYZ reason more reverse transcriptase than usual? Will his-her DNA be altered?
blargmaster42_8 6y ago
Do not question! INJECT! INJECT!
myrandomcomment 6y ago
So one of my takeaways from all of this is we cannot wait long enough based on current methods anymore. This virus is just one and it is likely to get worse. We need to invest now into large scale computer simulation of vaccines or things will become much worse. There is risk here, however I feel strongly that if we do need to move faster or today will become normal and that cannot become the normal! I read that most of the vacancies only took a few weeks for the scientist to create, however the current testing methods are why we are nearly 9 months to delivery. We as a society have to invest on new methods to move forward creation to delivery faster. I am not claiming any expertise here - I majored in Biochemistry but never finished (moved to tech). I do have 14 doctors / geneticist / infection disease specialist in my family that share this view.
- castratikron 6y ago
  I've been wondering the same thing. How big of a computer would you need to accurately simulate an immune system? Or at least accurate enough to cut down on some of the tedious and time consuming work? Could something like this be built today with enough effort? I know nothing about immunology BTW.
  - shellfishgene 6y ago
    The knowledge is not there to simulate the immune system in any useful way. Apart from that the main issue why it takes long to test vaccines are side effects. Checking for those would require simulating the whole body including various interactions with its environment.
- Nbox9 6y ago
  > This virus is just one and it is likely to get worse. We need to invest now into large scale computer simulation of vaccines or things will become much worse. This seems like a logical leap to me. Yes we need to do something to make us less open to viral threats, but you don’t present any evidence that improved computer simulations can be a useful tool in helping develop/test vaccines faster.
  - 6y ago
lazyjones 6y ago
What is the error rate in mass production of mRNA? What can mRNA with a few flipped/wrong molecules do?
- shellfishgene 6y ago
  There are various options for RNA polymerases commonly used in vitro [1], generally the error rate is considered to be "pretty low", something like 1 in 10k. An error will also have to result in a change of amino acid, which less likely due to the redundancy of the code. So any error mRNA will probably only have one amino acid changed. This could cause the resulting spike protein to aquire some new characteristic, but it's not very likely I would guess. Also, in the clinical trials they test the actual produced vaccine, with all errors included. [1] https://international.neb.com/tools-and-resources/selection-charts/rna-polymerase-selection-chart https://international.neb.com/tools-and-resources/selection-...
  - shellfishgene 6y ago
    Thinking about this some more, there may even be an advantage: The virus also mutates, so some error mRNAs may actually confer additional immunity to future or current virus strains. In reality there are probably way to few errors for this to make a difference...
- LarvaFX 6y ago
  Genetic code is highly redundant. A few flipped characters will therefore probably not affect the produced protein much.
  - shellfishgene 6y ago
    I wouldn't call it "highly" redundant, more than two thirds of mutations will cause an amino acid change.
  - thamer 6y ago
    It's highly redundant when there are 2 strands, as is the case with DNA. RNA has a tendency to accumulate mutations quickly, as evidenced by the many hundreds of variants of SARS-CoV-2 that have already been sequenced (and that's with only ~30,000 bases).
Bombthecat 6y ago
They just need to get a hold on the allergic reactions..
- driverdan 6y ago
  Allergic reactions are like shark attacks. Extremely rare but get tons of press coverage, making them seem more common than they are. All vaccines have a risk of allergic reactions. This is why you're supposed to be monitored for at least 10 minutes after the injection. This is especially important for people who have a history of such reactions to vaccines.
- fsh 6y ago
  None of the 18860 participants of the Phase 2/3 trial reported allergic reactions after either dose of the vaccine [1]. Over the entire duration of the study, one member of the treatement group suffered an anaphylactic reaction and one member of the placebo group an anaphylactic shock [2]. There is no hint that this particular vaccine is more likely to trigger allergic reactions than any other kind of medication. [1] Section 6.3.3.2.2.1. in https://www.fda.gov/media/144246/download https://www.fda.gov/media/144246/download [2] Table 23, Ibid.
deleted 6y ago
[deleted]
deleted 6y ago
[deleted]
mybrid 6y ago
How do they classify something like this as safe for the long term if long term experiments are not conducted? Is there any substitute for time trials for drugs other than these new vaccines? These are the questions my relatives are asking me and my answers are I don't know, I don't. The scientific community needs to do a better job of communication. Why are we confident that a trial of only three months is sufficient when the only efficacy test for long term effects is long term trials?
- valarauko 6y ago
  They are not classified as safe for long term use - they're still not approved. They're been cleared by an EUA for emergency use. We don't know how safe they are for long term use yet, since those trails are still ongoing - Pfizer's 3rd Phase trials run till the summer of 2021, and Moderna's trial runs till mid 2022. We'll have more concrete answers then. That's why an Emergency Use Authorization is just that - there's an emergency. The FDA is well aware that long term safety is still unclear, but given the circumstances, the risks posed by vaccination for the general public are outweighed by the benefits.
  - mybrid 6y ago
    The only problem is from a communication with the public is that as many people has physically possible will be vaccinated. How is this "emergency" approval any different then a general approval if the end result of the same? " but given the circumstances, the risks posed by vaccination for the general public are outweighed by the benefits. " That's the problem, we don't. We don't know what the risk is long term, it is unknown. It is illogical to say that an completely unknown risk has any logical comparison.
    - valarauko 6y ago
      While we don't have an exact handle on the risks posed by the vaccine long term, we do have reasonable bounds on what they may be. For example, it's entirely possible 0.05 - 0.6% of people who receive the vaccines develop long term severe negative outcomes. Perhaps that number is 3% - we don't know, but more unlikely. We can be fairly certain that number isn't as high as 40%. We don't have all the numbers, but we have reasonable assumptions - these are non integrative mRNAs that have a very short lifespan inside the body, so long term effects other than immunity are not expected. Of course, there is uncertainty in everything. This is more uncertainty than the FDA would accept in the usual course of events - but this is an unusual time. The FDA has no adequate, approved, and available alternatives to the emergency authorization when faced with the pandemic. The investigational vaccine appears to be safe and effective against COVID-19 for the general population. Yes, the vaccine poses some unknown risks, but they are very likely vanishingly smaller than the very present health risks posed by the pandemic. For any given individual, they're much more likely to suffer negative health outcomes within the next 5 years from COVID than from the vaccine. Nobody is stating that risk to be zero. But that also doesn't mean "the risk is completely unknown so why even bother?" How is the emergency authorization any different from an approval? If tomorrow an effective treatment for COVID-19 were to be approved or the pandemic ends, the EUA for the vaccine would be rescinded. Pfizer/Moderna must also track any adverse reactions more closely, and report them to the FDA on an ongoing basis. They also cannot sell them to private players - they're being provided to the FDA & their authorized parties. The vaccines are not licensed for COVID or any other use.
garfieldnate 6y ago
How does the immune system keep a memory of what every single non-foreign protein looks like so that it can recognize foreign ones? That's the most amazing thing here, to me.

