Research and Development to Decrease Biosecurity Risks from Viral Pathogens

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.


Published: April, 2018

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.

What is the problem?

Our shallow investigation into biosecurity describes the broader problem as we see it.1 In brief, we think natural and engineered pathogens have the potential to cause global catastrophes.

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.

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.2

    Further 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).

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.

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:

  1. 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
  2. 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.
  3. 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.
  4. 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.

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

Vaccine candidate formulation

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.

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:

  1. Identify antigens that can be used to prepare a nucleic acid vaccine
  2. Use computational methods to produce recombinant vaccines in cell cultures
  3. Clone antibodies that might be useful for generating passive immunity sera
  4. 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.

Antivirals for pandemic preparedness

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

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.

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

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?

Sources

Document Source
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)
  • 1. “What is the problem?

    Biosecurity covers a wide range of risks, including:1

    • Natural pandemics.
    • Bioterrorism and the intentional deployment of biological weapons.
    • Dual use research and the possibility of accidental deployment of biological agents.

    We see biosecurity issues as separate from typical global health issues in that they represent relatively low-probability risks of bad outcomes with potentially global impacts, rather than ongoing health issues to be managed at the local or regional level.

    We are not aware of any systematic estimates of the magnitudes of the risks discussed below. Our guess is that natural pandemics likely present the largest current threat, but that the development of novel biotechnology could lead to greater risks over the medium or long term.

    Natural pandemics

    Natural flu pandemics occur relatively frequently, and may be the most serious biosecurity threat, though exact probabilities are difficult to estimate.2

    The worst flu pandemic in the past century was the “Spanish” flu epidemic of 1918, which is believed to have been responsible for about 50 million deaths.3 Due to globalization, a similar pandemic today would likely spread around the world much more quickly, though modern medical advances would also likely reduce the health impacts of such a pandemic.4

    The H5N1 (avian flu) virus could be significantly more harmful than the 1918 flu pandemic were it to become more transmissible between humans, which could happen with relatively few genetic changes.5

    Bioterrorism and biological weapons

    The probability of a terrorist attack using a biological weapon is extremely difficult to estimate.6

    A terrorist attack with biological weapons could take a variety of forms:

    • A noncontagious biological agent, such as anthrax.7
    • A contagious natural pathogen, such as smallpox, which has been eradicated and accordingly is no longer vaccinated against.8
    • A contagious engineered pathogen, such as a manipulated version of H5N1 that is more transmissible between humans.9 (This type of risk is discussed more fully below.)

    The magnitude of harms caused by potential bioterror attacks could vary widely based on the agents employed as well as a number of other factors, but may be less significant than a major flu pandemic.10

    Dual use research

    “Dual use” research describes research that could be used either for positive or negative ends: scientists doing legitimate research may accidentally release a harmful agent or create tools or techniques that allow malicious actors to do so with greater ease.11 For instance, there has been significant controversy recently over research aiming to alter the host range of the H5N1 flu virus to make it transmissible between ferrets, a model for humans.12

    We have not seen any systematic assessments of the risks of dual use research or the likely impacts of an engineered pathogen. We would expect that as technology is developed further, these risks will increase and that the level of training required to use widely available technology to produce dangerous pathogens will fall, making dual use research and synthetic biology a significantly larger source of risk in the future.

    While the expected harms of different kinds of biosecurity risks are extremely difficult to estimate and compare, dual use research carries at least the conceptual possibility of creating a pathogen significantly more harmful than anything that has naturally evolved.13” The Open Philanthropy Project’s shallow investigation into biosecurity

