Jacob Lagerros got excited about RaDVaC early and came to the Lightcone team a few months ago saying we should arrange funding for them. I believe talks have occurred between relevant parties though I’m not certain of exactly where things ended up.
Summary: I suspect funding has been provided, mostly want to give credit to those who noticed early and worked to make it happen.
I found a low six figure donor who filled 25% of their funding gap. The rest has not been filled. EDIT: They also got an ACX grant, but not enough to fill the whole funding gap I believe. I can intro donors who want to fill it to the radvac team. Email me at jacob at lesswrong.com
I’m happy to hear that my cries resulted in at least some founding being moved to them even if it’s still sad that there’s still a funding gap.
In addition to what Eliezer already said about RaDVaC being good because it uses technology that can easily scaled up, RaDVaC has the potential to reduce infection by COVID-19 when given in addition to traditional vaccines because it potentially creates a mucosal immune system response in the upper respiratory system which the vaccines we currently have don’t.
While there’s some potential that Omicron will end COVID-19 that is optimistic. We might need something like RaDVaC to finally end this pandemic.
Regarding the remaining funding gap you mention, did you take the recent $100,000 ACX grant into account?
Alex Hoekstra, $100,000, for the Rapid Deployment Vaccine Collaborative (RaDVaC) to make open-source modular affordable vaccines. … RaDVaC still needs more funding …
Hi all, this is Alex and Preston from RaDVaC. Thank you Eliezer for your thoughtful words of support. And thank you again Jacob L, your ongoing support is very much appreciated. We’re also thrilled about receiving an ACX grant; not only is the money enabling, but the added recognition has already been extremely positive, and we have received additional donations following the award announcement. As Eliezer noted, we still don’t have all the funding we need to accelerate badly needed change in vaccine access and independence, but we do have funds to make great progress this year in ongoing projects.
One key goal is to establish an iterative cycle of vaccine improvement and testing, which will depend on improving our ability to measure immune responses. Another major goal for this year is to move toward full vaccine production independence, especially of vaccine antigens that are likely to be resilient against ongoing mutations. Vaccines based on recombinant antigen proteins produced in yeast are increasingly common, and we are in the early stages of designing yeast antigen factories that can be stored, shipped, and used as a foundational component for rapidly deploying vaccine factories just about anywhere in the world. And unlike peptides, RaDVaC should be able to share them freely, since the strains are not drugs or vaccines. This approach using the industrial yeast Pichia pastoris (a.k.a. K. phaffii) is highly scalable and relatively inexpensive, especially after the upfront design and optimization work which we’re taking on. We continue to watch the mRNA vaccine space, and will ramp up investment when the time is right, but at the moment, the most affordable and scalable vaccines are based on these more tractable technologies.
One major goal that we are working on, but do not have sufficient funding to complete, is the establishment of working models for accelerated vaccine trials. Such trials create protracted delays in otherwise rapid vaccine deployments. We are working with others outside the US on improving both challenge trials and more conventional randomized clinical trials. If you would like to contribute to this effort, please get in touch us.
We’ve just started a RaDVaC project Discord where you can connect with us, and where we plan to post regular updates to the project, as well as communicating + collaborating with others interested in the work. If you’re interested in keeping up with our work there, please let me know and I’ll pass along an invite. Thanks from the RaDVaC core team!
Is there any empirical evidence yet that RaDVaC’s alleged vaccines are in any way effective in making those who use them less likely to get COVID-19, or less likely to get it badly?
[EDITED to add:] I did take a look on the RaDVaC website, and if I’m understanding the FAQ there correctly the answer is (1) you have “positive indications” from your “preliminary assays” (I am guessing this means: very weak evidence?) that RaDVaC elicits some sort of immune response in the nose, and (2) you have no direct evidence at all that it has any effect on either whether one gets COVID-19 or how severe its effects are if you do. But maybe you can say more here than you have on your website?
