By Emily Johnson, Biodefense MS Student
The United States is experiencing a decline in COVID-19 cases, but SARS-CoV-2 is still a prominent topic here and internationally. The American Biological Safety Association’s (ABSA) 64th Annual Association for Biosafety and Biosecurity Conference took place October 25-27, 2021, bringing together a global community to discuss these topics while aiming to provide solutions to tackle the most challenging issues, present fascinating case studies, and showcase the latest developments in biosafety and biosecurity. The conference was presented virtually, offering a platform similar to a live conference including a lobby, exhibit hall, poster hall, networking lounge, and live presentations.
Overview of ABSA Virtual Conference Report
I attended this virtual conference along with my GMU Biodefense Program colleague, Mr. Konnor Heyde. To provide our readership with a comprehensive report on the ABSA conference, we self-assigned the sessions we would write about. This report provides an overview, details, and comments on the following sessions:
- Session I: Virology in the Time of a Pandemic
- Session III: The COVID Pandemic: The Evolving Reality
- Session XII: Gene Therapy
- Professional Development: Identifying and Overseeing Potential DURC: A practical Guide for the Biosafety Professional
Session I: Virology in the Time of a Pandemic
When a novel virus emerges in a population there is no substitute for preparedness in improving the effectiveness and timeliness of the response. The conference commenced with Dr. Dirk P. Dittmer from the University of North Carolina—Chapel Hill discussing the causative agent of COVID-19, testing, and disease outlook.
He began by utilizing a case study format, presenting an “old” pandemic: HIV. The progression of the pandemic was separated into three phases and compared to the current pandemic. It began with a phase he designated as “pre” which, for HIV, was before publication of the July 1981 MMWR report recognizing abnormal presentation of pneumonia in both San Francisco and New York. The rate of occurrence increased exponentially creating a bell curve which was the pandemic phase. The curve dropped precipitously, though never returning to zero even after effective treatment using antiretrovirals was approved. This was the transition to the “post” phase. For the COVID-19 pandemic, Dr. Dittmer defined the “pre” phase as the period leading up to the release of the article in the New England Journal of Medicine on A Novel Coronavirus from Patients with Pneumonia in China, 2019. Dr. Dittmer considers the pandemic phase as ending with the FDA approval of a vaccine in August of this year in addition to an EUA for other treatments.
The Global Initiative on Sharing Avian Influenza Data (more commonly known by its acronym- GISAID) is a worldwide repository of genomic sequences historically used to catalog international influenza variants. It played a critical role in the identification and tracking of emerging strains of SARS-CoV-2 variants. By March of 2020, the G614 variant was present in the US, exhibiting lower CT values (referring to the PCR cycle threshold where a florescent signal is first detectable) suggesting a higher viral load and therefore an increase in transmissibility over the wild type. This does not necessarily indicate more severe disease. In May 2021, the delta variant arrived in the US and, as of September, was indicated in over 90% of cases.
Dr. Dittmer referred to the pre-pandemic period as a time of blissful ignorance and squandered opportunities. He identified one failure as the self-imposed bottleneck by the single PCR test manufactured in a single place that slowed testing in the US. Another example of this is the underfunding of proposed basic science research on viruses related to HIV or SARS-CoV-2 prior to their respective outbreaks. Limited funding resulted in few experts on coronaviruses. The lesson to be learned is that while research will escalate during a pandemic, basic science research should be supported between public health emergencies.
Constant preparedness is crucial. Previous work on techniques to increase accuracy in virus detection resulted in a broad knowledge base from which researchers could build when faced with the testing demands of the COVID-19 pandemic. Plaque assays measure infectious virus, but they are time consuming. QPCR overestimates viral load because it includes viral segments. This means the CDC assay is more sensitive because it measures full genome as well as segments while the WHO assay only reports full genome.
Dr. Dittmer’s lab is using Rapid NextGen Sequencing methods. There is a linear relationship between viral load and number of reads, therefore it can also be used as a viral load assay, albeit an expensive one. It takes about 100,000 reads to determine a whole genome. The results suggest that most genomic material sequenced was whole genome, therefore eliminating the advantage of the CDC assay over the WHO assay.
NextGen sequencing can be used in fragment detection, even with a low number of reads. If the segments are dispersed throughout the target genome it is likely the fragmented virus was present in the sample. Although further testing is needed, he proposes a relationship between sequence coverage and infectivity. The higher the number of reads, the more likely the sample contained infectious virus. The remaining barrier is cost.
The next pandemic cannot be predicted. There is no magic bullet. The best way to prepare is to be ready for the unpredictable. This, Dr. Dittmer, says is the value of basic science.
