 Hi, everyone. Hi, Devcom. My name is Alex Hoekstra. I am a molecular biologist and I'm one of the co-founders and scientists at the Rapid Deployment Vaccine Collaborative or RANVAC. I'm excited and I'm grateful to talk to Biohacking Village about open source technology in vaccine development, building the kind of tools that fill gaps in global vaccine infrastructure. My goal in this session is to present the case for open source vaccine development and the tools that enable that kind of development, which RANVAC we've been trying to think of as developer kits or vaccine developer kits, because it's very clear that vaccines are a uniquely important tool in biosecurity and there's so much more room for improvement in various facets of vaccinology, especially with regards to accident. We think that many aspects of vaccinology should and with the right kind of tools can be made more accessible for more people in more places around the world and that the vaccinology itself could grow and be improved by that kind of inclusive participation. So during the COVID-19 pandemic, obviously all kinds of gaps were built in public health infrastructure and biosecurity and there's more reason than ever to think seriously and creatively about how to fill these various gaps going forward. I guess both for the ongoing reality for billions of us still struggling through COVID and this pandemic, but also for inevitable future emerging diseases, which we might be able to minimize and even prevent the right tools. So I want to introduce some work by discussing some concepts regarding vaccines that I think may will be familiar to a lot of people here who are already familiar with space, but I also want to get into some hopefully exciting and new ideas for a lot of people across the biosciences. Since vaccinology has been heavily shaped by IP laws for the last seven or so decades, there's a lot of room for creative improvement, especially when you begin thinking kind of outside that box. I think it's important to bring up a few foundational topics like vaccine economics and the unique role of the vaccine to play in epidemiology and as well as the immunology as it relates to vaccine platforms or the technology themselves. Then we'll take a quick look at those issues before we get into what RADVAC is doing in particular because I think they're helpful in identifying the gaps and why they exist presently. Ultimately I do want to get into what we've been doing at RADVAC in terms of open source efforts, what open source efforts can do to kind of bridge those economic technical and logistical gaps. We at RADVAC have been working on building a particular platform for intranasal peptide-based vaccine candidates against SARS-CoV-2 virus, but we also think that these these principles of development may be more valuable in their generalizable form than any single development project on its own. So I want to get into why vaccines are uniquely important, uniquely leverageable tool in public health and defense against infectious disease. Vaccines serve to combat disease in a number of ways, primarily by inhibiting infection, inhibiting disease, inhibiting transmission, and inhibiting replication, which subsequently inhibits mutations and the evolution of new pathogens. And although there are a variety of important and even very useful tools to achieve some of these functions, in fact, things are arguably the most the Swiss cheese model. It's something that I'm borrowing from Ian McKay who adopted a similar illustration for COVID. Out of the mind is only showing a handful of risk prevention interventions and isn't really to scale in terms of each intervention's efficacy, it's stopping pathogens from infecting a person. I think the illustration is still a useful one insofar as it makes the case for applying multiple layers, additive layers to mitigate risk. Vaccines, though, are unique among these interventions because they both augment a person's ability to fight off infection if the prior layers of protection fail. But also, if applied at scale across the population, vaccines can limit the collective exposure to these pathogens by reducing the number of available hosts and transmitters. And in the next slide, we're going to get into just a little bit of math. I promise it won't be too much and that'll be the end of the math. But essentially, the network effects may be one of the most important features to vaccines, which are good on a personal level, good for individual health, but so much better on population scale. But a lot of things have to go right in order to achieve those population scale network effects. And as of now, as of July 2021, almost a full 16 months after the first COVID vaccines were actually developed. And now seven months after those vaccines were authorized and made available in the US and other high income countries, we're still not yet achieving the full benefit or benefits of those network effects on disease prevention that these vaccines could and hopefully will soon provide once they're made more accessible and more widely deployed. There's a good amount of math involved with considering how to prevent or endopend them, accounting for things like population characteristics, age, health status, mobility, environmental conditions, and a lot more. But one of the most important concepts is understanding the effective reproductive number for a given disease. Effective reproductive number is sometimes written as R or R sub e. And it's a bit different from basic reproductive number, which is more commonly talked about, it's R not or R sub zero. Because effective reproductive number R sub e basically takes into consideration the percentage of a population that's susceptible to infection, essentially the percentage that is not immune, sometimes written as S. So R not on the other hand, is meant to be a metric of a disease's contagiousness or a transmissibility. You can calculate effective reproductive number by multiplying the basic reproductive number by S. So killing a pandemic