Starting with early generations of RaDVaC vaccine designs, some of our core group engaged in self-experimentation to assess safety, as well as testing of some immuno-efficacy biomarkers. Four of us took a series of blood, saliva, & nasal wash samples over several months to determine antibody response in each. A few others also donated samples, which we also tested. We performed early antibody ELISA testing in our lab with custom tests. In parallel with our own testing efforts, we also established collaborations with academic researchers to perform antibody testing and neutralization assays on our samples, and we connected with colleagues in industry to perform T cell testing of various kinds.
In our lab, some of the data were encouraging but some results were conflicting, and overall, they were irreproducible. At the time we were self funded and couldn’t afford more mistakes. Collaborators in both academia and industry were instructed by management and legal counsel not to test our samples. Even though our samples were obtained with full disclosure and individual consent, lawyers for otherwise collaborating institutions declared our project untouchable due to the absence of institutional review board approval (which was impossible to obtain on the accelerated timelines required during the pandemic).
Unfortunately, the available commercial antibody assays at the time were very insensitive and barely registered a signal from our positive control convalescent samples. Those tests use full-length Spike, RBD, or nucleocapsid and are optimized for detecting the presence of multiple antibody species against these larger targets. Plus, our intranasal mode of delivery results in lower levels of systemic IgG. These limitations rendered commercial antibody tests insufficient for our needs.
We didn’t get these testing problems sorted until early 2021, at which point all of us had received commercial vaccination, which prevented us in the core group from obtaining meaningful antibody test data using epitopes that weren’t differentiated from commercial vaccines.
Nevertheless, a collaborating group publicly presented data from antibody assays of their parenteral adaptation of Gen 8⁄9 (https://www.youtube.com/watch?v=eH7i0aPTFEU), which helped validate the antigen selection in those generations of vaccine design. As we have reported in white papers since Gen 10, because of these and other data, we substantially redesigned Gen 10 because vaccination of these naive recipients with pre-Gen 10 designs elicited immune responses in only a minority of them. Since the launch of Gen 10, we have not attempted to retest ourselves because each of us has been vaccinated with multiple commercial and RaDVaC vaccines; instead, we’ve been focused on vaccine design, production, and longer-term and more rigorous testing in animals, and eventually in human clinical trials.
However, opportunities have arisen recently that allow us to return to testing aspects of immunity due to RaDVaC vaccines. First, Omicron is very different from previous variants and vaccines, allowing clear differentiation of antibody responses. Therefore, we have designed a Gen 12 vaccine containing a new Omicron-specific receptor binding motif epitope that should allow us to differentiate between antibody responses generated by commercial vaccines and by Gen 12 (or omicron infection). Second, we have begun working with a company in California to do T cell testing specifically for epitopes in RaDVaC vaccines that are not present in the commercial vaccines most of us have received. They are a small company and our individual consents are sufficient for them to test our samples.
We have funding to do these limited tests on animals and in human subjects on a small scale, but eventually we will need to test vaccines in more complex and costly human clinical trials–challenge trials may be ideal–after we have solid animal data.
[Edited to clarify the legal complications of testing human samples]
Thanks for the detail. I think that means that the answers to my questions are “no, not at all, for the more recent versions of RaDVaC, and in fact for earlier versions what we have is evidence that it usually doesn’t produce any immune response”, and “no, not at all, for any version of RaDVaC”.
For the avoidance of doubt, I’m not saying that this means you’re bad people, or that it means your thing doesn’t work, or that it means no one should give you money. I’m just trying to assess how likely we should think it is that what you’re doing will turn out to be useful.
I think, in particular, that when Eliezer (in the OP) says
They’ve pretty much proved themselves. They should be nurtured and scaled up to where they can start to replace US and Earth defunct state capacity to do the R&D that leads up to being able to rapidly design new vaccines that rapidly scale in production and deployment.
that first sentence is 100% false unless “proved themselves” means something like “proved that they are smart people” or “proved that they are acting in good faith” rather than “proved that they have something that works”, which means that the second is waaaay premature.