288 points by respinal 6y ago

How do they ensure that antibodies for the spike protein don't interfere with other processes in the body? E.g. if the spike protein bears a sufficient resemblance to part of another protein expressed by healthy human tissue, is there a risk of an immune response? Presumably the Phase 1 trial would sort that out for the most part, just wondering if there is any kind of ability to screen for that ahead of time.

ch4s3 6y ago
The viral spike proteins aren’t like other proteins the float around in your body, but the are like the proteins on other viruses. Your immune system also has a baroque system for determining which things in your body belong to you.
- programmarchy 6y ago
  Do we really know this? Obviously the spike proteins are using an existing mechanism (ACE2) in our bodies to bind to cells. Of primary importance to both viruses and our reproductive system is the membrane fusion function for instance. We must also consider how our bodies developed in the first place; “RNA world” and “virus world” theories predict our genetics evolved from RNA-based processes or even a primordial graveyard of viral RNA. We also don’t fully understand what causes autoimmune disease, but various environmental causes have been explored including bacterial and viral infections. Presumably if a viral infection could trigger an autoimmune response in certain genetically predisposed groups, then so could a vaccine designed to mimic a virus. Unfortunately the incentives in our medical system are not designed to find cures for autoimmune diseases, although they are very much incentivized for palliative care, so progress has been painfully slow in understanding the deeper complexities of the immune system.
  - deleted 6y ago
    [deleted]
  - Exmoor 6y ago
    > Presumably if a viral infection could trigger an autoimmune response in certain genetically predisposed groups, then so could a vaccine designed to mimic a virus. This is true. Some of the extremely rare auto-immune issues that have impacted people who have been vaccinated for specific flu viruses in, IIRC, 1976 and 2009, were thought to occur at even higher rates and severity with people who contracted the virus. So, vaccination might impact you, but likely worse the the virus itself due to the greater amount of virus in your system. I am not a scientist, but I would expect that the mRNA vaccines would have less of a chance of having an auto-immune reaction since they contain only one of the many proteins contained in the actual virus.
    - programmarchy 6y ago
      Yeah, I’m actually very hopeful that mRNA medicine will be able to overcome issues like these in ways traditional vaccines couldn’t. For example, variations could be developed that are more effective for each racial group, rather than a one-size-fits all approach that may be biased. From there, perhaps even individuals who have autoimmune disease markers could have variants developed for them as well.
      - axiosgunnar 6y ago
        Are you saying there are genetic differences between races?
        mschuster91 6y ago
        Yes, certain medications have different dosages depending on ethnic groups: https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.107.704023 https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.... There exist even special medicine to account for genetic differences in Black people: https://en.wikipedia.org/wiki/Isosorbide_dinitrate/hydralazine https://en.wikipedia.org/wiki/Isosorbide_dinitrate/hydralazi...
- tamrix 6y ago
  Yeah, I'm not going first on this technology lol
  - Godel_unicode 6y ago
    That ship sailed months ago, when pfizer ran a clinical trial with 43,538 participants who were willing to go first if it meant helping find a vaccine.
    - amanaplanacanal 6y ago
      And unless you are in a high risk group, there will be millions more that will have gotten the vaccine before you even have the chance to make that choice.
- super_mario 6y ago
  Apparently, protein (Syncytin-1) present in the spike of SARS-COV2 is also present in human placenta. If the vaccine produces anti-bodies for this protein, it could also lead to infertility in women. I think the answer to this questions would be nice to have. "Several vaccine candidates are expected to induce the formation of humoral antibodies against spike proteins of SARS-CoV-2. Syncytin-1 (see Gallaher, B., “Response to nCoV2019 Against Backdrop of Endogenous Retroviruses” - http://virological.org/t/response-to-ncov2019- http://virological.org/t/response-to-ncov2019- against-backdrop-of-endogenous-retroviruses/396), which is derived from human endogenous retroviruses (HERV) and is responsible for the development of a placenta in mammals and humans and is therefore an essential prerequisite for a successful pregnancy, is also found in homologous form in the spike proteins of SARS viruses. There is no indication whether antibodies against spike proteins of SARS viruses would also act like anti-Syncytin-1 antibodies. However, if this were to be the case this would then also prevent the formation of a placenta which would result in vaccinated women essentially becoming infertile. To my knowledge, Pfizer/BioNTech has yet to release any samples of written materials provided to patients, so it is unclear what, if any, information regarding (potential) fertility-specific risks caused by antibodies is included."
  - kypro 6y ago
    Occurring to the AP this is inaccurate, > Jacob Yount, an associate professor of the department of microbial infection and immunity at Ohio State University, College of Medicine, has studied the syncytin proteins as well as SARS-CoV-2. Yount said the COVID vaccines do not contain syncytin-1 protein or mRNA encoding syncytin-1, and thus there is no reason to think that an immune response against syncytin-1 would be developed. > “We don’t see infertility with the flu vaccine and that is also targeting a viral fusion protein in a similar way that the spike is a viral fusion protein of the coronavirus,” he said. https://apnews.com/article/fact-checking-9856420671 https://apnews.com/article/fact-checking-9856420671
    - deleted 6y ago
      [deleted]
    - hajile 6y ago
abcc8 6y ago