requires bringing that effective reproductive number to under one. Since the spread of infectious disease is essentially an exponential function in which every infected person can infect a certain number of other non-immune people, a reproductive number, a reproduction number greater than one will increase the transmission at an exponential rate. Whereas the reproduction number below one decreases transmission, approaching zero new infections over time. So here we can see a few illustrated graphs on what happens to an exponential function when that constant is above one and when it is below one. So the state is related to herd immunity threshold hit, which is also a function of a disease's reproductive number. Essentially the higher the reproductive number for that disease, the higher the threshold for population scale immunity. The population is immune to a disease in excess of that disease's immunity threshold. The number of cases reduces at a faster rate, outbreaks are less likely to happen and outbreaks that do occur are smaller than they would have been otherwise. It's probably important to note that the herd immunity threshold doesn't represent the point at which a disease stops spreading altogether, but rather the point at which each infected person infects fewer than one additional persons on average, essentially modulating the effective reproductive number and diminishing the incidence of disease. So these are useful formulas when thinking about vaccine readiness and roll out in situations of emerging disease where populations begin with virtually no pre-existing immunity. So the effective reproduction rate is actually very high and can be brought down by vaccines that are both effective and very importantly available. So what happens when there's no pre-existing immunity? So S is very high and we're met with a disease that has a high basic reproductive number. Well we are living it with SARS-CoV-2. Since SARS-CoV-2 is a new virus and since it replicates with high efficiency, COVID-19's debut has been devastating. A COVID toll on human health won't be fully calculable for years now, but we're still very much in this pandemic globally where immunization rates are low and the effective reproductive rate is greater than one in many places. Again, no matter how effective a vaccine is on an individual level, the key to ending pandemics is decreasing R, that effective reproductive rate, which means decreasing the number of susceptible non-immune folks S. So bear in mind that the production, authorization, and roll out of safe and effective vaccines for an emerging disease in under a year is historically unprecedented and a very, very good thing, but it's also clear that the cost of not being prepared, both in terms of prevention and in response, those costs are vast and indeed far, far greater than the cost of building the kind of biosecurity infrastructure, including vaccines that were, you know, we already largely know how to make them. So I'd like to explore why this infrastructure was lacking and then maybe get into some solution-oriented ideas. I think it's important also to talk about the ecosystem of vaccine development that existed leading into 2020 and why COVID caught us all off guard, despite years and years of scientists and people who listened to scientists agreeing that such an outbreak was really only a matter of time. So Professor Andrew Lowe, MIT Professor of Economics there has done some really interesting analyses on the economic landscape of vaccine development over the last few decades, which taken together revealed some interesting insights about why despite their importance and despite the high rate of technical success in development, vaccines are less than 10 percent of industrial biotech investment. It turns out the vaccines have a uniquely high probability of success and end development, close to 40 percent compared to 11 percent across all therapeutic groups, but industrial sponsors have been pulling out of the vaccine development business for at least the past two decades. So Professor Lowe and others began to understand that vaccines are a high cost and low financial reward, low margin investment, and generally a turnoff for industrial or industry sponsors, biotech pharmaceutical companies, as well as their investors. Dr. Lowe and his colleagues point out that these analyses of vaccine landscape reveal some big gaps in investment, waning vaccine or in the participation and ultimately inhibited vaccine access that predate 2020 by a number of decades. And they suggest that public sector support may be useful in filling in these gaps left by kind of a lack of capital market incentives. And this itself is a really interesting line of thinking because with what we know about how vaccines leverage network effects at a population scale, lowering S, lowering R by increasing immunity throughout that population, we could ask, could vaccine development and vaccine innovation be driven by sort of rethinking of vaccines, not as a market dependent good, but instead as a sort of international public, since they clearly have international public benefits, and since the market incentive structure has failed to make those investments profitable for profit driven developers so far. Anyway, the need for public sector support should probably include scientists, many of whom also happen to be members of the public, many of whom may actually be listening right now. So, vaccinology is really a constellation of a dozen or so disciplines that field the science of public health, epidemiology, immunology, psychology, chemistry, economics, policy, clinical trials, ethics, informatics. We've actually had a couple of physicists reach out and offered to assist us in characterizing our vaccine candidates. So, it's clear that there's a need for skilled people of all kinds to take an active part in building global scientific and logistical highway system that can deliver vaccines to populations more quickly with high levels of efficacy, safety, trust, and access. But