Session III: The COVID Pandemic: The Evolving Reality
In 2005, Dr. Michael T. Osterholm published an article in the New England Journal of Medicine outlining the inevitability of an imminent pandemic and a strategy to prepare. These warnings went mostly unheeded. In this fireside chat, he discussed the state of the COVID-19 pandemic, posed questions to be investigated, and measures that should be taken to prepare not only for the next inevitable pandemic, but for the impending surges of COVID-19 the US is likely to continue to experience. He is a leading epidemiologist, director of the Center for Infectious Disease Research and Policy, professor at the University of Minnesota, and in November of 2020 was appointed to President-elect Joe Biden’s Transition COVID-19 Advisory Board.
Dr. Osterholm began by discussing the mystery of the four- to six-week surges in geographical hot spots of COVID-19 cases during which he draws parallels between this phenomenon and the 2009 H1N1 outbreak. At the beginning of that pandemic, there was a surge in cases during the March/April timeframe followed by a significant drop with no mitigation factors in place. This repeated in the late Fall. That winter, the cases of H1N1 were sparce, but more interestingly, there was an international phenomenon of a drop in seasonal flu cases. Similarly in 2020, all respiratory diseases appeared to decrease in prevalence. He observes that this is not the result of human action as it was equally demonstrated in countries with and without mitigations.
The Dawn of the Age of the Variants
In November 2020, the SARS-CoV2 alpha variant was detected in the UK. It was this point where he said his analogy changed from which inning of the COVID-19 pandemic baseball game we were in to how many minutes of the game had passed. Variants can be associated with changes in transmissibility, severity, or the ability to evade natural defenses and vaccine immunity. There is potential for emergence of novel variants as the pathogen continues to spread. With 65 million eligible Americans still unvaccinated and Russia experiencing an uptick in cases due to similar hesitancy among the Russian population to accept the Sputnik vaccine, we have a population ripe for the spread of this virus for months or years to come. However, Dr. Osterholm believes that COVID-19 is likely to present seasonally in the future.
Another point where SARS-CoV-2 is not analogous to seasonal influenza is that when a pandemic influenza becomes a seasonal virus, it attenuates into a seasonal pattern and genetic changes are unlikely to result in it becoming more challenging. Conversely, we do not know what severity or transmissibility modifications future SARS-CoV-2 variants will exhibit.
Vaccines: Study, Learn, Implement, Repeat
When mRNA data was originally released, it showed high rates of safety and over 90% protection from severe illness, hospitalization, and death. The Johnson & Johnson adenovirus-based vaccines showed lower initial immune response, only reaching about 74%.
The mRNA vaccines exhibit waning immunity over time. It is still unclear what this will mean over the long term, but he predicts break through cases will continue to increase in number and in younger populations as they received their initial vaccine later than the older population and are now reaching a valley of immunity.
Dr. Osterholm believes the adenovirus-based vaccines will be the game changers with COVID-19. Although the mRNA vaccines initially reached a higher rate of protection, it dropped over time while the Johnson & Johnson vaccine improved over time, reaching the low 80% range by six months post-immunization. A second dose increases numbers into the 90% range, and this may be more enduring. We must learn how to best use these vaccines concerning mixing, dosing, and timing. There may be multi-strain vaccines in the future, but improvements seen in second or third generation COVID vaccines will likely be developments related to temperature tolerance and, possibly, coverage for variants.
During his tenure on the Natural Science Advisory Board for Biosecurity, he was very critical of the research on mammalian transmission of H5N1, citing his respect for the importance of laboratory and biologic safety issues. He views the origins of SARS-CoV-2 in a similar light and is concerned with lab safety. However, he believes that while it is possible the virus originated in a lab, it is likely the result of a spillover event like SARS or MERS. He went on to point out that Wuhan is a transportation hub in China with millions of travelers traversing the city daily. In addition, there is a thousand-mile reach for food, particularly live animals, coming to the markets of Wuhan. This evidence supports a spillover scenario. He dismissed the cleavage site evidence of a human-manipulated genome citing similar genetics in coronaviruses found in caves in Laos.
To demonstrate his point, he proposes the hypothetical situation of a novel virus emerging in the Caribbean. One of the initial regions the virus would be clinically detected is Atlanta, Georgia due to it being a transportation hub between North America and the Caribbean. Would the international population assume the virus escaped from a CDC lab?
Question & Answer Session
When asked why there were more cases in the US than China where it originated, Dr. Osterholm was quick to point out that those two elements are not related. China imposed draconian quarantine measures and rampant testing while the US has not. There are many factors contributing to the respective countries’ reported number of cases.
