This is a writeup of a medium investigation, a relatively brief look at an area that we use to decide how to prioritize further research.
In a nutshell
What is the problem? We think natural, and to a greater extent engineered, pathogens have the potential to cause global catastrophes. We expect that as biotechnology advances, the risk of dangerous outbreaks will increase. Our impression is that viral pathogens seem especially likely to contribute to catastrophic pandemics because they have the potential to be highly virulent and transmissible compared to other pathogen types, and there are very few broad-spectrum therapeutics for use against pathogenic viral outbreaks and they have undesirable side effects. This report focuses primarily on reducing the risk from viral pathogens through scientific research and development, especially on vaccines and therapeutics.
How could the problem eventually be solved or substantially alleviated? We believe that if a subset of the following abilities/resources were developed, the risk of a globally catastrophic pandemic would be substantially reduced:
- A better selection of well-stocked, broad-spectrum antiviral compounds with low potential for development of resistance
- Ability to confer immunity against a novel pathogen in fewer than 100 days
- Widespread implementation of intrinsic biocontainment technologies that can reliably contain viral pathogens in the lab without impairing research
- Improved countermeasures for non-viral conventional pathogens
- Rapid, inexpensive, point-of-care diagnostics for all known pathogens
- Inexpensive, ubiquitous metagenomic sequencing
- Targeted countermeasures for the most dangerous viral pathogens
A deeper understanding of the immune system also seem useful for its potential to expose new potential threats and countermeasures, though we see this as a source of potential important “unknown unknown” considerations rather than having a specific vision for how the research will lead to alleviating the problem.
This report focused on vaccines and antivirals because we investigated them in relatively greater depth. We did that because they seemed like broad and important areas where we guessed that we might be able to uncover particularly promising projects related to averting catastrophic viral pandemics. We didn’t look as deeply into the other areas listed above because our briefer investigations indicated to us that a deep investigation was relatively less likely to be fruitful, generally because the areas seemed less important and/or less neglected.
A spreadsheet we drafted summarizes our overall views on this subject.
What are the possible research interventions? There are a wide variety of methods of conferring passive and active immunity to pathogens. As computational models and gene editing techniques have become more advanced, new strategies involving these technologies have become increasingly feasible. Research into novel and technologically advanced vaccine and passive immunoprophylaxis (which we here categorize with vaccines) development methods, such as ab initio antigen and antibody design, and vectored immunoprophylaxis, currently appear especially promising for their potential to expand the range of pathogens against which immunity can be conferred. Thus far, we have identified only a few specific promising projects in this space, and many of the most promising-seeming lines of research may be fully funded already.
Within research and development related to antivirals, host-directed antiviral compounds (i.e. antivirals that target part of the hosts’ cellular machinery, rather than targeting the virus) appear promising to us since some inhibit machinery used by a large number of viruses, making them likely to be relatively broad-spectrum, and making it seem less likely that individual pathogens will develop resistance to them. We think these compounds are unlikely to prove fully efficacious against all viruses in humans, but that they merit further investigation, and note that more extensive research on their antiviral effects in vitro, in animals, or on humans could be funded.
Who else is working on it? Our Scientific Research Program Officers’ general impression is that there are many academics and companies working on vaccine and diagnostics research and development. We are unsure how much of this work is relevant to understanding and mitigating the risk of globally catastrophic pandemics (as opposed to developing improved vaccines for known pathogens with less pandemic potential). We speculate and have seen anecdotal evidence that companies may not be incentivized to focus on work related to rare but potentially catastrophic outbreaks, because those areas generally provide weaker and less reliable revenue streams than work related to chronic conditions (e.g. HIV, hepatitis). However, we encountered several efforts that appear especially relevant to the effort to develop vaccines and therapeutics specifically for the purpose of countering novel and/or potentially pandemic viral outbreaks.
Of the areas discussed above, our impression based on our research is that:
- Broad-spectrum antivirals are receiving limited attention. We’re planning to fund work in this area.
- Vaccine R&D is generally a crowded space, though it seems possible to us that a deeper investigation into more of the specific subtopics would reveal additional opportunities.
- Diagnostics R&D seems highly crowded.
1. Our process
We decided to investigate scientific research and development that could assist with our Biosecurity and Pandemic Preparedness Program. Much of the research was conducted by our Scientific Research Program Officers, Chris Somerville and Heather Youngs (“Chris” and “Heather” throughout the rest of this writeup), who are biochemists and scientific generalists with no prior expertise in this topic. Former Open Phil scientific advisor Daniel Martin-Alarcon also contributed to this research. We asked them to survey the fields of vaccine and antiviral research and development, identify promising projects that were not being pursued, and help us understand how much progress is being and seemingly could be made on the development of rapid vaccines and broad-spectrum antivirals if various potential research projects were successful. Chris wrote an analysis of what steps could be taken to create a vaccine (or multiple vaccines) against a novel pathogen in approximately 100 days or fewer, and what scientific advances this would require (this may already be possible in some cases). They also briefly investigated the topic of the development of diagnostics for potential pandemic pathogens. We chose those topics because we thought they had the potential to be most relevant to preventing or reducing harm from pathogens with the potential to be globally catastrophic.