we at RandVac took a systems view of the gaps in vaccine infrastructure, and across four different elements of the vaccine response, including R&D, testing, approval, and deployment of vaccines. It seems to us that each of these steps could be potentially augmented, improved, sped up, and made more accessible globally by increasing the kind of access and powers participation in each of those central processes. We believe that the ability to take part is a fundamental prerequisite for things like vaccine equity, inclusivity, transparency, ultimately entrust safety efficacy as well. And ultimately, in developing great ideas about how vaccines work both on a technical level, but also on a systemic, worldwide people and global health level. RandVac actually began when Dr. Press and ESA sent out an email asking me and some of our other colleagues if any of us had heard of projects to accelerate vaccine development through public participation, essentially citizen science. He figured that since vaccines are fairly old and fairly well understood technology, or at least that many vaccines were built on very well established technological platforms, it might not be out of reach for vaccines to be developed quickly, even on a low budget, maybe even with massively parallel distributed, kind of a global scheme. Several of us got really interested in that idea and we formed the core of the RandVac team, so I'd love to tell you what we've been working on. So we began with a couple principles in mind. Because of decades of extensive research on both pathogens and on the development of vaccines, modern vaccines are actually very quick and easy for experts to develop. And they have, again, by far the highest probability of success of any therapeutic class. So access to vaccines and the process of developing vaccine, research and development vaccine is presently, it's expensive, it's fairly well guarded by intellectual property, again, relating to the expense and investors having to recoup their investment. But we think that that participation should be enhanced and can be enhanced through open source information, research and resource sharing. And one of the most powerful principles, motivating principles for us was that, in this crisis, we should help. We should do something rather than waiting for the status quo, rather than waiting for the sort of authoritative pre-existing infrastructure to do its thing. And so we did. We are trying and we will continue to try. And our method of trying has a kind of unique structure to it, which is sort of intrinsically open source, open source is kind of a central component of our development platform. When we say free and open source, we mean it both in free like speech and free like beer, that is the Libre and the Gratis definition. But essentially, it's meant to inspire this sort of positive feedback loop of researching, prototyping, refining, sharing, and then getting feedback from other collaborators throughout this shared challenge. We took into consideration some sort of basic design principles when considering how to develop vaccine candidates that fit the needs of this pandemic and potentially a future pandemic. So we opted for safe, inexpensive, accessible, and primarily off-the-shelf materials, very few custom components, and very few that required sort of, I guess, high grade or inaccessible laboratory infrastructure. We also wanted these prototype vaccines or vaccine candidates to be rapidly reproducible, that is rapidly producible, but also with high enough fidelity and enough simplicity that they could be reproduced in other labs so that you could have parallel implementations and maybe parallel experiments happening in multiple places at once. Obviously, for that to work, it has to be safe, both in terms of development, which means no infectious components, and also on the sort of administration side, which also if you are working with safe materials, it certainly helps with safe administration, although those two are totally equivalent. We also wanted well-characterized antigenic targets, which could ideally be adapted over time as more research began to focus on the selection of certain epitopes that elicited the strongest or the best or the most immunologically useful responses from post-immune system. All encompassing within this is the idea that this work should be shared, and that it shouldn't be contained to a single laboratory or a single team or a single brain. It isn't necessarily against the traditional model, but it is potentially enhancing of the traditional model. We've seen this with other open-source developments in other areas, that the Android operating system leverages open-source technology, but Google still makes a good amount of money either on Android or Android components. This is not an anti-profit model. It's not an anti-revenue. It's not an anti-business model. It is a pro-sharing and sort of pro-accessibility model. In order to catalyze that participation, in mid-2020, we published our first white paper describing the initial proposed vaccine candidates against SARS-CoV-2. We had four authors, the original white paper with 43 pages. We had 19 epitopes from SARS-CoV-2 that were identified in the research or predicted in other research to be of high value in terms of eliciting immunogenic response from the host. We also gave kind of a primer background research and provided this sort of library of pre-existing research on mucosal and cellular and tumoral immunity. Again, epitope selection and immunogenicity and resilience against future variants by selecting for conserved epitope. We also went into not a great length, but considerations for safety and efficacy testing for short and long term, for shelf life and stability, for booster doses, and for ethics. We think that's important during a global crisis like this. As of 2021, as of July of this year, we've released over a dozen updates to our white paper. We have more than 20 authors, 90 pages, more than 200 references. We've updated and in many ways