5 ms·

No. Yes. This approach is like sneaking in blueprints to a factory (cell) that makes (proteins using mRNA) whatever it has blueprints for, and gets inspectors

No. Yes. This approach is like sneaking in blueprints to a factory (cell) that makes (proteins using mRNA) whatever it has blueprints for, and gets inspectors that come around occasionally (immune surveillance), or very frequently under active infection, looking for contraband. When the body start producing this foreign proteins in the presence of something to trigger the immune system (called an adjuvant which all vaccines use to make the body recognise as bad and not harmless/irrelevant) the immune system starts producing a response against that.

rolph 6y ago
adjuvent is not neccesary for immune response, it is nessecary for spreading out the antigen producing character among more doses, rather than using a concentration of mRNA that in itself produces enough protien to induce immune response
- nicwilson 6y ago
  What? > adjuvent [sic] is not neccesary[sic] for immune response, Completely false. Unless the immune system has been exposed to something similar before (e.g. SARS/MERS n.b. made up example I have no idea if the spikes of SARS or MERS are molecularly similar enough), no adjuvant means situation normal for the immune system. If there is nothing to signal to the immune system that this new antigen is bad then it will treat it as neutral suppressing any vaccine response, which is worse that if the vaccine had not been delivered at all. >is nessecary[sic] for spreading out the antigen producing character among more doses the point of booster shots is to ensure that antibodies are maintained at sufficient levels to fight off a real infection. If a response has been established, i guess adjuvants are not as necessary? (did biomed, but not a vaccine researcher) I have no idea if they are included or not for boosters. > rather than using a concentration of mRNA that in itself produces enough protien[sic] to induce immune response A high concentration won't do shit if the immune system doesn't have anything to activate it, it will just see a high concentration of irrelevant new, i.e. foreign protein.
  - rolph 6y ago
    >> Completely false. Unless the immune system has been exposed to something similar before (e.g. SARS/MERS n.b. made up example I have no idea if the spikes of SARS or MERS are molecularly similar enough), no adjuvant means situation normal for the immune system. If there is nothing to signal to the immune system that this new antigen is bad then it will treat it as neutral suppressing any vaccine response, which is worse that if the vaccine had not been delivered at all. << This is Completely false. Natural immunity does not require adjuvent. spreading out a scarce valuable resource by use of adjuvent is a standard practice. ANY complex not recognized by the MHC will elicit an invader response, the immediate vigor of this response is attenuated by inclusion of adjuvent in the final formulation of the vaccine. we would all die 100% of the time if adjuvent was required to mount immune response, to infection.
    - nicwilson 6y ago
      Ah, I had assumed you were talking about the vaccine immune response. > we would all die 100% of the time if adjuvent was required to mount immune response, to infection. Indeed, but it is required for a vaccine to function properly.
      - rolph 6y ago
        no, it is not, it is required for a vaccine to be economicaly efficient, and to maximize benefit with minimized expenditure without adjuvent many vaccines would need much greater concentration of the antigen producing component. by inducing an attenuated response, using an adjuvent, you can manufacture many more doses of the vaccine using less mRNA in each dose.
    - AbortedLaunch 6y ago
      Natural immunity requires activation of the innate immune system by pathogen associated molecular patterns (PAMPs) such as dsRNA, LPS or peptidoglycan. One role adjuvants play is to mimic these PAMPs.
      - 6y ago
jbaudanza 6y ago
Yes, that makes sense. I was just wondering if the target virus is already RNA encoded, if that provides any shortcuts. It sounds like maybe not.
- rolph 6y ago
  while it is possible to harvest SARS genomic RNA and excise dangerous components this is expensive time and money wise and dangerous, this reduces to the better approach being a synthetic novel S protien manufactured from raw materials.
- nicwilson 6y ago
  It doesn't. The vaccine is a piece of mRNA (in this case part of the spike protein) which has a cap on one end to stop degradation from the start of the message (which would garble it completely). This piece of RNA is not replicated. Whereas the virus encodes the whole spike, the capsid protein and whatever else the virus needs to replicate like promoter sequences and an origin of replication. It is much larger and is replicate. Basically it skips all the viral machinery and just codes for a small piece that identifies the virus to the immune system.
zackees 6y ago
It's one thing to inject an antigen that your body makes antibodies for. It's one thing to use a viral vector to reprogram some number of cells. Due to the Emergency Use Authorization, much of the safety testing has been skipped.
- pas 6y ago
  What was skipped? phase 1, 2, 3 happened, right?
  - weaksauce 6y ago
    nothing was skipped maybe aside from testing on animals first. it was however on a compressed observational and manufacturing timeline. normally a company doesn't want to run the next trial while the previous trial is ongoing. they compressed stages one and two(safety studies where they do tens of people and then hundreds of people to strictly look for adverse outcomes). Then they did a efficacy trial in stage three of thousands (which also looks out for large adverse outcomes). the regulatory review stage was also shortened because the drug manufacturers were supplying more real time data to the regulators to expedite the approval. the normal way they do it is to run every stage back to back and then after stage 3 is finished they would submit the data to the fda and get an approval back within a year or two. Then the manufacturing would start to ramp up... this was a moonshot type of project that hoped the trial would be successful and started to manufacture the drug before full approval occurred. you can see timelines here: https://www.bbc.com/news/health-55056016 https://www.bbc.com/news/health-55056016 tldr: nothing skipped; however it was compressed.
- ahartmetz 6y ago
  AFAIU time-compressed is more accurate than skipped. Obviously, observation of long term effects has been skipped. Other mRNA vaccines have been tested though (but not introduced) so the class of vaccines does have long-term data available and there are no known risks worse than other vaccines. Seems safe enough. Hopefully not famous last words...
- rolph 6y ago
  mRNA is not a viral vector. the mRNA vaccine does not contain the entire viral code, and is not carried by the SARS virion but by a constructed liposome used as an mRNA delivery vector