Chris, Heather, and Daniel conducted literature reviews and collectively wrote about 150 pages of rough material on this area, which was shared internally. Topics investigated included viral zoonosis, identification of new human pathogens, antigen discovery, candidate vaccine development and testing, animal models, systemic scientific issues, clinical trials, and technologies for scale-up and distribution. They declined to publish these materials without doing a significant amount of work to clarify and refine them, and Open Phil decided it would not be a worthwhile use of their time. In aggregate, Chris and Heather spent about 7 weeks each researching the topics in this report, and Daniel Martin-Alarcon spent approximately 2 weeks.
Claims not cited are generally based on the internal report produced by, and subsequent conversations with, Chris and Heather. In some cases throughout this text, citations are provided as examples of support for the associated claims, but may not be the primary or original reason we believe the claims to be true (often, our belief is based on information and impressions conveyed to us by Chris and Heather, which stems from both their general understanding of many of these topics and their speculation based on a wide range of readings, which we expect would be unduly time-consuming and ultimately unsatisfying to attempt to cite fully). We may continue and extend this investigation in the future.
Nick Beckstead and Claire Zabel reviewed the materials produced by Chris and Heather.
I, Claire Zabel, drafted this page, and it was reviewed by Chris and Heather and some other Open Phil staff before it was published.
Note that this report does not constitute a comprehensive overview of our thoughts on this area. We omitted information when we thought the public discussion of the topic (either of particular types of risks or countermeasures we find promising because they might address those risks) could contribute substantially to the risks while not offering commensurate benefits.
2. What is the problem?
We expect that as biotechnology advances, the risk of deliberate attacks or accidental releases of dangerous pathogens will increase. If scientists and health professionals had the capacity to quickly and accurately identify pathogens, had access to reliable broad-spectrum therapeutics, and could rapidly develop effective vaccines against novel pathogens, it seems like many of the biosecurity risks we are most concerned about would be substantially smaller. We’re particularly concerned about pandemic risk from viruses because of (i) their potential for high transmissibility and virulence, and (ii) the lack of effective therapeutics for many viral diseases.
Because of this, we’re interested in research interventions that could be useful against a variety of potentially dangerous pathogens (especially viral pathogens), and could make medical countermeasure development faster and more effective.
3. How could the problem eventually be solved or substantially alleviated?
This section focuses on imagining how scientific advances could eventually make it possible to prevent or substantially reduce the risk of a catastrophic pandemic. A spreadsheet we drafted summarizes our overall views on this subject. We go into greater detail on the subjects which seemed most promising to us once the initial research review was completed.
Those subjects include:
- Establishing a portfolio of strategies to rapidly and reliably develop efficacious and safe vaccines. If researchers had many different ways to stimulate immunity to novel viral pathogens, and thus develop vaccine candidates within months, that seems likely to substantially reduce the chances that pathogen could cause a globally catastrophic event, compared to worlds in which it takes many years to develop a vaccine or researchers are unable to develop vaccines against some pathogen types.
- Investigating and developing efficacious broad-spectrum antivirals against which it is unlikely that a virus could evolve resistance. If these antivirals were successfully developed, they could be deployed in the event of a dangerous viral outbreak, possibly as soon as the outbreak was announced. We speculate that government offices such as the Biomedical Advanced Research and Development Authority (BARDA) might stockpile the antivirals in advance for this purpose, if the antivirals were available.
It seems plausible to us that substantial scientific progress could be made in the two areas listed above within years or a few decades.
Research in the following areas might lead to the recognition of additional risks or strategies for reducing risks. Because these areas are more exploratory, we have found it more difficult to anticipate which concrete positive outcomes they might lead to and timelines on which those might be realistic, and we don’t have particular concrete visions for how this could happen. We see these areas as sources of unknown unknown considerations with the potential to change our understanding of the risk landscape in important but unpredictable ways.
- Basic research in immunology: greater knowledge of how the immune system works might aid in the design of more effective and safe immunogens (molecules that stimulate an immune response in the host), as well as open up new lines of research into other potential countermeasures. Chris and Heather’s impression was that scientists still lack understanding of many aspects of the human immune system, and thus they have limited ability to predict which methods stimulate immunity to different pathogens (i.e. it is very difficult to generate a good vaccine). Further research could lead to insights into the human immune system, which we imagine could enable scientists to identify new sources of risk and better predict which strategies for creating new therapeutics and vaccines are likely to succeed.