Those developing the vaccine likely studied which viral epitopes (structural elements of the virus, consisting of multiple amino acids in a specific folded conformation) were recognized by antibodies from previously infected individuals. The frequency with which antibodies from different individuals are specific to any given epitope can indicate which epitopes might be best used in a vaccine.
flobosg 6y ago
> Tissue cross-reactivity assay is a standard method based on immunohistochemistry, required prior to phase I human studies for therapeutic antibodies. ―https://en.wikipedia.org/wiki/Cross-reactivity#Applications_in_drug_development https://en.wikipedia.org/wiki/Cross-reactivity#Applications_... EDIT: The mRNA vaccines are obviously not therapeutic antibodies, but they probably checked for cross-reactivity of the engineered spike protein as well as the generated antibodies using similar methods. I’m not 100% sure, though.
- jcims 6y ago
  This is perfect thank you!!!
- tn890 6y ago
  > EDIT: The mRNA vaccines are obviously not therapeutic antibodies, but they probably checked for cross-reactivity of the engineered spike protein as well as the generated antibodies using similar methods. I’m not 100% sure, though. There is a study[0] showing cross-reactivity between SARS-CoV-2 antibodies and other human tissues, thus predisposing the host to autoimmune diseases. This should apply even more so to any vaccine since vaccines produce a more robust immune response. Phase 2/3 of Pfizer-BioNTech did, however, include people with autoimmune diseases [1]. Other vaccine trials did not, as far as I am aware. This does not really shine a light on pre-disposition to an autoimmune disease 6-9-12 mo down the road. Reading this comment again before I post made me realize it sounds very gloomy, so I feel obliged to say I'll be getting whatever vaccine I can get my hands on at the soonest possible date. [0] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246018/#__ffn_sectitle https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246018/#__ffn_... [1] https://www.fda.gov/media/144245/download https://www.fda.gov/media/144245/download
  - flobosg 6y ago
    Thank you for the links! Here’s a review about autoimmunity in COVID-19: https://www.sciencedirect.com/science/article/pii/S0896841120301281#sectitle0075 https://www.sciencedirect.com/science/article/pii/S089684112... > There is a study[0] showing cross-reactivity between SARS-CoV-2 antibodies and other human tissues, thus predisposing the host to autoimmune diseases. This should apply even more so to any vaccine since vaccines produce a more robust immune response. Since the antibody tested in the study was a commercial, monoclonal one, this is somewhat hard to assess. But I think you’re right given what they found in the blood tests. > This does not really shine a light on pre-disposition to an autoimmune disease 6-9-12 mo down the road. Autoimmune reactions should happen in the short run, right?
deleted 6y ago
[deleted]
m3kw9 6y ago
Right, meaning isn’t the generated spike protein supposed to bind to ACE2 receptors? If it binds, wouldn’t that disrupt some thing?
- arrosenberg 6y ago
  ACE-2 is a popular target for blood-pressure related medications, but I highly doubt the vaccine is creating enough spike proteins to cause a systemic effect. Otherwise you'd see people showing up with oxygenation and other blood/lung related issues, just like actual COVID patients. You just create a little bit of spike protein to give your immune system a benign target to work off of.
  - jcims 6y ago
    One thing I haven't been able to find yet is how many spike proteins are generated per strand of mRNA. Is it 1:1 or is the mRNA reused a few/buncha times before it degrades?
    - usrusr 6y ago
      I don't know, but I think that if it was just 1:1 it would be far easier to get the protein manufactured by cells living in a petri dish (that can be subjected to much more drastic changes) and inject those protein copies directly instead of mRNA wrapped in some fancy vector molecules.
      - tachyonbeam 6y ago
        The fancy vector molecules are just oils. AFAIK the reason they use mRNA is precisely because it's easy to make lots of it quickly through simple chemical processes. Proteins are much more complex, and harder to synthesize using traditional chemical processes.
    - tachyonbeam 6y ago
      Not all the mRNA makes it into your cells, but for the mRNA that does, it probably produces thousands of spike proteins before degrading.
deleted 6y ago
[deleted]
AntiImperialis3 6y ago
The same way they ensured that DDT doesn't have any long-term adverse environmental side-effects. The same way they did with antibiotics.
shawnz 6y ago
Wouldn't a real infection carry the same risks? Why would an mRNA vaccine be worse in that way?
- flavius29663 6y ago
  It depends how different the response to the vaccine vs the virus is. e.g. the vaccine immune response is based on the spike, while the virus could trigger an immune response based on some detail on the virus, but not the spike
  - shawnz 6y ago
    But there would still be a period of time where the spike protein was present in the body. Are you saying introducing other markers as well would make the presence of the spike protein less risky? Why would that be the case?
    - flavius29663 6y ago
      I didn't say that. I said that the antibodies might behave differently (this is purely theoretical, I have no idea) when presented with a spike vs a spike attached to a corona. That different behavior might cause different long term effects. It might be that the virus causes the worse long term effects and an auto immune attack... In fact, I personally know someone who got an auto-immune induced arthritis from getting a virus infection in central America.
      - deleted 6y ago
        [deleted]
aquadrop 6y ago
Considering that the original virus has this protein as well, I think getting the illness still will be worse. And in vaccine they can control amount of proteins produced. And they can check a lot of things before even hitting human trials, so risk should be minimal.
zilian 6y ago
Our bodies ard entirely capable of doing that without external mRNA. Im also interested in potential side effects when we already have an autoimmune disorder.