  • 2. “The ‘molecular biocontainment’ method, honed by Benjamin tenOever and his colleagues at the Icahn School of Medicine at Mount Sinai in New York, involves engineering flu viruses to contain short sequences encoding target sites that cause specific microRNAs in host cells to bind the influenza RNA transcripts, priming them for destruction. TenOever’s team engineered two subtypes of the influenza A virus, similar to H5N1, 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, which serve as the primary animal model for flu. They then exposed ferrets and mice to these modified viruses and saw that the incorporation of miR-192 target sites had no effect on flu replication and transmissibility in the ferrets, but it did attenuate the pathogenicity of the virus in the mice. In this way, the scientists showed that animals infected with viruses containing species-specific microRNA sequences are protected from illness—suggesting that adding human-specific microRNA sequences to pathogens under study in the lab might protect people.” Devitt 2013, pg 1077.
  • 3.
    • “Dr. Ben tenOever’s approach of “molecular biocontainment” might limit the potential risks from GOF experiments, but researchers might reasonably be concerned about whether the approach could affect the outcome of their experiments. Even if controlled experiments were done to show that using a molecular biocontainment approach didn’t affect experimental results in some pathogens, researchers could wonder whether tenOever’s technique would affect the outcomes of experiments on new pathogens where such experiments had not been done.” The Open Philanthropy Project’s non-verbatim summary of a conversation with Gigi Gronvall, October 6, 2014.
    • “Molecular biocontainment: Researchers have engineered extra pieces of genetic information which can be added to viruses to prevent them from growing in certain species. “MicroRNA targeting” biocontainment strategies have very significantly reduced the risks of infection from some viruses in laboratory settings. More research needs to be done to show that molecular biocontainment strategies do not skew experimental results before this method is widely accepted in the scientific community.” The Open Philanthropy Project’s non-verbatim summary of a conversation with Wendy Barclay, October 2, 2014

    Chris and Heather agree that this is a substantial barrier to adoption of such technologies.

  • 4. “Antibiotic resistance is now evolving faster than new antibiotics are being developed, with the result that antibiotic resistance is a significant and growing public health threat.1 The pipeline of new antibiotics is limited both because much of the “low-hanging fruit” has already been picked (i.e. antibiotics that are easy to discover have already been developed) and because antibiotics are less profitable for drug companies to develop than other drugs.2


    Some experts have suggested that without major changes, we will face a “post-antibiotic era,” in which many medical technologies taken for granted in the developed world are no longer available.3 Our understanding is that the loss of antibiotics would have extremely negative effects in terms of morbidity and mortality, but would not eliminate most of the 20th century’s significant medical progress.4 Unfortunately, we are not aware of any systematic assessments of the likely global morbidity or mortality impacts of such a scenario.” The Open Philanthropy Project’s shallow investigation into Antibiotic Resistance

  • 5. “Here we present sequence data and analysis of 142 Ebola virus (EBOV) samples collected during the period March to October 2015. We were able to generate results in less than 24 hours after receiving an Ebola positive sample, with the sequencing process taking as little as 15-60 minutes. We show that real-time genomic surveillance is possible in resource-limited settings and can be established rapidly to monitor outbreaks.” Quick et al. 2016
  • 6. A biosensor is an analytical device, used for the detection of an analyte, that combines a biological component with a physicochemical detector.
  • 7. This is speculative, and Chris and Heather are uncertain about whether computational tools are sufficiently advanced to achieve this goal. See below for an example of work in this area demonstrating the use of computational tools to develop synthetic antibodies that appear to have been effective for use against respiratory syncytial virus.

    “Here we show, with a neutralization epitope from respiratory syncytial virus (RSV), that computational protein design can generate small, thermally and conformationally stable protein scaffolds that accurately mimic the viral epitope structure and induce potent neutralizing antibodies… More generally, the results provide proof of principle for epitope-focused and scaffold-based vaccine design, and encourage the evaluation and further development of these strategies for a variety of other vaccine targets including antigenically highly variable pathogens such as HIV and influenza.” Correia et al. 2014
  • 8. For example, Willis et al. explore a similar strategy during their investigation of polyspecificity (the ability of some antibodies to bind to multiple antigens) and found that they were able to predict this general trait.