We focused on topics where we thought it was most likely we could identify neglected but broadly significant research areas related to averting viral pandemics. However, some other themes we did not investigate and report on as thoroughly are listed below:
- Preventing accidental release and making deliberate misuse more difficult with biosafety measures that don’t interfere with research. This is based mainly on our speculation about the possibility of altering pathogens to make them usable and safe for research in the lab but inviable outside it. For example, Benjamin tenOever and his colleagues at the Mount Sinai Medical Center devised a method for engineering flu viruses to “carry a 21-base-pair-long sequence that complements miR-192, a microRNA found in human and mouse lung cells but not in the respiratory tract of ferrets….” This microRNA binds with influenza RNA transcripts, flagging them for destruction within the cell. Viruses engineered with this method caused symptoms in ferrets but not mice and, by extension, presumably not humans. This method, which they call “molecular biocontainment” could potentially be used to create viruses that could be studied realistically in model organisms but would be unable to harm humans if they were released from a lab.2Further work in this area could test whether strategies that have already been proposed would interfere with research, or lead to the development of new molecular biocontainment strategies. We speculate that if molecular biocontainment tools were robust and in widespread use, the risk of accidental release of dangerous pathogens would be substantially reduced. However, it seems plausible that uptake would in fact be low and some or many labs might continue to engage in more dangerous practices. More experiments could be done to determine whether this technique could interfere with experimental results.3
- Platform technology for diagnostics: Research and development of diagnostics could help healthcare workers reliably and cheaply identify common, rare, or novel pathogens. This could be valuable for quickly identifying the presence and spread of outbreaks, and ensuring that infected individuals receive appropriate treatment, if it’s available. Chris and Heather’s impression is that:
- A wide variety of rapid diagnostics are currently available or under development and the field is well funded at the moment.
- Many companies are already working in this space to improve on current technology and reduce costs.
But they also note the following limitations:
- Some diseases that don’t provoke a strong immune response and/or reside in certain relatively inaccessible tissues (e.g. brain tissue) remain difficult to diagnose. However, our Scientific Research Program Officers suspect that highly infectious pathogens will be relatively more straightforward to find with a diagnostic because those pathogens will likely be shedding large amounts of virus into bodily fluids.
- Some diagnostics are relatively imprecise (e.g. it might be possible to identify that a patient suffers from influenza, but not to easily identify the strain).
- Some diagnostics require a relatively long time (days) to yield results, which can make treating individuals and identifying potentially pandemic viral outbreaks at the outset of the outbreak more difficult.
- Some diagnostics require access to equipment that is expensive and/or hard to use in the field.
It seems to us that work on this area is likely to be broadly useful for diagnosing more common pathogens as well as those that might cause dangerous pandemics, and so we would guess this area is less likely to be neglected than research and development in areas that have fewer common applications. So, we have tentatively decided against prioritizing this area as highly as the ones listed above for conventional grantmaking. This line of reasoning suggests, however, that if there are types of diagnostics that are mainly useful for identifying pathogens likely to be involved in potentially catastrophic pandemics (for example, novel ones), those types of diagnostics might be relatively neglected.
- Non-viral therapeutics (antibiotics, fungicides, etc.): Work on therapeutics for non-viral pathogens could also lead to the development of new countermeasures. Focusing on antivirals seems in expectation more impactful to us because (i) it’s our impression that conventional non-viral pathogens are less likely to be responsible for catastrophic pandemics and (ii) broad-spectrum therapeutics exist for many non-viral pathogens (e.g. antibiotics are effective against many types of bacteria), though resistance to existing therapeutics sometimes renders them ineffective.4 However, we have not investigated this area deeply, and we otherwise restricted this writeup to R&D related to viral pathogens only.
- Medical countermeasures aimed at addressing specific pathogens: Research and development using known techniques could expand the range of medical countermeasures available to target specific pathogens of concern. Examples of this kind of work might include creating influenza vaccines that are effective against the most virulent forms of influenza. Our understanding is that certain projects along these lines, if they are aimed at providing fairly robust defenses against some of the pathogens that seem most dangerous, may be highly impactful, but that projects aimed at pathogens that seem less concerning are lower-priority for funders with our focus.
- Metagenomic sequencing for enhanced surveillance: The cost of metagenomic sequencing (sequencing from environmental samples which may contain genetic material from diverse organisms) might fall and systematic sampling, e.g. at airports, might be established such that it becomes feasible to rapidly and reliably identify pathogens with pandemic potential. We anticipate that that would make it substantially easier to contain dangerous outbreaks, but have deprioritized the area because our strong impression has been that there are many actors focused on the goal of reducing the cost and difficulty of metagenomic sequencing. Establishing a system for detecting outbreaks early and reliably is an area of interest to us, but does not seem directly related to the focus of this report (scientific research and development related to potentially catastrophic viral outbreaks).