narrowed our list of well-characterized epitopes that we think are highly useful in eliciting an immunogenic response against SARS-CoV-2 and protective against COVID-19. Along that line, we've produced 10 generations of vaccine candidates so far. We've expanded our discussions on safety and efficacy and epitope selection and booster regimens and heterologous booster regimens, optimizing production, optimizing stability, optimizing valence or multi-valence. We talk about the breadth of immunity that's provided by a vaccine and whether it is resilient against these future variants and mutations that might otherwise minimize vaccine efficacy. It has become a collaborative living document and catalyst for collaborative living research. I mentioned earlier some of the parallels in other open source development and open source initiatives. Linux, for instance, is a great example of how we hope we might be able to contribute with developer kits. Linux clearly is such an infrastructural tool in software development and hardware development and really promoting accessibility for most of the world at this point. It's clear that there are reasons that Linux is superior to alternatives that have to do with its open source mess, its collaborative development ecosystem, and the ability for multiple people in multiple places to take part without restrictions. We conceptualize viruses as non-digital pathogen, kind of funny because the name went the opposite way. Computer viruses are the digital appropriation of the actual biological virus. We're kind of going in the opposite direction now. In software developer tool kits, there's a number of key features that are really useful, maybe required in order for people to actually use them and pick them up and develop cool things with them. Chief among them are a compiler, a debugger, and a software framework and some of the components that are critical are libraries, documentation, code samples, processes, and guides. We think that the vaccine developer tool kit should mirror and encompass all of those components that are essential to collaborative and open source and even just good vaccine development. Again, in open source, you don't have to necessarily share and share like. You can take it and if you adapt it well enough, you can actually even patent it. You can protect it with IP. Even when it is open source, there's no real reason you can't start a company. You can run with these products in a profit or even in a revenue-driven way. But to put it into context of vaccine development, we think that providing a framework of reproducible, simple, accessible, adaptable vaccine technology is really useful. In terms of processes, we want detailed production protocols. In terms of libraries, we want vast documentation of past studies that are related to vaccine immunogenicity, vaccine safety, various aspects of vaccine technology. Code samples for us come down to the design specifications for specific vaccine candidates. In terms of debugging vaccine candidates, you got to talk about protocols and considerations for preclinical and clinical testing. Ultimately, it has to play well with other and this is achievable through open source licensing like Creative Commons and through an active, engaged developer ecosystem. Ideally, one that is committed to this concept of working together or at least learning from one another as they each do maybe their own thing. Along that line, we think that our white paper is a foundational open source VDK, a vaccine developer kit. It may be that there's huge room for improvement in the construction and the composition of VDKs. There are certainly components of the white paper that don't exist yet. We've done a lot to characterize our method of epitope selection and various other things that I've already talked about, but it still lives in a PDF. I don't think PDF is necessarily anyone's preferred format of engaging with a project or engaging with... It's not necessarily a collaborative ecosystem in and of itself. We've started a researcher's map in hopes of connecting people who are interested in doing vaccine development together or learning from one another or sharing ideas, sharing resources, that kind of thing. But really it's in its foundational stages. What I hope to achieve here is both to pitch the idea that open source vaccine development is useful and achievable, but also that it's worth your time, that it's worth the engagement and the efforts of people of all kinds of skill sets. I think that we're at the beginning. I think that we're facing a variety of possible futures, but one of which is of open source infrastructure for vaccine development and essentially that infrastructure extending the ability to participate in vaccine research to historically excluded people. The cost of exclusion, the cost of exclusivity in vaccine development are things that we're feeling very acutely during the COVID-19 pandemic, but also that unless we resolve them are not going to be fixable with the old way of doing things. It's interesting then to think about what would biosecurity look like if it were decentralized from these centralized nodes of pharmaceutical companies with very, very high budgets or potentially very high budgets doing the majority of these developments. What if we were able to decentralize a little bit by bringing down certain infrastructural costs or infrastructural barriers? The BDK I think are a way to make vaccinology easy, affordable, accessible and for people who want to start vaccine companies, which may be the only way to get to a billion doses. I think again by reducing those costs we can get more people involved. We can see more vaccine innovation. We can see better vaccines that get developed and approved faster and more effectively. With that I thank you. I hope that you got something out of the presentation. I hope that you'll get curious about what an open source vaccine development future might look like. Reach out to us at radvac.org or elsewhere and thank you for your time.