iridium_core 6y ago

Should I get vaccinated if I have already been infected with COVID?

ch4s3 6y ago
I think that depends on your risk factors and where you are « in line ». IMNADB, talk to your doctor
SamBam 6y ago
The current recommendation is yes, you should get vaccinated. (If we continue at the incredibly slow pace of vaccinations we're going, though, I wouldn't be surprised if experts start recommending people who have had Covid get lower priority. An expert recently shared that, at this rate, it will take ten years to get to herd immunity in the US. [1]) 1. https://twitter.com/DrLeanaWen/status/1343920976854196225 https://twitter.com/DrLeanaWen/status/1343920976854196225
- Ericson2314 6y ago
  Well hopefully they approve the Oxford-AstraZeneca vaccine too, which should be much easier to roll out are greater scale.
  - grawprog 6y ago
    I'm probably going to be downvoted for this...pointing out any issues in any measures towards covid seems to have this effect. But how is astrazeneca's methodology reasonable? https://www.astrazeneca.com/media-centre/press-releases/2020/azd1222hlr.html https://www.astrazeneca.com/media-centre/press-releases/2020... >Over 23,000 participants are being assessed following two doses of either a half-dose/full-dose regimen or a regimen of two full doses of AZD1222 or a comparator, meningococcal conjugate vaccine called MenACWY. The placebo in the study was a meningitis vaccine that actually caused issues that halted the study and because astrazeneca's vaccine was deemed more effective than that, the vaccine was deemed a success. In what way is that anywhere near a reasonable clinical study?

biotico 6y ago

> Unlike DNA vaccines, mRNA vaccines do not have to cross the nuclear envelope, they pose no risk of genomic integration, and they work in both dividing and non-dividing cells. This reads too much like a whitepaper / marketing material. Of course mRNA doesn’t cross the nuclear envelope. It doesn’t mean that it’s not a potential danger to the cells, though. I’m not anti-vax. But, I don’t want to gloss over the danger with vaccines that were fast-tracked and now will be given to a few billion people. What could go wrong? Lots, but if we don’t take it, that could be much worse.