4. What are the possible research interventions?
Additional research could be pursued on all of the topics listed above. However, we focus below on impressions about and future research directions that seem promising related to:
- Platform technologies and strategies for the rapid development of vaccines (i.e. technologies and strategies that might be useful for developing many potential vaccines quickly, not only ones directed against one or a few existing pathogens).
- Broad-spectrum antivirals
We focused on those because they seemed the most likely to be useful against a globally catastrophic biothreat in the near future, and we thought a systematic review of the literature might turn up promising giving opportunities for a new funder. However, we also think additional research in the other areas described above could prove valuable, and we have sufficient uncertainty that it would not surprise us if research on those topics proves as or more valuable.
5. Platform research and development related to vaccines
5.1 Background on vaccine development
Developing and using vaccines has several established advantages over other types of medical countermeasures; namely, vaccines often only need to be used once or relatively rarely to protect an individual from a disease, and (partly because of this) vaccines are often cheap enough to be widely deployed in the developing world. In addition, once a vaccine is developed a population can often be preemptively vaccinated, meaning there is a relatively large window of time in which this intervention can be usefully deployed if the threat can be identified in advance.
These advantages, while substantial, seem relatively less important for addressing the biosecurity threats we are most concerned about (which may involve novel threats that are only likely to arise once or rarely, and which are difficult to predict with sufficient specificity to immunize the general population in advance), than they are in the context of most work on public health. Nonetheless, if it were possible to create new vaccines rapidly, it seems likely that they’d prove invaluable tools against potential viral pandemics, because they can be customized to provoke the immune system to provide strong protection against specific pathogens of concern. This is in contrast to therapeutics like antivirals (which seems likely to be less efficacious and accompanied by more severe side effects, based on our general understanding of the track record of these types of medical countermeasures). Chris and Heather believe that eventually immunization is likely to be possible against many or all dangerous pathogens, and that rapid vaccine development against most pathogens of concern is slightly more likely than not to become possible in the next 20 years.
Chris and Heather broke the process of vaccine development for a novel pathogen into four steps:
- Sequencing the pathogen’s genome: Chris and Heather report that sequencing the pathogen is likely to be straightforward and rapid (though working with dangerous pathogens often requires substantial protective gear and specialized facilities), and there are already significant extraneous pressures to reduce the cost and increase the speed of sequencing, so we did not think searching for giving opportunities at the sequencing stage of the process was likely to be as impactful as work on the next two stages. They noted that during the 2014 Ebola outbreak, in-field sequencing of the samples was completed within 24 hours.5
- Antigen discovery and design: The process of identifying antigens, molecules that stimulate the production of antibodies and other components of an immune response against the relevant pathogen, and possibly designing antigens that provoke a strong immune response that neutralizes the pathogen. This step may be unnecessary if conventional vaccine development methods, such as injecting deactivated or weakened forms of the pathogen, are effective and safe.
- Vaccine candidate formulation: The process of developing candidate vaccines. Generally, vaccine development involves delivering the relevant antigens in some form to the relevant population so that the patient’s immune system produces the necessary antibodies. However, short-term immunity may in some cases be achieved by delivering antibodies produced in a lab in cells from another organism instead (this is called passive immunization, and sometimes is not counted as a type of vaccine development, though we group it here for simplicity). Multiple vaccine development strategies could be deployed simultaneously.
- Testing: The process of testing a vaccine candidate for safety and efficacy, generally first in animals and then in humans. We expect that this process might be substantially abbreviated in the event of a sufficiently severe outbreak.
Steps two and three seemed the most likely to have neglected-yet-impactful opportunities for improvement from a scientific R&D perspective. Below we enumerate some parts of the antigen discovery and vaccine candidate formulation process that we investigated.
5.1.1 Antigen discovery
This is the process of discovering a pathogen’s antigens, the molecules on the pathogen that stimulate an immune response in the host. This step is primarily used in the development of vaccine design in cases in which conventional vaccine development methods, such as using an attenuated (weakened) or deactivated pathogen, is infeasible or ineffective. Below are some areas of research related to this process that could improve or hasten vaccine development.
- Biosensor platforms: Researchers could develop better biosensor6 platforms for detecting the binding of antibodies to an antigen. This might allow them to better distinguish the immunogenicities of different antigens. Chris and Heather report that many platforms are already available and we think this is unlikely to be the bottleneck on the development of effective vaccines and prophylactics, though there may be room to incrementally improve the data quality of high-throughput devices.
- Structural/computational protein design: Research in this area could advance vaccine development in a few different ways:
- Once the amino acid sequence of an antigen is known, it is not necessarily the case that if it is synthesized separately from the rest of the original pathogen, it will form the same shape as the antigens in the virus and continue to bind to the relevant antibodies. This increases the difficulty of creating effective vaccines using methods of vaccine development that don’t involve the entire virus (either deactivated or attenuated). Computational tools could be used to predict protein interactions and design delivery platforms (e.g. nanoparticles or virions) for proper antigen display.