Which, again, doesn’t mean that the RaDVaC project shouldn’t be nurtured. Maybe it should. All science and technology starts out unproven, after all.
Eliezer, if you happen to be reading this: Do you, in the light of the discussion above, still consider that “they’ve pretty much proved themselves”, and are you still confident that the project needs only nurturing and scaling-up before it is ready to start replacing the planet’s existing vaccine R&D efforts? If so, what is it that you think I’m missing?
Actoverco’s data were informative about (positive) safety and immunogenic response in RaDVaC’s Gen 8+9 designs. These data aren’t immediately straightforward (antibody response was greater in immunologically “primed” individuals than in immunologically naive individuals), but really informative along the line of antigen selection, presentation, and dosing.
We (writ large) need vaccines that can be deployed rapidly and are focused on that rapid accessibility. There’s no question that safe & effective vaccines can be made. The question for us is how to make safe & effective vaccines rapidly & simply enough to be widely accessible. Our approach has been to create and share designs openly, that can be (re)produced, adapted, tested, and studied without restriction. We couldn’t do every stage of development in our own lab, so we invited others to use their expertise to contribute. Several have and still are, but I agree that it’s time for us at RaDVaC to invest more (and more directly) in producing data that we can guarantee be shared openly.
that first sentence is 100% false unless “proved themselves” means something like “proved that they are smart people” or “proved that they are acting in good faith” rather than “proved that they have something that works”, which means that the second is waaaay premature.
RaDVaC is not only about the particular technology but also about the way the organization runs differently. The approach of being public about the technology and regularly iterating it is very different than the way vaccines are traditionally produced.
RaDVaC is for example right now both looking into the small peptide version they started out with as well as looking at subunit vaccines.
This is correct. RaDVaC is not committed exclusively to a single technology platform; we evaluated (and continuously re-evaluate) the advantages and disadvantages of vaccine platforms like VLP, subunit, peptide, DNA, and mRNA.
All our designs so far have been based on self-assembling nanoparticles transporting peptide antigens, because all materials for both nanoparticle and peptide antigens are highly accessible: readily available, relatively inexpensive, individually safe (not requiring any advanced biosafety conditions for shipping, storage, or use), and quick to source. This design is also very easily produced.
That basic nanoparticle platform (which we’ve open-sourced, along with our peptide designs) is adaptable to other antigens, such as larger recombinant subunits, which we are working on now, for consideration to add to a future version of our white paper. Advantages to recombinant antigens include likely better immunogenicity than peptides, and greater production independence/decentralizability–plus, cells producing such an antigen would likely be a shareable resource.
Adaptability is, I think, quite a cool feature of a platform, and it’s a feature that’s shared in principle by nucleic acid vaccines. The drawback there is largely one of accessibility: modifying code is no big deal, but executing that code is, in practice, far more difficult than producing peptides or even larger proteins. (For now. Many of us at RaDVaC anticipate that the costs associated with both pseudouridine-mRNA and LNP production will come down drastically over the next few years. We’re excited about that.)
One major goal that we are working on, but do not have sufficient funding to complete, is the establishment of working models for accelerated vaccine trials.
Do you have an idea of what order of magnitude of funding this would need?
We’re working with outside people and groups to create appropriate trialing models and protocols, including a focus on challenge trials. We’re looking to hire at least 2 consultants for the process (medical writing, trial design experts) and at least 2 onsite medical staff with fluency in the regulatory & logistics context of wherever a trial is to be run. (Depending upon location, we may also need an IRB’s services to review and approve any trial design; definitely necessary for anything done within the US). One of the groups we are working with, 1DaySooner, has already created and published trial designs, and our trial design will be different but informed by the excellent foundation they’ve provided. We estimate that this preparatory phase will cost $500k-$1M.
