9 ms·

There's some known HIV "bnAbs", or broadly neutralizing antibodies. The thing is, these are not the antibodies most humans develop in response to HIV. Previou

by mlyle 5y ago

There's some known HIV "bnAbs", or broadly neutralizing antibodies. The thing is, these are not the antibodies most humans develop in response to HIV. Previous HIV vaccine attempts have only done a fair job at eliciting these broadly neutralizing responses. e.g. SAV001, a "whole killed" HIV vaccine, only produces broadly neutralizing antibodies in about a third of recipients (and less broadly neutralizing response in a much bigger fraction). The mRNA approach, like some recombinant approaches, seeks to generate just portions of envelope protein to tailor the response to produce these bnAbs.

hn_throwaway_99 5y ago
Thank you! Just the kind of explanation I was looking for, most appreciated.
f6v 5y ago
I’m not familiar with vaccine tech. Can’t you grow the peptide of interest and package it in a traditional vaccine?
- mlyle 5y ago
  > Can’t you grow the peptide of interest and package it in a traditional vaccine? Traditional way to do this is recombinant approaches (mentioned). These are also in progress. mRNA is much quicker to iterate, though. They tried a few candidate sequences in sHIV to guide their human vaccine development. mRNA vaccines are kind of neat in the way that they create a few day long pulse of new virus-like particles showing up, to ensure the immune system gets really annoyed.
  - throwaway2037 5y ago
    When you wrote <<sHIV>>, did you mean <<Simian immunodeficiency virus (SIV)>>? Ref: https://en.wikipedia.org/wiki/Simian_immunodeficiency_virus https://en.wikipedia.org/wiki/Simian_immunodeficiency_virus
    - mlyle 5y ago
      No, I meant sHIV or SHIV, which are a family of human-created viruses with SIV structure and HIV sequences within. https://journals.asm.org/doi/10.1128/JVI.00372-19 https://journals.asm.org/doi/10.1128/JVI.00372-19
- siver_john 5y ago
  Strictly speaking you can, and not knowing the exact reasons this approach is moved to human trials where others have not, I can only conjecture. However, the mRNA vaccine may be more stable in a way that makes it easier to make or store or for entrance into the body. Not to mention purification steps may be easier. You don't need to make this in some exotic cell line which creates a protein soup you have to purify. It may be easier on the body (less likely to develop a severe immune reaction), or it may be better at generating a sufficient immune reaction because a lot of mRNA development has gone into finding molecules that are readily taken up by the immune system regardless of cargo. These are a few reasons I can think I am sure I am missing some and there may be a stated answer out there that I have yet to search for.
  - mlyle 5y ago
    > this approach is moved to human trials where others have not, I can only conjecture. Actually, a whole lot of recombinant approaches have moved to human trials (along with viral vector approaches). They early ones showed no efficacy; the newer ones we just don't know (yet). The main benefit of mRNA is iteration: you can try a whole lot of different protein mixes and see what works best in an animal model. A secondary benefit is that the sustained churning out of proteins for a few days seems to generate a much broader antibody response, making getting some of those elusive bnAbs more likely. A big problem with killed HIV vaccines and purified fragments of HIV is that growing virus in human immune cells is extraordinarily costly, and you really wouldn't want to have some live HIV leak through your purification process. So this is why we're mostly talking about other approaches to make proteins (viral vectors, recombinant DNA in bacteria and other cells, mRNA vaccines, etc)
    - siver_john 5y ago
      >Actually, a whole lot of recombinant approaches have moved to human trials (along with viral vector approaches). I should have been more clear here, I meant specifically trials of what I presume could have been attempted if the vaccine was expressed as protein instead of mRNA. But thanks for the clarification. And the mention of viral vectors which are an area I was less aware of till recently but it has been cool to see them in more places.
aleks224 5y ago
>An "elite controller" is a person living with HIV who is able to maintain undetectable viral loads for at least 12 months despite not having started antiretroviral therapy (ART) . Elite controllers are rare: for every two hundred people living with HIV, approximately one may be an elite controller (0.5%). > It is not entirely understood why some patients are able to achieve undetectable viral loads without ART. https://www.aidsmap.com/about-hiv/faq/what-elite-controller https://www.aidsmap.com/about-hiv/faq/what-elite-controller
- dillondoyle 5y ago
  And undetectable === untransmittable. Just in case people here didn't know.
  - hdjjhhvvhga 5y ago
    I didn't know this. Could you explain the reason?
    - baq 5y ago
      No detectable virus means no transmissible virus.
      - Drdrdrq 5y ago
        To reiterate the question, why is that?
        XzAeRosho 5y ago
        That's the million dollar question
        JulianMorrison 5y ago
        Detection means there is enough virus physically present in the sample for the detection technology to identify it. Infection requires virus particles to be physically present in transmission vectors (fluids, droplets, etc). There's generally also a dose-response effect where more particles means more chance of evading the immune system well enough to establish replication in the victim. So a lack of anything to detect, means a lack of anything to spread an infection.
dnautics 5y ago
> "these are not the antibodies most humans develop in response to HIV." In many cases. One case, for example was identified from a prostitute in sub-saharan africa who managed to be completely HIV-free. It turned out she had a mutation in her antibodies that caused the antibodies to latch onto things with four sites instead of just 2 (think X shaped instead of V shaped).
- andrewflnr 5y ago
  That sounds fascinating. Got any links or search terms?
  - dnautics 5y ago
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136306/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136306/
    - andrewflnr 5y ago
      Awesome.
- mlyle 5y ago
  That's why I said "most humans". bnAbs are generally antibodies that are detected in (few) humans. In addition to the people with seeming immunity through missing receptors or unusual antibody morphology, there's also about 1 in 200 infected that are "elite controllers" that do not develop high viral loads or severe symptoms when infected by HIV-- generally in large part to their bodies making multiple bnAbs.
  - dnautics 5y ago
    I wasn't contradicting you, I was adding more specifics.
maxerickson 5y ago
The IAVA press release discusses some of this: https://www.iavi.org/news-resources/press-releases/2022/iavi-and-moderna-launch-trial-of-mrna-hiv-vaccine-antigens https://www.iavi.org/news-resources/press-releases/2022/iavi... Sounds like the mRNA platform is being tested as a delivery mechanism for immunological work that was done separately.
- XorNot 5y ago
  Specifically it's advantageous because bnAB development requires 2 separate immune stimulii applied over months. Injecting protein bolus (traditional vaccines) then requires something like 6+ separate, different vaccines - so 6 synthetic paths, production lines etc. mRNA eliminates all of that. The 2 immune pathways can be combined into 1 vaccine, and the multiple vaccines can all be produced with the same synthetic pipeline and the same distribution and administration requirements. mRNA may make a huge difference here.
  - ImaCake 5y ago
    Yep. In fact mRNA vaccines are almost trivially easy to produce. I know for a fact that many biology labs around the world bought the reagents needed to make homebrew mRNA vaccines in earl 2020. Just in case big pharma screwed up. It would have only been a few days work for them to produce it for themselves and I wouldn’t be surprised if some American and European labs actually did it.
    - sterlind 5y ago
      mRNA vaccines don't use regular mRNA though, they use nucleoside analogues to avoid triggering an innate immune response to the mRNA itself. is it really that easy to homebrew that? plus encapsulating it into lipid nanoparticles etc. sounds like it'd be a major project..
      - ImaCake 5y ago
        The lipid vesicles part is pretty simple I think. You don’t need it to last a long time, just long enough to snort it up your nose. I am not sure about the XNAs. You might be able to get around it with increasing the dose (trivial if you are producing your own RNA) or it might be possible to use XNAs in a standard synthesis protocol. It would depend on the RNA Pol I think.
deltaonefour 5y ago
I'm pretty sure that if the this vaccine succeeds there's going to be a new strain of HIV that can get around it.