- Chris and Heather speculate that those tools could help researchers design antigens ab initio that are better at stimulating the appropriate immune response than the antigens in the original pathogen.7 Artificial antigen design might be worthwhile because some diseases, such as influenza, do not naturally present antigens to the body that are capable of stimulating a strong immune response (instead, the antigens they present mutate rapidly, so immunity to influenza is usually fleeting and restricted to only some strains of the disease). These tools are being applied in the lab, but the research is still at the relatively preliminary stage and they have not yet led to vaccines which are approved for use in humans.
- Alternatively, Chris and Heather theorize that in the future researchers may be able to use information about antigen-antibody interactions and computational tools to predict the optimal antibodies for binding to the antigen.8 In that scenario, those antibodies could then be tested, synthesized (if successful), and injected to deliver passive immunity (discussed in more detail below). This could be useful in a scenario in which there have not been instances of successful immune responses clearing the pathogen outside the lab.
However, Chris and Heather are uncertain about whether computational models have advanced sufficiently to be able to routinely achieve these goals.
Overall, it seems like further research into the development of methods for identifying and presenting antigens that will lead to the synthesis of improved antibodies has the potential to be useful in the event of the release of a dangerous pathogen, especially one engineered to escape the natural immune response. Funding work on improving computational models seems like a promising opportunity for a philanthropist interested in this area, and we have funded one project in this space.9
There are several well-established methods of developing new vaccines, including using live attenuated or inactivated versions of the pathogen, among others.10 We don’t focus on these in this writeup, because it was our impression that additional research on these methods would be less likely to have substantial impact. We made this judgment because we believe that there is likely to be more low-hanging fruit related to new strategies and because we believe the new strategies are more likely to expand the range of pathogens that can be vaccinated against. However, some ideas involving the application of new gene-editing technology to older methods also seem promising to us.11
Our Scientific Research Program Officers looked at some less-established (partially overlapping) strategies for vaccine (and passive immunoprophylaxis) candidate development. These include:
- Nucleic acid vaccines: Nucleic acid vaccines involve delivering nucleic acids (DNA or RNA) coding for the antigens to cells, not the antigens themselves (as is the case with conventional vaccines). Once the antigens are produced by the patient’s cellular machinery, their immune system (hopefully) produces antibodies, generating immunity to the disease. No vaccines of this type have been approved for use in humans, though several DNA vaccines are in use to prevent diseases in nonhuman animals12 and trials on many nucleic acid vaccines are ongoing.13 There are many DNA vaccines in development, including the recently approved vaccines for Zika, however, the effectiveness has been lackluster in clinical trials.14 Improvements in delivery and adjuvant activation are ongoing and may result in effective DNA vaccines. RNA vaccines may be more efficacious because they don’t need to be delivered to the cell nucleus. Our Scientific Research Program Officers’ overall impression is that RNA vaccine testing thus far indicates good results in animals and appears promising in humans.
- Viral vector delivery: DNA or RNA coding for the antigens of viral pathogens (but not the other, harmful parts of the virus) could be integrated into a virus that is generally not pathogenic in humans, or encapsulated in a viral coat so that it can deliver the nucleic acid into human cells with high efficiency. Then people could be infected with that (non-pathogenic) virus and the viral machinery could induce the infected people to create the antigens, and subsequent immune response, conferring immunity.15 If effective, this could address some of the delivery problems with nucleic acid vaccines raised above. Adeno-associated viruses (AAVs) are among the most-studied candidates for this method of delivery, though there are others.16 While this strategy involves risks such as not working in the fraction of the population that had already been exposed to the relevant virus, it nonetheless seems possible to us that it would be one of several useful strategies to pursue in the event of the emergence of a potentially catastrophic disease outbreak.
- Passive immunoprophylaxis: Instead of delivering antigens and thus stimulating a full immune response, researchers could inject the relevant antibodies (which the immune system produces in response to the antigens). These antibodies might be delivered in the form of antisera (human or nonhuman blood serum containing antibodies from a survivor of the pathogen), or produced in a recombinant cell line or organism (e.g., plant). Once the antibodies have been delivered and if the process is effective, the host will have short-term immunity against the pathogen of concern but the immunity will be limited because no memory B cells (cells which produce the relevant antibodies and which are indirectly stimulated by the antigens) will be produced. Another limitation of this strategy is that some diseases require T-cell immunity or other aspects of immune response, in addition to the production of neutralizing antibodies, which this approach doesn’t deliver. However, this strategy has the following advantages: 1) it could be used to rapidly immunize people who are incapable of producing effective antibodies 2) in the future it’s possible that this strategy could be used to administer artificial antibodies that are superior to the ones human produce naturally.