An order-of-magnitude estimate for the full cost of a completed trial would depend on scale and location, but the cost for a relatively small but sufficiently powered trial in our current focus location of the Bahamas is in the $10M range.
Jacob Lagerros got excited about RaDVaC early and came to the Lightcone team a few months ago saying we should arrange funding for them. I believe talks have occurred between relevant parties though I’m not certain of exactly where things ended up.
Summary: I suspect funding has been provided, mostly want to give credit to those who noticed early and worked to make it happen.
I found a low six figure donor who filled 25% of their funding gap.
The rest has not been filled.EDIT: They also got an ACX grant, but not enough to fill the whole funding gap I believe. I can intro donors who want to fill it to the radvac team. Email me at jacob at lesswrong.comOriginal thread and credit to ChristianKl who picked up on and alerted me to rumours of the funding gap: https://www.lesswrong.com/posts/fBGzge5i4hfbaQZWy/usd1000-bounty-how-effective-are-marginal-vaccine-doses?commentId=XwA8mtvK8YCob2pLK#comments
I’m happy to hear that my cries resulted in at least some founding being moved to them even if it’s still sad that there’s still a funding gap.
In addition to what Eliezer already said about RaDVaC being good because it uses technology that can easily scaled up, RaDVaC has the potential to reduce infection by COVID-19 when given in addition to traditional vaccines because it potentially creates a mucosal immune system response in the upper respiratory system which the vaccines we currently have don’t.
While there’s some potential that Omicron will end COVID-19 that is optimistic. We might need something like RaDVaC to finally end this pandemic.
Regarding the remaining funding gap you mention, did you take the recent $100,000 ACX grant into account?
Hi all, this is Alex and Preston from RaDVaC. Thank you Eliezer for your thoughtful words of support. And thank you again Jacob L, your ongoing support is very much appreciated. We’re also thrilled about receiving an ACX grant; not only is the money enabling, but the added recognition has already been extremely positive, and we have received additional donations following the award announcement. As Eliezer noted, we still don’t have all the funding we need to accelerate badly needed change in vaccine access and independence, but we do have funds to make great progress this year in ongoing projects.
One key goal is to establish an iterative cycle of vaccine improvement and testing, which will depend on improving our ability to measure immune responses. Another major goal for this year is to move toward full vaccine production independence, especially of vaccine antigens that are likely to be resilient against ongoing mutations. Vaccines based on recombinant antigen proteins produced in yeast are increasingly common, and we are in the early stages of designing yeast antigen factories that can be stored, shipped, and used as a foundational component for rapidly deploying vaccine factories just about anywhere in the world. And unlike peptides, RaDVaC should be able to share them freely, since the strains are not drugs or vaccines. This approach using the industrial yeast Pichia pastoris (a.k.a. K. phaffii) is highly scalable and relatively inexpensive, especially after the upfront design and optimization work which we’re taking on. We continue to watch the mRNA vaccine space, and will ramp up investment when the time is right, but at the moment, the most affordable and scalable vaccines are based on these more tractable technologies.
One major goal that we are working on, but do not have sufficient funding to complete, is the establishment of working models for accelerated vaccine trials. Such trials create protracted delays in otherwise rapid vaccine deployments. We are working with others outside the US on improving both challenge trials and more conventional randomized clinical trials. If you would like to contribute to this effort, please get in touch us.
We’ve just started a RaDVaC project Discord where you can connect with us, and where we plan to post regular updates to the project, as well as communicating + collaborating with others interested in the work. If you’re interested in keeping up with our work there, please let me know and I’ll pass along an invite. Thanks from the RaDVaC core team!
Is there any empirical evidence yet that RaDVaC’s alleged vaccines are in any way effective in making those who use them less likely to get COVID-19, or less likely to get it badly?