by mlyle 5y ago

hn_throwaway_99 5y ago

Thank you! Just the kind of explanation I was looking for, most appreciated.

f6v 5y ago

I’m not familiar with vaccine tech. Can’t you grow the peptide of interest and package it in a traditional vaccine?

mlyle 5y ago
> Can’t you grow the peptide of interest and package it in a traditional vaccine? Traditional way to do this is recombinant approaches (mentioned). These are also in progress. mRNA is much quicker to iterate, though. They tried a few candidate sequences in sHIV to guide their human vaccine development. mRNA vaccines are kind of neat in the way that they create a few day long pulse of new virus-like particles showing up, to ensure the immune system gets really annoyed.
- throwaway2037 5y ago
  When you wrote <<sHIV>>, did you mean <<Simian immunodeficiency virus (SIV)>>? Ref: https://en.wikipedia.org/wiki/Simian_immunodeficiency_virus https://en.wikipedia.org/wiki/Simian_immunodeficiency_virus
  - mlyle 5y ago
    No, I meant sHIV or SHIV, which are a family of human-created viruses with SIV structure and HIV sequences within. https://journals.asm.org/doi/10.1128/JVI.00372-19 https://journals.asm.org/doi/10.1128/JVI.00372-19
siver_john 5y ago
Strictly speaking you can, and not knowing the exact reasons this approach is moved to human trials where others have not, I can only conjecture. However, the mRNA vaccine may be more stable in a way that makes it easier to make or store or for entrance into the body. Not to mention purification steps may be easier. You don't need to make this in some exotic cell line which creates a protein soup you have to purify. It may be easier on the body (less likely to develop a severe immune reaction), or it may be better at generating a sufficient immune reaction because a lot of mRNA development has gone into finding molecules that are readily taken up by the immune system regardless of cargo. These are a few reasons I can think I am sure I am missing some and there may be a stated answer out there that I have yet to search for.
- mlyle 5y ago
  > this approach is moved to human trials where others have not, I can only conjecture. Actually, a whole lot of recombinant approaches have moved to human trials (along with viral vector approaches). They early ones showed no efficacy; the newer ones we just don't know (yet). The main benefit of mRNA is iteration: you can try a whole lot of different protein mixes and see what works best in an animal model. A secondary benefit is that the sustained churning out of proteins for a few days seems to generate a much broader antibody response, making getting some of those elusive bnAbs more likely. A big problem with killed HIV vaccines and purified fragments of HIV is that growing virus in human immune cells is extraordinarily costly, and you really wouldn't want to have some live HIV leak through your purification process. So this is why we're mostly talking about other approaches to make proteins (viral vectors, recombinant DNA in bacteria and other cells, mRNA vaccines, etc)
  - siver_john 5y ago
    >Actually, a whole lot of recombinant approaches have moved to human trials (along with viral vector approaches). I should have been more clear here, I meant specifically trials of what I presume could have been attempted if the vaccine was expressed as protein instead of mRNA. But thanks for the clarification. And the mention of viral vectors which are an area I was less aware of till recently but it has been cool to see them in more places.