- Vectored immunoprophylaxis: Researchers could engineer DNA or RNA that codes for the creation of antibodies, then integrate that DNA or RNA into a (relatively safe) virus (for example, an AAV), as is described in the case of viral vector nucleic acid vaccines (above), except with antibodies instead of antigens. Susceptible groups could then be deliberately infected with the non-pathogenic virus. If effective, this would cause the body to produce the antibodies, temporarily protecting the vaccinated person against the pathogen of concern if he or she becomes infected.17 Similar limitations to the ones described above for passive immunity (e.g. impermanence) apply, though it may be substantially easier to immunize large numbers of people this way. This is because we expect it to be substantially easier and cheaper to produce the nucleic acid sequence coding for an antibody and insert it into a virus than it would be to produce and administer the antibody protein itself en masse.
There are several other lines of research on vaccines that seem like they could plausibly be impactful, including the ones listed below (though, none of the below both strongly attracted our interest and were not already being pursued). We note them here only briefly with the purpose of representing more of the breadth of possible research topics:
- Adjuvants: vaccines that stimulate an insufficient immune response alone are sometimes accompanied by compounds called adjuvants that increase the immune response to the vaccine. Further research on adjuvants could lead to stronger responses to vaccines with otherwise low efficacy.
- Vaccine production platforms: different vaccines are produced using different platforms. For example, whole animals, eggs and cell lines can be used to generate whole (live, attenuated, or killed) vaccines, whereas cell lines or plants are more appropriate for recombinant vaccines and/or virus-like particles. Not all systems are suitable for all pathogens. New platforms could facilitate more rapid production of vaccines.
- Effective surrogates for safety and immunity. In order to make more effective or new vaccines, it would be useful to have a non-human organism that has an identical immune response to humans and similar sensitivities for toxicity in which to test the safety and efficacy. Because of the development of new genome editing technologies it is is now theoretically possible to strongly modify the immune systems and other biochemical pathways of animals to more closely resemble that of humans.
- Polysaccharide antigens: Like other antigens, polysaccharides and glycosylated protein antigens can elicit part of innate immune responses, in addition to stimulating the production of neutralizing antibodies. And, Chris and Heather note that mutations that alter glycosylation may alter presentation of classical antigens, reducing vaccine efficacy. However, most of the new approaches to vaccine design, such as producing nucleic acid vaccines, are not expected to be useful for this, and the immune responses to polysaccharides or protein glycans are poorly understood and difficult to study, and tools for artificial synthesis are lacking.
5.2 Vaccine R&D in preparation for a potentially catastrophic pandemic
In the event of an outbreak of a highly virulent and transmissible pathogen, we would guess that multiple lines of research might be pursued simultaneously. For example, researchers might in parallel attempt to:
- Identify antigens that can be used to prepare a nucleic acid vaccine
- Use computational methods to produce recombinant vaccines in cell cultures
- Clone antibodies that might be useful for generating passive immunity sera
- Create a live attenuated vaccine
Chris and Heather report that in some cases it’s possible to develop an initial vaccine candidate within six months or faster (although in most circumstances completing and evaluating the clinical trials necessary for the vaccine to be approved by the FDA takes years). We know of several examples of this, although they are importantly disanalogous to the likely situation we’d expect would occur with a novel viral outbreak:
- Flu vaccines are prepared twice annually in preparation for seasonal flu,18 although our understanding is that the development processes depend on the vaccine backbones and organizational infrastructure developed in previous years (facilitating accelerated development).
- Related to the above, Dormitzer et al. (2013) reports that “[w]ithin 6 months of the [2009 H1N1 outbreak] pandemic declaration, vaccine companies had developed, produced, and distributed hundreds of millions of doses of licensed pandemic vaccines.” although it also notes that these vaccines were for the most part not ready until after the pandemic had already entered a natural decline.19
- The World Health Organization (WHO) announced the Zika outbreak in February of 2016, and by August 2016 several Zika vaccine candidates were in clinical trials.20 We do not know when development of those vaccine candidates began, and the WHO announcement may not be a good indicator of when vaccine development began.
This space seemed fairly crowded to our Scientific Research Program Officers, and they did not encounter many gaps in the research being pursued. Their overall impression is that there are not substantial obstacles remaining to developing vaccines in under 100 days, depending on the pathogen type,21 although to the best of our knowledge it has never been done and both (potentially severe) scientific obstacle we haven’t identified and logistical issues could arise. However, this would not include testing for safety and efficacy.
They commented that, based on the level of sophistication of the science, they were surprised that relatively few new and effective vaccines have been developed in recent years, and they did not know why that was the case. They are reasonably confident that further advances in vaccine development will result in novel useful vaccines in the coming years, and that emergency scenarios would (if they occurred) spur more rapid development of relevant vaccines, as evidenced by the recent responses to Zika and Ebola. However, we are uncertain about whether this would substantially increase investment and progress in platform technology related to vaccine development.
Overall, our impression is that the following seem particularly likely to be valuable to prepare in advance of the emergence of a potentially globally catastrophic pathogen:
- Ab initio protein design for improved antigens and antibodies
- Vectored immunoprophylaxis
But thus far, we have identified only a few specific promising projects in this space.