    “We used computational design algorithms to explore antibody sequence space rapidly and predict optimal sequences to achieve polyspecificity. The resulting designed sequences recapitulated the germline gene segment sequences and highlighted residues critical for achieving polyspecificity. These results suggest how a finite set of antibody germline gene segments can encode antibodies that can engage a large number of antigens.” Willis et al. 2013
  • 9. See 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
  • 10. These methods are explained in more detail in the following bullet points:
    • Live-attenuated vaccine: “Live, attenuated vaccines contain a version of the living microbe that has been weakened in the lab so it can’t cause disease. Because a live, attenuated vaccine is the closest thing to a natural infection, these vaccines are good “teachers” of the immune system: They elicit strong cellular and antibody responses and often confer lifelong immunity with only one or two doses.

      Despite the advantages of live, attenuated vaccines, there are some downsides. It is the nature of living things to change, or mutate, and the organisms used in live, attenuated vaccines are no different. The remote possibility exists that an attenuated microbe in the vaccine could revert to a virulent form and cause disease. Also, not everyone can safely receive live, attenuated vaccines. For their own protection, people who have damaged or weakened immune systems—because they’ve undergone chemotherapy or have HIV, for example—cannot be given live vaccines.”
    • Inactivated vaccine: “Scientists produce inactivated vaccines by killing the disease-causing microbe with chemicals, heat, or radiation. Such vaccines are more stable and safer than live vaccines: The dead microbes can’t mutate back to their disease-causing state. Inactivated vaccines usually don’t require refrigeration, and they can be easily stored and transported in a freeze-dried form, which makes them accessible to people in developing countries.

      Most inactivated vaccines, however, stimulate a weaker immune system response than do live vaccines. So it would likely take several additional doses, or booster shots, to maintain a person’s immunity. This could be a drawback in areas where people don’t have regular access to health care and can’t get booster shots on time.”
    • Subunit: “Instead of the entire microbe, subunit vaccines include only the antigens that best stimulate the immune system. In some cases, these vaccines use epitopes—the very specific parts of the antigen that antibodies or T cells recognize and bind to. Because subunit vaccines contain only the essential antigens and not all the other molecules that make up the microbe, the chances of adverse reactions to the vaccine are lower.”
    • Toxoid: “For bacteria that secrete toxins, or harmful chemicals, a toxoid vaccine might be the answer. These vaccines are used when a bacterial toxin is the main cause of illness. Scientists have found that they can inactivate toxins by treating them with formalin, a solution of formaldehyde and sterilized water. Such “detoxified” toxins, called toxoids, are safe for use in vaccines.”
    • Conjugate vaccines: “If a bacterium possesses an outer coating of sugar molecules called polysaccharides, as many harmful bacteria do, researchers may try making a conjugate vaccine for it. Polysaccharide coatings disguise a bacterium’s antigens so that the immature immune systems of infants and younger children can’t recognize or respond to them. Conjugate vaccines, a special type of subunit vaccine, get around this problem.”

    All from Vaccines.gov “Types of Vaccines”