aleks224 5y ago

>An "elite controller" is a person living with HIV who is able to maintain undetectable viral loads for at least 12 months despite not having started antiretroviral therapy (ART) . Elite controllers are rare: for every two hundred people living with HIV, approximately one may be an elite controller (0.5%). > It is not entirely understood why some patients are able to achieve undetectable viral loads without ART. https://www.aidsmap.com/about-hiv/faq/what-elite-controller https://www.aidsmap.com/about-hiv/faq/what-elite-controller

dillondoyle 5y ago
And undetectable === untransmittable. Just in case people here didn't know.
- hdjjhhvvhga 5y ago
  I didn't know this. Could you explain the reason?
  - baq 5y ago
    No detectable virus means no transmissible virus.
    - Drdrdrq 5y ago
      To reiterate the question, why is that?
      - XzAeRosho 5y ago
        That's the million dollar question
      - JulianMorrison 5y ago
        Detection means there is enough virus physically present in the sample for the detection technology to identify it. Infection requires virus particles to be physically present in transmission vectors (fluids, droplets, etc). There's generally also a dose-response effect where more particles means more chance of evading the immune system well enough to establish replication in the victim. So a lack of anything to detect, means a lack of anything to spread an infection.

dnautics 5y ago

> "these are not the antibodies most humans develop in response to HIV." In many cases. One case, for example was identified from a prostitute in sub-saharan africa who managed to be completely HIV-free. It turned out she had a mutation in her antibodies that caused the antibodies to latch onto things with four sites instead of just 2 (think X shaped instead of V shaped).

andrewflnr 5y ago
That sounds fascinating. Got any links or search terms?
- dnautics 5y ago
  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136306/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136306/
  - andrewflnr 5y ago
    Awesome.
mlyle 5y ago
That's why I said "most humans". bnAbs are generally antibodies that are detected in (few) humans. In addition to the people with seeming immunity through missing receptors or unusual antibody morphology, there's also about 1 in 200 infected that are "elite controllers" that do not develop high viral loads or severe symptoms when infected by HIV-- generally in large part to their bodies making multiple bnAbs.
- dnautics 5y ago
  I wasn't contradicting you, I was adding more specifics.

maxerickson 5y ago

The IAVA press release discusses some of this: https://www.iavi.org/news-resources/press-releases/2022/iavi-and-moderna-launch-trial-of-mrna-hiv-vaccine-antigens https://www.iavi.org/news-resources/press-releases/2022/iavi... Sounds like the mRNA platform is being tested as a delivery mechanism for immunological work that was done separately.

XorNot 5y ago
Specifically it's advantageous because bnAB development requires 2 separate immune stimulii applied over months. Injecting protein bolus (traditional vaccines) then requires something like 6+ separate, different vaccines - so 6 synthetic paths, production lines etc. mRNA eliminates all of that. The 2 immune pathways can be combined into 1 vaccine, and the multiple vaccines can all be produced with the same synthetic pipeline and the same distribution and administration requirements. mRNA may make a huge difference here.
- ImaCake 5y ago
  Yep. In fact mRNA vaccines are almost trivially easy to produce. I know for a fact that many biology labs around the world bought the reagents needed to make homebrew mRNA vaccines in earl 2020. Just in case big pharma screwed up. It would have only been a few days work for them to produce it for themselves and I wouldn’t be surprised if some American and European labs actually did it.
  - sterlind 5y ago
    mRNA vaccines don't use regular mRNA though, they use nucleoside analogues to avoid triggering an innate immune response to the mRNA itself. is it really that easy to homebrew that? plus encapsulating it into lipid nanoparticles etc. sounds like it'd be a major project..
    - ImaCake 5y ago
      The lipid vesicles part is pretty simple I think. You don’t need it to last a long time, just long enough to snort it up your nose. I am not sure about the XNAs. You might be able to get around it with increasing the dose (trivial if you are producing your own RNA) or it might be possible to use XNAs in a standard synthesis protocol. It would depend on the RNA Pol I think.

deltaonefour 5y ago

I'm pretty sure that if the this vaccine succeeds there's going to be a new strain of HIV that can get around it.