More generally, our Scientific Research Program Officers think developing a more mechanistic (i.e. coming from an understanding of the mechanisms involved in stimulating immunity) rather than empirical (i.e. trying out different approaches and checking if they succeed) process for developing vaccines is likely to result in more reliable and rapid production of new vaccines.
6. Antivirals for pandemic preparedness
6.1 Background on antivirals
In contrast to vaccines, it’s our impression that relatively little work has gone into antiviral research and development in recent years. And, it seems to us that the majority of antivirals currently available are not likely to be useful countermeasures in the event of a potentially globally catastrophic pandemic. That’s because:
- Many of them are not broad-spectrum; most only treat one or a few different viral diseases.22
- Existing antivirals have variable effectiveness, and over time viruses have been evolving resistance to them.23
6.1.1 Host-directed antivirals
Some compounds which exhibit antiviral activity are host-directed, meaning that they target proteins in the host that the virus depends on rather than the virus itself. The ones we know of are inhibitors of chaperone proteins, proteins which assist in the folding of other proteins, including viral proteins. Our Scientific Research Program Officers’ reading of the literature suggests that these types of antivirals may be unsuitable for long-term use, since their mechanism of action relies on interfering with host-cell machinery, and thus they may cause relatively severe side effects.24
However, some of them (Hsp90 inhibitors) have been tested for medium-term use as therapeutics for cancer patients, and have been tolerated.25 Hsp90s are “chaperone” proteins. It appears that dependence on Hsp90s among viruses is widespread, and may be universal.26 Hsp90 inhibitors appear particularly promising to us because the ones we know of seem likely to be relatively broad-spectrum and difficult for viruses to evolve resistance against (because the antivirals target relatively conserved virus-host interactions). Hsp70s are also chaperone proteins with inhibitors which we think may be promising, although Chris and Heather report that there is some weaker evidence of broad-spectrum antiviral activity among Hsp70 inhibitors and less evidence indicating that they may be safe for human use.
Overall, we think these compounds merit further investigation, though we think they’re unlikely to prove fully efficacious and safe against viruses in humans due to the low overall base rate of discovery of new, highly effective pharmaceuticals. If these compounds were effective against highly virulent viruses at similar doses to those used for treating cancer patients, it seems likely to us that these side effects would be considered acceptable. Chris and Heather speculate that these antivirals would only be employed for short-term (i.e. on the scale of days or weeks) use against a virus; the idea would be to use them to mitigate the effects of the virus and “buy time” for the immune system to launch an immune response and clear the virus.
Chris and Heather thought it was unlikely that viruses could evolve or be easily engineered to have resistance to host-directed antivirals, because the pathway of protein folding is both complex and very fundamental, and so they said that many mutations would be required obviate the requirement for a given chaperone protein.
There are other proteins involved in the chaperone protein complex with inhibitors that may also prove useful as broad-spectrum antivirals, but the Hsp90 inhibitors seem the most promising because those are the only chaperone protein inhibitors that have been studied extensively in humans and have been found to be relatively safe.
A funder could fund studies on these antivirals’ efficacy against different viruses in vitro or in animal models or humans, for viral pathogens against which they have not yet been tested. We are in the process of investigating funding opportunities in this space.
7. Who else is working on it?
Our Scientific Research Program Officers’ overall impression is that there is a lot of commercial activity related to infectious disease vaccine and therapeutic development, and there are many companies working on the development of vaccines and diagnostics for use against viruses with greater economic potential in the developed world (e.g. influenza, hepatitis). However, we found it challenging to evaluate what proportion of the work is likely to be relevant to addressing pathogens with the potential to cause globally catastrophic pandemics. We did not look deeply into this topic because we thought it would be more useful to first identify more specific research topics that seemed most promising in this space, then investigate those. Thus, this section is relatively perfunctory compared to similar sections in other cause reports of ours.
It seemed plausible to us that this area might be neglected relative to its importance because the relevant people and groups might not see work on it as their responsibility or in their best interest; for example, we speculated that pharmaceutical companies might not be incentivized to develop vaccines and therapeutics designed specifically for use in a catastrophic pandemic, especially if they have side effects that make them unsuitable for use against less severe diseases, or diseases for which less dangerous alternative treatments exist. That’s because developing pharmaceuticals is generally very expensive,27 and we think that the relevant opportunities are relatively unlikely to deliver continual and reliable revenue streams (because the risks are rare and disproportionately associated with societal disruption), compared to e.g. treatments for chronic and common diseases.