Another attendee asked why immunity from infection was not equal to that of the vaccine. Dr. Osterholm explained that we do not fully understand what immunity to COVID-19 is yet. In the first weeks after mRNA vaccination, study participants showed high levels of protection from disease, but almost undetectable antibody levels. Cellular immunity was playing some role in that protection that is not yet fully understood. There is conflicting data on what immunity is offered by natural infection. While it does afford some protection, how good it is and how long it lasts are still unknown. There is strong evidence that those who receive a vaccine after natural infection are at a lower risk, similar to the natural infection acting like a first dose.
A question asked by many since the pandemic began is, “What could have been done differently in the beginning?” He replied that not much can be done once a respiratory virus establishes itself in a population. There is no magical solution. The US could have improved in preparations for a major health event. A better prepared healthcare system will be integral in successful navigation of future pandemics. He also cited improving communication with the public.
Lastly, he believes there is a zero chance of eradication. It is more likely that with long-term vaccination, COVID-19 will eventually present in a seasonal manner like influenza.
Session XII: Gene Therapy Research Boom and Future Challenges
Dr. Daniel Eisenman of Advarra shared an overview of the progression of gene therapy research and the changes relevant to an institutional biosafety committee.
To review the process of regulatory oversight of gene therapy research, it begins with preclinical research and development involving only animal models. When potential has been shown, an application for an Investigational New Drug (IND) is submitted to the FDA. Phase two is the first clinical phase involving humans. It usually involves 20 to 100 subjects, although Dr. Eisenman pointed out that the trial for a COVID-19 vaccine had around 30,000. The focus of phase two is to prove safety. In phase three, the focus shifts to showing efficacy, it involves more participants, and it has determined optimal dosing. After successfully completing phase three, FDA approval is requested. Phase four includes post approval research.
Immediately preceding the pandemic, Dr. Eisenman published an article in Applied Biosafety which demonstrated the dramatic, explosive growth in the number of gene therapy IND applications per year. By 2020, that number had flatlined. Why? As a result of COVID-19, many clinical trials were suspended.
Prior to COVID-19, most gene therapy submissions were for oncological application. Now, among the most recent approvals, there were eight for oncology, but six for infectious diseases (two of which were COVID-19 vaccines) and two for rare diseases. These successes pave the way for future therapies.
Two gene therapy success stories were presented. The first was treatment for retinitis pigmentosa, a disease characterized by night blindness at a young age that progresses to total blindness. The therapy reversed vision loss demonstrated by the speed with which they were able to navigate a dimly lit maze. The other example of a successful application was treatment of spinal muscular atrophy type 1. SMA1 usually results in death during toddlerhood due to the inability to control muscles involved in breathing. Children who have undergone treatment are living into childhood and are even able to walk and run on their own.
There are currently over 350 gene therapies in phase three trials. In a recent statement on advancingthe development of safe and effective cell and gene therapies, the FDA suggested that gene therapy may be at a turning point similar to that of monoclonal antibodies in the late 1990s. The technology has the potential to become a backbone of modern treatment regimens.
Dr. Eisenman then went on to discuss some changes in Institutional Review Board (IRB) involvement in multi-site studies. Traditionally an IRB review is done at each institution where the clinical trial is being carried out. This can be inefficient. As of 2018, all NIH funded multi-site studies are required to utilize a single IRB. Other federally funded studies made the change in 2020.
NExTRAC is the Novel and Exceptional Technology and Research Advisory Committee. It no longer oversees individual clinical trials but instead relies on prompts which would direct public deliberation on certain research. This is one result of the burden of oversight shifting from NIH to the FDA.
One recommendation Dr. Eisenman hasd is for the public to request more formal FDA requirements for shedding data during clinical trials. Currently it is risk based and more of a recommendation as FDA exemptions are regularly requested and granted. He suggested it should be included for all vector-based studies and replication-competent microbes, including vaccines.
The presentations shared at the conference were very informative, thought provoking, and had a general feeling of collegiality from living the pandemic and experiencing similar struggles. One of the presentations exhibiting ingenuity resulting from COVID-19 was given by Benjamin Fontas. He discussed the development of Short Term Use Biocontainment Bubbles at Yale (STUBB-Y) where researchers drew on their expertise to provide professionals working in high risk occupations at Yale temporary protection from aerosols at the beginning of the pandemic. This was just one example of the innovative applications of biosafety experience that presenters contributed to their institutions to mitigate safety concerns during the pandemic.