xiphias2 6y ago
They are so fragile that the risk of danger is much lower than with DNA based therapy. It's not just marketing: there was a COVID DNA vaccine competitor and it lost.
arcticbull 6y ago
The "vaccine was rushed" thing is really all too common, and not at all a fair assessment of what happened. We got here a lot faster in many different ways. 1. Moderna only took 2 days to develop this COVID vaccine. [1] That was thanks to major advancements in vaccine development over many, many years. It wasn't just Moderna, other vaccine candidates were developed extra quick too thanks to advancements in science. 2. This vaccine was developed taking advantage of research done on very similar human coronaviruses over decades, starting from SARS in 2002. 3. Most diseases just aren't very prevalent in the population. For instance, if you created an ebola vaccine, there were a total of 14,000 cases globally between 2014 and 2016. Determining the efficacy would take years. On the other hand there have been 82 million cases of COVID since March. 19.2M in the US alone -- that's a prevalence of 5% (!!). It doesn't take long to prove the vaccine works when 1 in 20 people in the US have or have had COVID. 4. Most of the time human and animal trials are done back-to-back to reduce risk. With the government footing the bill and high confidence you can do them both at the same time. All in all the result is a vaccine much faster but with all the usual rigor. [1] https://www.businessinsider.com/moderna-designed-coronavirus-vaccine-in-2-days-2020-11 https://www.businessinsider.com/moderna-designed-coronavirus...
- 6y ago

supernova87a 6y ago

I think the incredibly historic accomplishments of these vaccines are unfortunately dulled quite a bit in this moment by the practical issues of how badly the US government and states are still bumbling the distribution of the vaccines. I'm not talking the mundane details of the logistics of shipping, etc. getting those boxes out. That's well understood. I'm talking strategy of who gets vaccinated, how they find out, how they get in line to receive the vaccine. How government tracks and ensures that the population is getting to an effective level of immunity. I have not seen a whiff of that information and management system being put in place. We're still random walking our way through this crisis. CVS has more information on the vaccination status of people in the country than the government does, for fuck's sake. It's almost as if we're leaving it to everyone to figure it out themselves, or on a voluntary basis. Do you know how you're supposed to get the vaccine? Has anyone contacted you or given you information? Have you seen any information on when you specifically are to sign up to receive the vaccine? A more contagious/virulent variant of the virus was just detected in Colorado, today. And we're still letting a patchwork of counties figure it out as it comes.

packetlost 6y ago
Each state is handling the logistics themselves, but overall it seems that healthcare and state/government employees will have appointments set up through their employers. For the next several months, it's going to be elderly and then those whose jobs are deemed 'more important', which means communication will likely come from employers first for most people until general availability.
- supernova87a 6y ago
  Employers are now responsible for ensuring the general public's health? Just for this initial stage? How frightening that is to realize. And for the rest of the population later? A massive abdication of responsibility / competence by the government.
  - packetlost 6y ago
    No, that is not at all what is happening. The government is deciding what occupations constitute early access to the vaccine. For now, they are prioritizing medical workers and government employees, especially those providing essential public services. The only possible way for that to work is through the employer themselves. This has always been the case, and has been publicly stated as such (frontline medical workers, assisted living workers, etc.). It was always going to be based on occupation initially. Once there's enough for general availability, individuals will likely be able to schedule vaccinations themselves or be contacted by their PCP to schedule one. Just because you have not seen any communication does not mean it is not happening.

biotico 6y ago

> For both products, adverse events elevated in the vaccine arm of the trial included ..., lymphadenopathy, nausea, erythema, Bell’s palsy and appendicitis. If those are the bad side effects of the two vaccines that didn’t make the cut yet, what about the two that did?

krallja 6y ago
Adverse events are not side effects. Side effects are included in adverse events. Other events, which are completely uncorrelated, are also included.

wpietri 6y ago

This is the part I find especially exciting: > What is perhaps most exciting is the potential for mRNA as a rapid and generic platform for any desired immunogen(s). As upstream computational design and downstream processing and manufacture are standardized, custom work will mostly involve optimizing specific mRNA constructs to express efficiently in cells of interest. It's always interesting to me when we shorten feedback loops like this. For example, could this significantly improve flu vaccines by allowing them to be more up-to-date? How much more quickly can we squash the next pandemic? Could we respond rapidly enough to help with common colds?

xiphias2 6y ago
Yes, Moderna announced a few month ago that they are developing a few vaccine. But I'm personally much more excited about the personalized cancer vaccines that they are developing by designing the vaccine for the specific tumor and human genome.
- tachyonbeam 6y ago
  How would that work?
  - adolph 6y ago
    As I understand it mRNA is one of the latter steps before a cell produces proteins that make up cells. The mRNA in the COVID vaccines is a precursor to immune system cells that can recognize COVID and deal with it. This represents a new way of training an immune system. The classical method is to put some dead or weakened disease cells in your body for your immune system to learn and practice defeating. One method of approaching a cancer treatment might be to train the immune system to recognize cancer cells as something to be defeated. This on its own isn't new. What's new is the approach toward making a pipeline that can be tested for efficacy/safety/etc. The Bio Eats World podcast linked below has an explainer. https://en.wikipedia.org/wiki/Messenger_RNA https://en.wikipedia.org/wiki/Messenger_RNA https://bio-eats-world.simplecast.com/episodes/moderna-covid-vaccine-mrna-technology https://bio-eats-world.simplecast.com/episodes/moderna-covid...