We did encounter some potentially relevant efforts in this space that we thought were worth highlighting:
- The National Institutes of Health (NIH) allocated an estimated $1.7B for “biodefense” research in 2016, $1.4B of which went through the National Institute of Allergy and Infectious Disease (NIAID).28
- The Coalition for Epidemic Preparedness Innovations (CEPI), a group formed in 2016, states that it intends to develop vaccines against known pathogens that may have epidemic potential.29 In January 2017, it was reported that approximately $500M in funding had been committed to CEPI.30
- In 2013, The Joint Science and Technology Office for Chemical and Biological Defense worked on post-infection antivirals including antibodies and FDA-approved drugs.31
- In February 2017, the Defense Advanced Research Projects Agency (DARPA) announced a four-year initiative called the Pandemic Prevention Platform (P3) program to prepare nucleic acid vaccines within 60 days of the identification of a novel pathogen.32
Other information that seemed relevant to us:
- The NIH does not report spending on antivirals as a distinct category.33 However, 55 grants related to “broad-spectrum antivirals,” representing ~$17M, were reported by Grantome in 2015.34
- Chris and Heather’s impression during this investigation was that there are a variety of funders and other actors involved in platform tools for vaccine development, such that the topics they investigated did not seem highly neglected.
- Chris and Heather contacted companies and researchers that had previously been involved in the development of Hsp90 and Hsp70 inhibitors, as well as some other groups in the field we thought might have insight into this, and did not find evidence of ongoing research on the development of these inhibitors as broad-spectrum antivirals.
- If countermeasures were developed, the Biomedical Advanced Research and Development Authority (BARDA) might stockpile them. BARDA’s stated mission is to develop and procure medical countermeasures that address public health threats, including pandemic influenza and other infectious diseases.35 The Department of Defence may also manufacture relevant medical countermeasures.36
- There may also be non-public governmental research related to pandemic pathogen countermeasure R&D
8. Questions for further investigation
- How neglected are the various themes discussed in this document that relate to vaccine development (e.g. “computational protein design,” “vectored immunoprophylaxis,” etc.)? What are the most promising unfunded projects related to these themes?
- On what timescales could we expect to achieve advances in vaccine production such that vaccines against the most dangerous pathogens can reliably be developed in 100 days or fewer? What would the likely positive consequences be in a pandemic if vaccines could be produced that much earlier?
- What types of viral pathogens with the potential to produce globally catastrophic pandemics could not be addressed with the advances discussed in this writeup? What research would help address the risks posed by those?
- Are host-directed antivirals relatively safe and effective in humans? What viral pathogens would they not be sufficiently effective against, if any?
- What types of research into immunology would be most likely to yield insights that prove useful for preventing catastrophic disease outbreaks?
|BARDA: BARDA unveils path forward in the BARDA Strategic Plan 2011-2016||Source (archive)|
|Carolson, 2016||Source (archive)|
|CEPI: Approach||Source (archive)|
|Clinicaltrials.gov keyword “DNA vaccine”||Source (archive)|
|Clinicaltrials.gov keyword “hsp90”||Source (archive)|
|Clinicaltrials.gov keyword “RNA vaccine”||Source (archive)|
|Cohen 2017||Source (archive)|
|Correia et al. 2014||Source (archive)|
|DARPA: “Removing the Viral Threat” 2017||Source (archive)|
|De Clercq and Li 2016||Source (archive)|
|Department of Defense Chemical and Biological Defense Annual Report to Congress, 2014||Source (archive)|
|Devitt 2013||Source (archive)|
|Dormitzer et al. 2013||Source (archive)|
|Geller, Taguwa, and Frydman 2012||Source|
|Grantome.com “broad spectrum antivirals”||Source|
|Hasson, Al-Busaidi, and Sallam, 2015||Source|
|Howe and Haystead, 2015||Source|
|Kutzler and Weiner, 2008: Table 2||Source (archive)|
|Morrison 2016||Source (archive)|
|NIAID Fiscal Year 2017 Congressional Budget Justification||Source (archive)|
|NIH Categorical Spending 2017||Source (archive)|
|Overview of the Department of Defense’s (DoD) Advanced Development and Manufacturing (ADM) Facility and Capabilities, 2017||Source (archive)|
|Quick et al. 2016||Source (archive)|
|The Open Philanthropy Project’s grant to the University of Washington for “Universal Flu Vaccine and Improved Methods for Computational Design of Proteins” November 2017||Source|
|The Open Philanthropy Project’s non-verbatim summary of a conversation with Gigi Gronvall, October 6, 2014||Source|
|The Open Philanthropy Project’s non-verbatim summary of a conversation with Wendy Barclay, October 2, 2014||Source|
|Shaw 2017||Source (archive)|
|Tripp and Tompkins 2014||Source (archive)|
|Tufts Center for the Study of Drug Development, 2014||Source|
|Sanders and Ponzio 2017||Source (archive)|
|Vaccines.gov “Types of Vaccines”||Source (archive)|
|Willis et al. 2013||Source (archive)|
|World Health Organization: Vaccines Against Influenza, 2012||Source (archive)|