  • 11. An example Chris and Heather relayed to us is the possibility of creating attenuated vaccines involving viruses in which the genes necessary for replication have been taken out of the pathogen and swapped into special cell lines which can be used to grow the virus for vaccine production. The idea is to use those cell lines with the added genes to produce large quantities of the virus which cannot reproduce without the special cells lines. Those replication-deficient viruses could then be injected into a human host, where they’d (hopefully) stimulate a robust immune response (causing immunity to the virus) without posing a danger to the human recipient of replicating and, thus, causing direct harm.
  • 12. See e.g. Kutzler and Weiner, 2008: Table 2, though it’s likely to be outdated.
  • 13. See e.g. the results for Clinicaltrials.gov keyword “DNA vaccine” and Clinicaltrials.gov keyword “RNA vaccine”.
  • 14. Chris and Heather noted the following examples:
    • “Nonetheless, the results of these early clinical trials were thwarting. The DNA vaccines were intact and well abide, yet they turned out to be inadequately immunogenic. The antibody titers induced has been found to be very low or absent; CD81 T-cell responses were desultory, and CD41 T-cell responses were of low frequency.” Hasson, Al-Busaidi, and Sallam, 2015
    • “Zika-neutralizing antibodies were lowest in animals given the DNA vaccine, and highest in those that had received the vaccine via an adenovirus vector. “Adenovirus vector-based vaccines are typically more potent than DNA vaccines,” reports Dan Barouch. [director of Harvard Medical School’s Center for Virology and Vaccine Research] But why that should be so, the researchers write in their paper, “remains to be determined.” Shaw 2017
  • 15. “Recombinant vector vaccines are experimental vaccines similar to DNA vaccines, but they use an attenuated virus or bacterium to introduce microbial DNA to cells of the body. “Vector” refers to the virus or bacterium used as the carrier.
    In nature, viruses latch on to cells and inject their genetic material into them. In the lab, scientists have taken advantage of this process. They have figured out how to take the roomy genomes of certain harmless or attenuated viruses and insert portions of the genetic material from other microbes into them. The carrier viruses then ferry that microbial DNA to cells. Recombinant vector vaccines closely mimic a natural infection and therefore do a good job of stimulating the immune system.
    Attenuated bacteria also can be used as vectors. In this case, the inserted genetic material causes the bacteria to display the antigens of other microbes on its surface. In effect, the harmless bacterium mimics a harmful microbe, provoking an immune response.” Vaccines.gov “Types of Vaccines”
  • 16. Our understanding is that the above points are generally accepted by researchers in the field. For an example of some of the viruses being explored for the development of influenza vaccines, see Tripp and Tompkins 2014 Table 1. The body of this paper also outlines some of the viruses being explored as vaccine vectors.
  • 17. “Vectored Immunoprophylaxis (VIP) is a novel approach designed to address these challenges. Rather than utilizing an antigen to trigger a response from the host’s immune system as is normally done with traditional vaccines, VIP genetically engineers the production of tailored antibodies from non-hematopoietic cells, bypassing the humoral immune system. Direct administration of genes encoding for neutralizing antibodies has proven to be effective in both preventing and treating several infectious diseases in animal models. While, a significant amount of work has focused on HIV, including an ongoing clinical trial, the approach has also been shown to be effective for malaria, dengue, hepatitis C, influenza, and more. In addition to presenting itself as a potentially efficient approach to solving long-standing vaccine challenges, the approach may be the best, if not only, method to vaccinate immunocompromised individuals. Many issues still need to be addressed, including which tissue(s) makes the most suitable platform, which vector(s) are most efficient at transducing the platform tissue used to secrete the antibodies, and what are the long-term effects of such a treatment.” Sanders and Ponzio 2017, abstract
  • 18. E.g. “To ensure optimal vaccine efficacy against prevailing strains in both the northern and southern hemispheres, the antigenic composition of the vaccines is revised twice annually and adjusted to the antigenic characteristics of circulating influenza viruses obtained within the WHO global influenza surveillance and response system (GISRS).” World Health Organization: Vaccines Against Influenza, 2012
  • 19. “The response to the 2009 H1N1 influenza pandemic was the fastest global vaccine development effort in history. Within 6 months of the pandemic declaration, vaccine companies had developed, produced, and distributed hundreds of millions of doses of licensed pandemic vaccines. Unfortunately, the response was not fast enough. Substantial vaccine quantities were available only after the second pandemic wave had peaked (1). Manufacture of influenza virus subunit vaccines requires a vaccine virus that grows well enough in eggs or cultured mammalian cells to produce sufficient amounts of the essential vaccine antigen, hemagglutinin (HA), to meet vaccine needs. Late availability of a high-yielding vaccine virus contributed to the delay in vaccine supply.” Dormitzer et al. 2013
  • 20. “Less than 6 months after Zika infection was declared a public health emergency, the first clinical trials of DNA vaccines against the virus are beginning. By the end of 2016 at least two vaccines against Zika will have completed Phase I safety trials, marking the first significant clinical progress towards preventing transmission of the virus. Farthest along the development pathway are two competing DNA vaccines from the biotech company Inovio and the US National Institute of Allergy and Infectious Diseases (NIAID), showcasing the technology’s potential advantages over traditional vaccine approaches.” Morrison 2016
  • 21. Chris and Heather note that some pathogen traits, such as a high mutation rate and a propensity for antigen switching, (e.g. malaria has genes for a number of variants of major surface antigens and it can at random turn on one of these genes at a time and then randomly turns that gene off again and turn another one on. As a result, the host organism is unable to develop a strong immune response to malaria.) make vaccine development more difficult
  • 22. We expect the claims in the two preceding sentences should be easily verifiable by reviewing the literature or asking relevant experts.