[EDITED to add:] I did take a look on the RaDVaC website, and if I’m understanding the FAQ there correctly the answer is (1) you have “positive indications” from your “preliminary assays” (I am guessing this means: very weak evidence?) that RaDVaC elicits some sort of immune response in the nose, and (2) you have no direct evidence at all that it has any effect on either whether one gets COVID-19 or how severe its effects are if you do. But maybe you can say more here than you have on your website?
Starting with early generations of RaDVaC vaccine designs, some of our core group engaged in self-experimentation to assess safety, as well as testing of some immuno-efficacy biomarkers. Four of us took a series of blood, saliva, & nasal wash samples over several months to determine antibody response in each. A few others also donated samples, which we also tested. We performed early antibody ELISA testing in our lab with custom tests. In parallel with our own testing efforts, we also established collaborations with academic researchers to perform antibody testing and neutralization assays on our samples, and we connected with colleagues in industry to perform T cell testing of various kinds.
In our lab, some of the data were encouraging but some results were conflicting, and overall, they were irreproducible. At the time we were self funded and couldn’t afford more mistakes. Collaborators in both academia and industry were instructed by management and legal counsel not to test our samples. Even though our samples were obtained with full disclosure and individual consent, lawyers for otherwise collaborating institutions declared our project untouchable due to the absence of institutional review board approval (which was impossible to obtain on the accelerated timelines required during the pandemic).
Unfortunately, the available commercial antibody assays at the time were very insensitive and barely registered a signal from our positive control convalescent samples. Those tests use full-length Spike, RBD, or nucleocapsid and are optimized for detecting the presence of multiple antibody species against these larger targets. Plus, our intranasal mode of delivery results in lower levels of systemic IgG. These limitations rendered commercial antibody tests insufficient for our needs.
We didn’t get these testing problems sorted until early 2021, at which point all of us had received commercial vaccination, which prevented us in the core group from obtaining meaningful antibody test data using epitopes that weren’t differentiated from commercial vaccines.
Nevertheless, a collaborating group publicly presented data from antibody assays of their parenteral adaptation of Gen 8⁄9 (https://www.youtube.com/watch?v=eH7i0aPTFEU), which helped validate the antigen selection in those generations of vaccine design. As we have reported in white papers since Gen 10, because of these and other data, we substantially redesigned Gen 10 because vaccination of these naive recipients with pre-Gen 10 designs elicited immune responses in only a minority of them. Since the launch of Gen 10, we have not attempted to retest ourselves because each of us has been vaccinated with multiple commercial and RaDVaC vaccines; instead, we’ve been focused on vaccine design, production, and longer-term and more rigorous testing in animals, and eventually in human clinical trials.
However, opportunities have arisen recently that allow us to return to testing aspects of immunity due to RaDVaC vaccines. First, Omicron is very different from previous variants and vaccines, allowing clear differentiation of antibody responses. Therefore, we have designed a Gen 12 vaccine containing a new Omicron-specific receptor binding motif epitope that should allow us to differentiate between antibody responses generated by commercial vaccines and by Gen 12 (or omicron infection). Second, we have begun working with a company in California to do T cell testing specifically for epitopes in RaDVaC vaccines that are not present in the commercial vaccines most of us have received. They are a small company and our individual consents are sufficient for them to test our samples.
We have funding to do these limited tests on animals and in human subjects on a small scale, but eventually we will need to test vaccines in more complex and costly human clinical trials–challenge trials may be ideal–after we have solid animal data.
[Edited to clarify the legal complications of testing human samples]
Thanks for the detail. I think that means that the answers to my questions are “no, not at all, for the more recent versions of RaDVaC, and in fact for earlier versions what we have is evidence that it usually doesn’t produce any immune response”, and “no, not at all, for any version of RaDVaC”.
For the avoidance of doubt, I’m not saying that this means you’re bad people, or that it means your thing doesn’t work, or that it means no one should give you money. I’m just trying to assess how likely we should think it is that what you’re doing will turn out to be useful.