elif 6y ago

Can someone with a good understanding of virology and a passable understanding of code explain to me how mRNA vaccines are not a regex, and don't have the hazards of a regex? What I mean is if the mRNA vaccine causes antigens that respond to a partial match of c-19 dna segments, which is how it is effective against even yet-to-be-developed spike proteins, isn't it necessarily associated with the hazards of fuzzy matching we have with regexes?

cmrdporcupine 6y ago
The antigens don't match on DNA segments. They match on proteins that the virus has on it. The mRNA sequence is specific to produce that very particular pattern. Not a wildcard.
- BurningFrog 6y ago
  To be extra clear, antigens match on the physical shape of the proteins resulting from the mRNA programming. They have no way to access the underlying DNA.
  - ashtonkem 6y ago
    And proteins have two major parts; the sequence of amino acids that they’re composed of, and how they’re folded. This folding detail is no small thing, as proteins don’t do the right thing when they’re folded wrong.
    - LarvaFX 6y ago
      And then there's a fourth stage, where different proteins come together to from a complex. The BioNtech-Vaccine accounts for this afaik, to prevent the spike-proteins from clumping.
      - SamBam 6y ago
        Actually, my understanding [1] is that the spike proteins are expected to come together to form a full spike, and that this is what the antibodies match off of. So, even further from regex. The RNA gets turned into a sequence of amino acids, which folds in an extremely complex 3D shape, which bind together with two other proteins to form a large structure, the full shape of which is matched by antibodies. 1. https://www.nytimes.com/interactive/2020/health/pfizer-biontech-covid-19-vaccine.html https://www.nytimes.com/interactive/2020/health/pfizer-biont...

StavrosK 6y ago

> The new vaccines were 90 percent and 94.5 percent effective, said Mr. Paul, Republican of Kentucky and a trained ophthalmologist. And “naturally acquired” Covid-19 was 99.9982 percent effective, he claimed. This is a good point, since you can't get COVID a second time if you're dead.

arcticbull 6y ago
Yeah, or in the 99% of people who recover either. A vaccine is obviously preferable though.
- StavrosK 6y ago
  The issue is that you don't know whether you're going to be in the "recovered" group before you get COVID (which is why the vaccine is preferable, you get good immunity without the pesky dying).
  - deleted 6y ago
    [deleted]
  - nytgop77 6y ago
    In theory: vaccine could work only on people who would anyway not die. Do they test for vaccine innefectiveness corelation with virus lethality and/or complications?
    - rswail 6y ago
      Why would the vaccine only work on people that wouldn't die? The vaccine trains the body to kill the virus (SARS-Cov-2) when it enters, not deal with the symptoms of the virus using the body to replicate (COVID-19). Vaccines stop infection. Therapeutics stop disease. The map is not the territory.
      - nytgop77 6y ago
        my (laymans) model/hipothesis how this could work. There are two groups of people. Latent antibody bombs (on slitghest signal antibodies go from zero to hero) and antibody deserts (where even at late stages of desease only low antibody counts are produced). Those which easily make antibodies, kill off the virus quick enough to get significantly less side effects compared to the other group. IF such model would hold, then it would be natural that antibody deserts dont produce much antibodies when reacting to vaccine, so there would be corellation between succeptible to covid mortality and vaccine innefectiveness.

purple_ferret 6y ago

It's ok. If you start to suffer from a persistent autoimmune reaction, I'm sure there's a therapeutic you can take for the rest of your life that only costs about 30k a month.

djsumdog 6y ago
And you'll have to pay for it yourself since pharma companies are immune from any vaccine related liability.
- rswail 6y ago
  For good reason. If they were liable, they wouldn't put it into production. See: https://www.ncbi.nlm.nih.gov/books/n/nap599/ddd00075/#ddd00081 https://www.ncbi.nlm.nih.gov/books/n/nap599/ddd00075/#ddd000... and the entire article for the problem. which is why, in the US, there is a "no-fault" fund: https://www.hrsa.gov/vaccine-compensation/index.html https://www.hrsa.gov/vaccine-compensation/index.html

JohnD95658 6y ago

I don't believe coivid-19 it's real. I think that some unknown people have made it up to have people from the fake vaccine