COVID-19 vaccines were also discussed by multiple speakers, specifically regarding the need to look at them as one of the tools in our toolbox, not a final solution. A recurrent theme was the importance of communication with the public to ensure their trust in science and scientific representatives. From misinformation about mitigations to questions about the ability of novel pathogens to escape a lab, it is more important now than ever that the public is communicated with in a way that encourages trust and understanding.
Professional Development Course on Dual Use Research of Concern
Professional development courses were offered in conjunction with the ABSA 2021 conference. I attended Identifying and Overseeing DURC: A practical Guide for the Biosafety Professional presented by Rebecca Moritz, Biosafety Director at Colorado State University.
Dual Use Research of Concern (DURC) is defined by the National Institutes of Health (NIH) as “life sciences research that, based on current understanding, can be reasonably anticipated to provide knowledge, information, products, or technologies that could be directly misapplied to pose a significant threat with broad potential consequences to public health and safety, agricultural crops and other plants, animals, the environment, materiel, or national security.” It is interesting to note there is a difference between dual use research and dual use research of concern. They both refer to research that could be used for both beneficial and malevolent purposes. However, DURC directly references a significant threat with broad consequences.
Historically relevant cases of DURC include the mousepox experiment by Jackson et. al in 2001 and the 1918 influenza research by Tumpey in 2005. In 2004, the National Academies of Sciences released Biotechnology Research in an Age of Terrorism, better known as the Fink Report. The goal was to better educate the scientific community on how their research could have unintended consequences.
To better guide those defining what should be considered concerning research, the National Science Advisory Board for Biosecurity released the Proposed Framework for the Oversight of Dual Use Life Sciences Research: Strategies for Minimizing the Potential Misuse of Research Information. The guiding principles focused around oversight that would maintain public trust by demonstrating that the scientific community recognizes potential security threats and is acting responsibly to protect the public safety and security. However, it cautions that there must be a balance that allows for both oversight and research advancement.
Similarly, research on potential pandemic pathogens (PPPs) is necessary to protect global health and security. The Department of Health and Human Services released the Framework for Guiding Funding Decisions about Proposed Research Involving Enhanced Potential Pandemic Pathogens (P3CO) in 2017. This framework guides department-level pre-funding review on research that may create, transfer, or use enhanced PPP.
The most recent DURC policy went into effect in 2015. The framework should be applied in cases that involves one of the 15 agents listed in the policy or if it has the potential to result in one of the seven experimental effects listed. This includes enhancements in consequences, resistance, or transmissibility, disrupting immunity, altering the natural host range, or reconstituting an extinct agent. Interestingly, the reference to a “novel pathogen” was dropped between the 2012 and the 2014 versions, but it is still a topic to be taken into consideration. In fact, it is possible for research outside the scope articulated in the policy to still be DURC and require review.
The Institutional Review Entity (IRE) board performs a risk assessment on any research or work done at the institution that is subject to DURC evaluation. The members should have sufficient expertise to assess dual use of a range of scenarios but may also contact consultants as needed. These plans, including mitigations, should be reviewed annually.
There are many points to consider when reviewing the whole lifespan of proposed research for DURC. They can be summarized by looking at how the work will be performed and results communicated, the scope of consequences with countermeasures taken into consideration, the potential timeframe for misuse, and the skill, knowledge, or technology needed to use the product for nefarious purposes. Potential benefits are also an essential aspect of the review. DURC should not be only associated with the unscrupulous application of science. The goal is knowledge or methods that will benefit humanity. If there are risks, it is important to consider if they target a specific population.
Recognizing a risk is present is not necessarily reason to deny the research from proceeding. Risk mitigation can reduce the risk to a level that is acceptable when compared to the potential benefits. These plans may include biosafety, biosecurity, personal protective equipment, standard operating procedures, occupational health plan like vaccines, training, and countermeasures. Institutions may apply varying mitigations as appropriate for each individual situation.
If existing measures are not adequate to mitigate conceivable risk, creating a mitigation plan may be the means to receive funding from a government source. Subsequently ensuring compliance with the plan is essential. One way to encourage this is by the IRE maintaining a positive relationship with the primary investigator and requesting that they report any changes that may alter the evaluation. Another source that may assist in identifying DURC is the institutions’ grant administrators. These mitigation plans may be subject to Freedom of Information Act requests and therefore should not disclose institutional proprietary or security information.
To close the session, dual use case studies were presented and evaluated. This was a learning opportunity to practice what had been taught, but also to experience how subjective interpretations can be. Those same case studies were used to develop risk mitigation plans that would alleviate the most pressing risks while still allowing the research to take place and be submitted for publishing, possibly with some changes.