    An example of a paper Chris and Heather read supporting the claims above, follows: “Importantly, antiviral compounds with broad-spectrum activity against different virus genotypes or subtypes are still welcome, because the effectiveness of most antiviral drugs is limited to only certain viral strains (466). For instance, some antiviral drugs (e.g., amprenavir)inhibit only HIV-1 but not HIV-2 (173). Many HCV inhibitors have been approved only for HCV genotype 1 but not for other genotypes (Table 2). Nevertheless, a number of antiviral inhibitors (brivudine, acyclovir, TDF, foscarnet, famciclovir, lamivudine, ribavirin, valacyclovir, PegIFN-2a, and PegIFN- 2b) have been licensed for the treatment of more than one virus (Table 2), supporting the idea of developing antiviral drugs against multiple infectious diseases in the future.” De Clercq and Li 2016
  • 23. “Despite the rapid advancement of pharmaceutical and biotechnological approaches (e.g., RNA interference [RNAi] [467]), the development of successful antiviral treatments remains a challenge. First, potent antiviral drugs that counteract the highly variable nature of virus genomes are still required, because emerging drug resistance mutations remain a major cause of treatment failure (10, 466, 468, 469).” De Clercq and Li 2016

    “The high mutation rates, short replication times, large population sizes, and compact genomes enable viruses to rapidly acquire mutations conferring drug resistance, thus circumventing inhibition by antiviral drugs. The ability of viruses to develop drug resistance to antiviral compounds targeting viral proteins is enormous, since the drug target is under the replicative control of the virus and therefore escape mutations are easily generated. In the case of antivirals targeting cellular factors required for viral replication, acquisition of drug resistance has also been observed, although it is more difficult as the virus must either dispense with the affected function or evolve to employ an alternative cellular pathway. The lack of successful antiviral therapies for most viruses create a pressing need for identification of novel antivirals that do not elicit drug resistance.” Geller, Taguwa, and Frydman 2012
  • 24. Heather comments: “In the short term, non-dividing cells can continue to function without a lot of new protein synthesis. The inhibitors, therefore, have a disproportionate effect on cells making a lot of new protein (e.g. rapidly dividing cancer cells and cells infected with replicating virus). However, this means the compounds are also likely to interfere with normal growth and repair mechanisms over time. In an antiviral context, we would expect only partial inhibition, with the biggest effects in cells undergoing viral reproduction. The hypothesis is that this activity will reduce viral titer sufficiently to allow the immune system to clear the infection quickly and with minimal harm.”
  • 25. Chris and Heather found that the clinical trials on HSP90 inhibitors generally reported that serious side effects with newer compounds were rare and included nausea, diarrhea, and vomiting. They found these clinical trials by searching clinicaltrials.gov using “hsp90” in the “other terms” search box (see Clinicaltrials.gov keyword “hsp90”). They also discussed this topic with Dr. Len Neckers, an oncologist at NIH who works with these compounds.

    More generally, we read that “The molecular chaperones, heat shock proteins 70 (HSP70) and 90 (HSP90), have been shown to be host factors that are utilized by a wide range of viruses, including HIV, influenza, polioviurs, and dengue virus for replication and propagation. There is an observed increase in HSP70 and HSP90 expression following viral infection. Additionally, HSP70 and HSP90 regulate anti-apoptotic pathways and assist in the proper folding of newly synthesized proteins during the viral lifecycle. The utilization of HSP70 and HSP90 in viral propagation is similar to the roles of these proteins in cancer progression. Small molecule inhibitors have been developed for both HSP70 and HSP90 as anticancer therapeutics, but there is recent evidence to suggest these inhibitors have indications as antiviral drugs.” Howe and Haystead, 2015