JohnD95658 6y ago

people have made up covid-19

aazaa 6y ago

> The new nucleoside-modified mRNA vaccines are chemicals that have been almost fully disclosed. They incorporate a trinucleotide cap 1 analog ((m27,3′-O)Gppp(m2′-O)ApG), contain N1-methylpseudouridine instead of uridine, and encode an optimized (P2-mutated) full-length S glycoprotein encapsulated in lipid nanoparticles (LNPs) containing polyethylene glycol and cholesterol. The BNT162b2 LNP also contains (4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate) and 1,2-distearoyl-sn-glycero-3-phosphocholine, whereas Moderna’s LNP contains SM-102 (most likely heptadecan-9-yl 8-((2-hydroxyethyl)(6-oxo-6-(undecyloxy)hexyl)amino)octanoate) and 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (PEG). ... I'll disagree here. Imagine I tell you a white powder of pure molecular composition is made up of just four elements: carbon; hydrogen; nitrogen; and oxygen. Would you ingest it? It could be strychnine (poison) or glycine (an amino acid). You have no way of knowing. Likewise, the physiological effects lipid nanoparticles (LNPs) are still mysterious. First, the exact composition isn't known or even revealed in the FDA filing (thus the "most likely" above). Second, even given known composition, there's no way to know how large, how stable, or how aggregated these particles are or what any of that means. The model for LNPs that gets most widely discussed is an artificial cell membrane. There's a water-filled center surrounded by a bilayer of lipid (grease). These particles may show variable sensitivity to degradation depending on how administered, composition, size, shape, trace impurities, and so on. For example, Moderna's vaccine contains cholesterol, presumably for the same reason our cells do - to modulate membrane fluidity. It's not clear just yet how persistent LNPs might be and what effects they might show, separate from the RNA payload.

maxerickson 6y ago
Haven't the companies producing them been studying things like stability? You say 'there's no way to know how large, how stable, or how aggregated these particles are or what any of that means', but they have been working with them for years. Of course they could be lying or hiding information, but it seems like researching them is a way to know things about them.
- aazaa 6y ago
  > ... but they have been working with them for years. True - in vitro and in limited human studies. But not at scale in human subjects. That's just this year. Studying this kind of thing is new as far as therapeutics go.

JohnD95658 6y ago

I'll be very happy if the vaccination decrease number

fatlasp 6y ago

correct me if I'm wrong but haven't all the mRNA vaccines skipped human studies / have 'emergency use' certification

karmelapple 6y ago
Human trials of both the Pfizer and Moderna vaccines were conducted, with tens of thousands participating. Your statement is wrong, and I’m glad you welcomed being corrected. Have a nice day. https://www.cbsnews.com/news/covid-vaccine-pfizer-phase-3-human-trial-united-states/ https://www.cbsnews.com/news/covid-vaccine-pfizer-phase-3-hu...
- adolph 6y ago
  August 21, 2020, 11:30 AM Two U.S. pharmaceutical giants, Pfizer and Moderna, are in the final phase of coronavirus vaccine development, and Oxford University is expected to start large-scale human trials of its vaccine in the U.S. this month.
  - em500 6y ago
    https://www.fda.gov/media/144245/download https://www.fda.gov/media/144245/download https://fda.report/media/144673/Moderna+COVID-19+Vaccine+review+memo.pdf https://fda.report/media/144673/Moderna+COVID-19+Vaccine+rev...
    - adolph 6y ago
      The initial numbers look awesome: Pfizer: 8/18,198 vaccine, 162/18,325 placebo; Moderna: 5/13,934 vaccine, 90/13,883 placebo for 7 and 14 days respectively after the second dose.
- tiziniano 6y ago
  How long were the trials? I recall a famous drug that was given in the 70s and it produced birth malformations. Took years for doctors to realize the cause and ban its use in pregnant women. Is there a possibility of unforeseen consequences from using RNA? What if someone has for XYZ reason more reverse transcriptase than usual? Will his-her DNA be altered?

blargmaster42_8 6y ago

Do not question! INJECT! INJECT!

myrandomcomment 6y ago

So one of my takeaways from all of this is we cannot wait long enough based on current methods anymore. This virus is just one and it is likely to get worse. We need to invest now into large scale computer simulation of vaccines or things will become much worse. There is risk here, however I feel strongly that if we do need to move faster or today will become normal and that cannot become the normal! I read that most of the vacancies only took a few weeks for the scientist to create, however the current testing methods are why we are nearly 9 months to delivery. We as a society have to invest on new methods to move forward creation to delivery faster. I am not claiming any expertise here - I majored in Biochemistry but never finished (moved to tech). I do have 14 doctors / geneticist / infection disease specialist in my family that share this view.

castratikron 6y ago
I've been wondering the same thing. How big of a computer would you need to accurately simulate an immune system? Or at least accurate enough to cut down on some of the tedious and time consuming work? Could something like this be built today with enough effort? I know nothing about immunology BTW.
- shellfishgene 6y ago
  The knowledge is not there to simulate the immune system in any useful way. Apart from that the main issue why it takes long to test vaccines are side effects. Checking for those would require simulating the whole body including various interactions with its environment.
Nbox9 6y ago
> This virus is just one and it is likely to get worse. We need to invest now into large scale computer simulation of vaccines or things will become much worse. This seems like a logical leap to me. Yes we need to do something to make us less open to viral threats, but you don’t present any evidence that improved computer simulations can be a useful tool in helping develop/test vaccines faster.
- 6y ago

lazyjones 6y ago

What is the error rate in mass production of mRNA? What can mRNA with a few flipped/wrong molecules do?