rolph 6y ago

adjuvent is not neccesary for immune response, it is nessecary for spreading out the antigen producing character among more doses, rather than using a concentration of mRNA that in itself produces enough protien to induce immune response

nicwilson 6y ago
What? > adjuvent [sic] is not neccesary[sic] for immune response, Completely false. Unless the immune system has been exposed to something similar before (e.g. SARS/MERS n.b. made up example I have no idea if the spikes of SARS or MERS are molecularly similar enough), no adjuvant means situation normal for the immune system. If there is nothing to signal to the immune system that this new antigen is bad then it will treat it as neutral suppressing any vaccine response, which is worse that if the vaccine had not been delivered at all. >is nessecary[sic] for spreading out the antigen producing character among more doses the point of booster shots is to ensure that antibodies are maintained at sufficient levels to fight off a real infection. If a response has been established, i guess adjuvants are not as necessary? (did biomed, but not a vaccine researcher) I have no idea if they are included or not for boosters. > rather than using a concentration of mRNA that in itself produces enough protien[sic] to induce immune response A high concentration won't do shit if the immune system doesn't have anything to activate it, it will just see a high concentration of irrelevant new, i.e. foreign protein.
- rolph 6y ago
  >> Completely false. Unless the immune system has been exposed to something similar before (e.g. SARS/MERS n.b. made up example I have no idea if the spikes of SARS or MERS are molecularly similar enough), no adjuvant means situation normal for the immune system. If there is nothing to signal to the immune system that this new antigen is bad then it will treat it as neutral suppressing any vaccine response, which is worse that if the vaccine had not been delivered at all. << This is Completely false. Natural immunity does not require adjuvent. spreading out a scarce valuable resource by use of adjuvent is a standard practice. ANY complex not recognized by the MHC will elicit an invader response, the immediate vigor of this response is attenuated by inclusion of adjuvent in the final formulation of the vaccine. we would all die 100% of the time if adjuvent was required to mount immune response, to infection.
  - nicwilson 6y ago
    Ah, I had assumed you were talking about the vaccine immune response. > we would all die 100% of the time if adjuvent was required to mount immune response, to infection. Indeed, but it is required for a vaccine to function properly.
    - rolph 6y ago
      no, it is not, it is required for a vaccine to be economicaly efficient, and to maximize benefit with minimized expenditure without adjuvent many vaccines would need much greater concentration of the antigen producing component. by inducing an attenuated response, using an adjuvent, you can manufacture many more doses of the vaccine using less mRNA in each dose.
  - AbortedLaunch 6y ago
    Natural immunity requires activation of the innate immune system by pathogen associated molecular patterns (PAMPs) such as dsRNA, LPS or peptidoglycan. One role adjuvants play is to mimic these PAMPs.
    - 6y ago

jbaudanza 6y ago

Yes, that makes sense. I was just wondering if the target virus is already RNA encoded, if that provides any shortcuts. It sounds like maybe not.

rolph 6y ago
while it is possible to harvest SARS genomic RNA and excise dangerous components this is expensive time and money wise and dangerous, this reduces to the better approach being a synthetic novel S protien manufactured from raw materials.
nicwilson 6y ago
It doesn't. The vaccine is a piece of mRNA (in this case part of the spike protein) which has a cap on one end to stop degradation from the start of the message (which would garble it completely). This piece of RNA is not replicated. Whereas the virus encodes the whole spike, the capsid protein and whatever else the virus needs to replicate like promoter sequences and an origin of replication. It is much larger and is replicate. Basically it skips all the viral machinery and just codes for a small piece that identifies the virus to the immune system.

zackees 6y ago

It's one thing to inject an antigen that your body makes antibodies for. It's one thing to use a viral vector to reprogram some number of cells. Due to the Emergency Use Authorization, much of the safety testing has been skipped.

pas 6y ago
What was skipped? phase 1, 2, 3 happened, right?
- weaksauce 6y ago
  nothing was skipped maybe aside from testing on animals first. it was however on a compressed observational and manufacturing timeline. normally a company doesn't want to run the next trial while the previous trial is ongoing. they compressed stages one and two(safety studies where they do tens of people and then hundreds of people to strictly look for adverse outcomes). Then they did a efficacy trial in stage three of thousands (which also looks out for large adverse outcomes). the regulatory review stage was also shortened because the drug manufacturers were supplying more real time data to the regulators to expedite the approval. the normal way they do it is to run every stage back to back and then after stage 3 is finished they would submit the data to the fda and get an approval back within a year or two. Then the manufacturing would start to ramp up... this was a moonshot type of project that hoped the trial would be successful and started to manufacture the drug before full approval occurred. you can see timelines here: https://www.bbc.com/news/health-55056016 https://www.bbc.com/news/health-55056016 tldr: nothing skipped; however it was compressed.
ahartmetz 6y ago
AFAIU time-compressed is more accurate than skipped. Obviously, observation of long term effects has been skipped. Other mRNA vaccines have been tested though (but not introduced) so the class of vaccines does have long-term data available and there are no known risks worse than other vaccines. Seems safe enough. Hopefully not famous last words...
rolph 6y ago
mRNA is not a viral vector. the mRNA vaccine does not contain the entire viral code, and is not carried by the SARS virion but by a constructed liposome used as an mRNA delivery vector