  • 26. Geller, Taguwa, and Frydman 2012
    • “Recent work has shown that the molecular chaperone Hsp90 is nearly universally required for viral protein homeostasis. As observed for many endogenous cellular proteins, numerous different viral proteins have been shown to require Hsp90 for their folding, assembly, and maturation. Importantly, the unique characteristics of viral replication cause viruses to be hypersensitive to Hsp90 inhibition, thus providing a novel therapeutic avenue for the development of broad-spectrum antiviral drugs. The major developments in this emerging field are hereby discussed.”
    • “Currently, Hsp90 inhibitors have been demonstrated to possess antiviral activity in tissue culture against picornaviruses (poliovirus, coxsackievirus, rhinovirus), influenza virus, paramyxoviruses (HPIV2, HPIV3, SV5, SV41), HCV, Ebola virus, vesicular stomatitis virus, La Crosse virus, severe acquired respiratory syndrome (SARS), FHV, HIV, vaccinia virus, and herpes viruses (HSV1/2, HCMV, VZV). This property makes Hsp90 inhibitors particularly attractive antivirals for existing viral diseases lacking therapies and for rapid response to newly emerging viral diseases. Secondly, administration of Hsp90 inhibitors to infected animals was shown to reduce the replication of two different viruses, poliovirus and HCV, with little toxicity to the infected host [33,99]. These experiments highlight the feasibility of using these inhibitors therapeutically in humans. Thirdly, Hsp90 inhibitors were demonstrated to be refractory to the development of drug resistance. This was clearly highlighted by poliovirus experiments, as this virus has been demonstrated to gain drug resistance to all antivirals tested to date whether they target viral or host factors. However, when poliovirus was repeatedly treated with Hsp90 inhibitors, no drug resistance was observed despite extensive passaging of the virus in the presence of Hsp90 inhibitors in cultured cells. Similarly, no drug resistance was observed in viruses recovered from Hsp90 inhibitor treated mice. The lack of viral drug resistance to Hsp90 inhibitors suggests such an antiviral approach may be particularly useful for treatment of chronic viral infections and treatment of RNA virus infections for which drug resistance is most frequently observed.”
  • 27. E.g. we read that: “Developing a new prescription medicine that gains marketing approval, a process often lasting longer than a decade, is estimated to cost $2,558 million, according to a new study by the Tufts Center for the Study of Drug Development.
    The $2,558 million figure per approved compound is based on estimated:
    • Average out-of-pocket cost of $1,395 million
    • Time costs (expected returns that investors forego while a drug is in development) of $1,163 million

    Estimated average cost of post-approval R&D—studies to test new indications, new formulations, new dosage strengths and regimens, and to monitor safety and long-term side effects in patients required by the U.S. Food and Drug Administration as a condition of approval—of $312 million boosts the full product lifecycle cost per approved drug to $2,870 million. All figures are expressed in 2013 dollars.

    The new analysis, which updates similar Tufts CSDD analyses, was developed from information provided by 10 pharmaceutical companies on 106 randomly selected drugs that were first tested in human subjects anywhere in the world from 1995 to 2007.” Tufts Center for the Study of Drug Development, 2014

    This number seems approximately in line with (i.e. within an order of magnitude of) other figures we’ve seen.

  • 28. NIAID Fiscal Year 2017 Congressional Budget Justification pg 9
  • 29. “CEPI wants to galvanise the development of new vaccines against diseases we know could cause the next devastating epidemic.
    We will achieve our vision by creating an innovative partnership between public, private, philanthropic and civil organisations. It is ambitious both in its scope and in the breadth of organisations involved.

    CEPI will take an end-to-end approach – we won’t take on discovery research or vaccine delivery, but we will work through all the steps in between. We will stay abreast of new discoveries and technologies, and we’ll work with other organisations to make sure any vaccines that are developed reach those who need them.