shellfishgene 6y ago
There are various options for RNA polymerases commonly used in vitro [1], generally the error rate is considered to be "pretty low", something like 1 in 10k. An error will also have to result in a change of amino acid, which less likely due to the redundancy of the code. So any error mRNA will probably only have one amino acid changed. This could cause the resulting spike protein to aquire some new characteristic, but it's not very likely I would guess. Also, in the clinical trials they test the actual produced vaccine, with all errors included. [1] https://international.neb.com/tools-and-resources/selection-charts/rna-polymerase-selection-chart https://international.neb.com/tools-and-resources/selection-...
- shellfishgene 6y ago
  Thinking about this some more, there may even be an advantage: The virus also mutates, so some error mRNAs may actually confer additional immunity to future or current virus strains. In reality there are probably way to few errors for this to make a difference...
LarvaFX 6y ago
Genetic code is highly redundant. A few flipped characters will therefore probably not affect the produced protein much.
- shellfishgene 6y ago
  I wouldn't call it "highly" redundant, more than two thirds of mutations will cause an amino acid change.
- thamer 6y ago
  It's highly redundant when there are 2 strands, as is the case with DNA. RNA has a tendency to accumulate mutations quickly, as evidenced by the many hundreds of variants of SARS-CoV-2 that have already been sequenced (and that's with only ~30,000 bases).

Bombthecat 6y ago

They just need to get a hold on the allergic reactions..

driverdan 6y ago
Allergic reactions are like shark attacks. Extremely rare but get tons of press coverage, making them seem more common than they are. All vaccines have a risk of allergic reactions. This is why you're supposed to be monitored for at least 10 minutes after the injection. This is especially important for people who have a history of such reactions to vaccines.
fsh 6y ago
None of the 18860 participants of the Phase 2/3 trial reported allergic reactions after either dose of the vaccine [1]. Over the entire duration of the study, one member of the treatement group suffered an anaphylactic reaction and one member of the placebo group an anaphylactic shock [2]. There is no hint that this particular vaccine is more likely to trigger allergic reactions than any other kind of medication. [1] Section 6.3.3.2.2.1. in https://www.fda.gov/media/144246/download https://www.fda.gov/media/144246/download [2] Table 23, Ibid.

deleted 6y ago

[deleted]

deleted 6y ago

[deleted]

mybrid 6y ago

How do they classify something like this as safe for the long term if long term experiments are not conducted? Is there any substitute for time trials for drugs other than these new vaccines? These are the questions my relatives are asking me and my answers are I don't know, I don't. The scientific community needs to do a better job of communication. Why are we confident that a trial of only three months is sufficient when the only efficacy test for long term effects is long term trials?

valarauko 6y ago
They are not classified as safe for long term use - they're still not approved. They're been cleared by an EUA for emergency use. We don't know how safe they are for long term use yet, since those trails are still ongoing - Pfizer's 3rd Phase trials run till the summer of 2021, and Moderna's trial runs till mid 2022. We'll have more concrete answers then. That's why an Emergency Use Authorization is just that - there's an emergency. The FDA is well aware that long term safety is still unclear, but given the circumstances, the risks posed by vaccination for the general public are outweighed by the benefits.
- mybrid 6y ago
  The only problem is from a communication with the public is that as many people has physically possible will be vaccinated. How is this "emergency" approval any different then a general approval if the end result of the same? " but given the circumstances, the risks posed by vaccination for the general public are outweighed by the benefits. " That's the problem, we don't. We don't know what the risk is long term, it is unknown. It is illogical to say that an completely unknown risk has any logical comparison.
  - valarauko 6y ago
    While we don't have an exact handle on the risks posed by the vaccine long term, we do have reasonable bounds on what they may be. For example, it's entirely possible 0.05 - 0.6% of people who receive the vaccines develop long term severe negative outcomes. Perhaps that number is 3% - we don't know, but more unlikely. We can be fairly certain that number isn't as high as 40%. We don't have all the numbers, but we have reasonable assumptions - these are non integrative mRNAs that have a very short lifespan inside the body, so long term effects other than immunity are not expected. Of course, there is uncertainty in everything. This is more uncertainty than the FDA would accept in the usual course of events - but this is an unusual time. The FDA has no adequate, approved, and available alternatives to the emergency authorization when faced with the pandemic. The investigational vaccine appears to be safe and effective against COVID-19 for the general population. Yes, the vaccine poses some unknown risks, but they are very likely vanishingly smaller than the very present health risks posed by the pandemic. For any given individual, they're much more likely to suffer negative health outcomes within the next 5 years from COVID than from the vaccine. Nobody is stating that risk to be zero. But that also doesn't mean "the risk is completely unknown so why even bother?" How is the emergency authorization any different from an approval? If tomorrow an effective treatment for COVID-19 were to be approved or the pandemic ends, the EUA for the vaccine would be rescinded. Pfizer/Moderna must also track any adverse reactions more closely, and report them to the FDA on an ongoing basis. They also cannot sell them to private players - they're being provided to the FDA & their authorized parties. The vaccines are not licensed for COVID or any other use.

garfieldnate 6y ago

How does the immune system keep a memory of what every single non-foreign protein looks like so that it can recognize foreign ones? That's the most amazing thing here, to me.