I think, in particular, that when Eliezer (in the OP) says
that first sentence is 100% false unless “proved themselves” means something like “proved that they are smart people” or “proved that they are acting in good faith” rather than “proved that they have something that works”, which means that the second is waaaay premature.
Which, again, doesn’t mean that the RaDVaC project shouldn’t be nurtured. Maybe it should. All science and technology starts out unproven, after all.
Eliezer, if you happen to be reading this: Do you, in the light of the discussion above, still consider that “they’ve pretty much proved themselves”, and are you still confident that the project needs only nurturing and scaling-up before it is ready to start replacing the planet’s existing vaccine R&D efforts? If so, what is it that you think I’m missing?
Following up to affirm two things:
Actoverco’s data were informative about (positive) safety and immunogenic response in RaDVaC’s Gen 8+9 designs. These data aren’t immediately straightforward (antibody response was greater in immunologically “primed” individuals than in immunologically naive individuals), but really informative along the line of antigen selection, presentation, and dosing.
We (writ large) need vaccines that can be deployed rapidly and are focused on that rapid accessibility. There’s no question that safe & effective vaccines can be made. The question for us is how to make safe & effective vaccines rapidly & simply enough to be widely accessible. Our approach has been to create and share designs openly, that can be (re)produced, adapted, tested, and studied without restriction. We couldn’t do every stage of development in our own lab, so we invited others to use their expertise to contribute. Several have and still are, but I agree that it’s time for us at RaDVaC to invest more (and more directly) in producing data that we can guarantee be shared openly.
RaDVaC is not only about the particular technology but also about the way the organization runs differently. The approach of being public about the technology and regularly iterating it is very different than the way vaccines are traditionally produced.
RaDVaC is for example right now both looking into the small peptide version they started out with as well as looking at subunit vaccines.
This is correct. RaDVaC is not committed exclusively to a single technology platform; we evaluated (and continuously re-evaluate) the advantages and disadvantages of vaccine platforms like VLP, subunit, peptide, DNA, and mRNA.
All our designs so far have been based on self-assembling nanoparticles transporting peptide antigens, because all materials for both nanoparticle and peptide antigens are highly accessible: readily available, relatively inexpensive, individually safe (not requiring any advanced biosafety conditions for shipping, storage, or use), and quick to source. This design is also very easily produced.
That basic nanoparticle platform (which we’ve open-sourced, along with our peptide designs) is adaptable to other antigens, such as larger recombinant subunits, which we are working on now, for consideration to add to a future version of our white paper. Advantages to recombinant antigens include likely better immunogenicity than peptides, and greater production independence/decentralizability–plus, cells producing such an antigen would likely be a shareable resource.
Adaptability is, I think, quite a cool feature of a platform, and it’s a feature that’s shared in principle by nucleic acid vaccines. The drawback there is largely one of accessibility: modifying code is no big deal, but executing that code is, in practice, far more difficult than producing peptides or even larger proteins. (For now. Many of us at RaDVaC anticipate that the costs associated with both pseudouridine-mRNA and LNP production will come down drastically over the next few years. We’re excited about that.)
Do you have an idea of what order of magnitude of funding this would need?
We’re working with outside people and groups to create appropriate trialing models and protocols, including a focus on challenge trials. We’re looking to hire at least 2 consultants for the process (medical writing, trial design experts) and at least 2 onsite medical staff with fluency in the regulatory & logistics context of wherever a trial is to be run. (Depending upon location, we may also need an IRB’s services to review and approve any trial design; definitely necessary for anything done within the US). One of the groups we are working with, 1DaySooner, has already created and published trial designs, and our trial design will be different but informed by the excellent foundation they’ve provided. We estimate that this preparatory phase will cost $500k-$1M.
An order-of-magnitude estimate for the full cost of a completed trial would depend on scale and location, but the cost for a relatively small but sufficiently powered trial in our current focus location of the Bahamas is in the $10M range.
That’s awesome, I didn’t know this.