    Equitable access will be a founding principle of CEPI, so that vaccines developed with its support are available to all who need them – price should not be a barrier – and they are available to populations with the most need.

    We expect that many of the vaccines CEPI helps to develop will not be profit-making, and will work with our partners to ensure that the risks, costs and benefits of development are shared proportionately.” CEPI: Approach

  • 30. “Formed last year without serious funding, CEPI has received $100 million commitments from the Wellcome Trust and the Bill & Melinda Gates Foundation, and the governments of Japan, Germany, and Norway have pledged to contribute an additional $260 million. As Science went to press, CEPI planned to announce the commitments at the World Economic Forum this week in Davos, Switzerland.” Cohen 2017
  • 31. “JSTO-CBD performed these studies in monkeys using a monoclonal antibody cocktail against lethal Ebola virus infection. Further progress in the immunotherapy area resulted in preliminary identification of a protective antibody against Alphavirus infection. Finally, JSTO-CBD identified novel, triple-reactive monoclonal antibodies with broad spectrum recognition of Filoviruses. For drug repurposing efforts, JSTO-CBD confirmed activity of several FDA-approved drugs in successfully treating Ebola infection in mice. Further initial screenings have discovered FDA-approved drugs with activity against several species of Alphaviruses and Flaviviruses. Other repurposing efforts identified and began characterizing two established FDA-approved cancer treatment drugs with activity against Filoviruses and Poxviruses.” Department of Defense Chemical and Biological Defense Annual Report to Congress, 2014 pg 7
  • 32. “Over the past several years, DARPA-funded researchers have pioneered RNA vaccine technology, a medical countermeasure against infectious diseases that uses coded genetic constructs to stimulate production of viral proteins in the body, which in turn can trigger a protective antibody response. As a follow-on effort, DARPA funded research into genetic constructs that can directly stimulate production of antibodies in the body.1,2 DARPA is now launching the Pandemic Prevention Platform (P3) program, aimed at developing that foundational work into an entire system capable of halting the spread of any viral disease outbreak before it can escalate to pandemic status. Such a capability would offer a stark contrast to the state of the art for developing and deploying traditional vaccines—a process that does not deliver treatments to patients until months, years, or even decades after a viral threat emerges.”


    “DARPA’s goal is to create a technology platform that can place a protective treatment into health providers’ hands within 60 days of a pathogen being identified, and have that treatment induce protection in patients within three days of administration. We need to be able to move at this speed considering how quickly outbreaks can get out of control,” said Matt Hepburn, the P3 Program Manager. “The technology needs to work on any viral disease, whether it’s one humans have faced before or not”….

    “DARPA-funded teams will be required to demonstrate their integrated platforms in five simulations during the planned four-year program; they will initially test their platforms using pathogens of their choice, but ultimately they will test using DARPA-selected pathogens, including two demonstrations in which the identity of the pathogen will remain opaque to the teams until the 60-day clock starts. To ensure the developed platforms can produce a quality product with a viable pathway for regulatory review, each team will be required to complete a Phase I clinical safety trial before the end of the program.” DARPA: “Removing the Viral Threat” 2017

  • 33. See NIH Categorical Spending 2017
  • 34. See Grantome.com “broad spectrum antivirals”. This appeared to be roughly representative of recent years. Note that minor changes to spelling did not change this number.
  • 35. “On October 4, 2011, the Biomedical Advanced Research and Development Authority (BARDA) issued the BARDA Strategic Plan 2011-2016, which articulates the guiding principles, goals, and strategies it will implement to enhance the capability of the U.S. government to develop medical countermeasures (MCMs) to these and other natural and intentional threats to public health.
    BARDA develops and procures needed MCMs, including vaccines, therapeutics, diagnostics, and non-pharmaceutical countermeasures, against a broad array of public health threats, whether natural or intentional in origin.” BARDA: BARDA unveils path forward in the BARDA Strategic Plan 2011-2016
  • 36. See e.g. Overview of the Department of Defense’s (DoD) Advanced Development and Manufacturing (ADM) Facility and Capabilities, 2017