Potential Risks and Benefits of Gain-of-Function Research Summary of a Workshop (2015) / Chapter Skim
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4 Potential Benefits of Gain-of-Function Research
4 Potential Benefits of Gain-of-Function Research
Pages 29-46
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From page 29... ...
techniques is no different with respect to what it can achieve in the long term, at least according to many of the symposium participants. Atlas noted that, although there was no attempt to achieve a consensus, no disagreement was voiced to the repeated claims of various presenters that in the short term GoF research is helpful for adapting viruses to growth in culture and for developing essential animal models for emerging pathogens, such as Middle East Respiratory Syndrome coronavirus (MERS-CoV)
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From page 30... ...
They also decide whether vaccines or candidate vaccine viruses are needed for emerging zoonotic threats. The national influenza centers conduct viral strain surveillance throughout the year, looking at the genetic information from human as well as emerging zoonotic viruses.
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From page 31... ...
She explained that the risk assessment tool is continually updated to add new information about molecular determinants of virulence and transmissibility. She believes that the more information we have, the better we will be able to predict the risk of a pandemic and then use that prediction to prioritize vaccine strain selections and make the vaccines available.
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From page 32... ...
Russell's work built on earlier work that attempted to predict pandemics. The earlier work from Jamie Lloyd Smith tried to establish a general rule, which is that infection begets transmission and transmission begets epidemics.
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From page 33... ...
Vaccine seed stocks can speed this up, but there are other ratelimiting steps, especially international agreements on the regulation and conduct of human trials. He also believes that the objectives should be to: • prioritize strains with evidence of infection and transmission; • cover antigen space, and monitor antigenic drift; • plug gaps in surveillance; • make more/faster seed stocks (Dormitzer et al., 2013)
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From page 34... ...
But the authors concluded that knowledge of genetic changes in circulating virus isolates by themselves obviously cannot be used to predict the impact of receptor binding specificity, let alone affect the results of future mutations (Stevens et al., 2006)
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From page 35... ...
Donis noted that the risk assessment tool is a product of the global community of scientists working on both human and animal health. It is a product of the realization of the gaps in surveillance that were noted in Fraser's presentation.
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From page 36... ...
The increases in understanding that have been achieved from the work that has been done so far have been helpful. In terms of translating directly into public health improvements, that is a pretty substantial leap to make.
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From page 37... ...
For instance, the Novartis research team routinely screens for phenotypic traits of interest and can specifically remove or mutate strains with either polybasic cleavage sites in the hemagglutinins (HA) (found in highly pathogenic avian influenza viruses [HPAIV]
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From page 38... ...
Importantly for public health implications, data further showed that existing vaccine and human monoclonal antibody therapy failed to protect against these two newly identified bat SL-CoVs, leading Baric to point out that "we are vulnerable" to SL-CoV bat strains that currently exist in nature. The second part of Baric's talk described how robust animal models are essential for vaccine/drug design, safety testing, and performance outcomes.
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From page 39... ...
In lieu of giving examples of how GoF research can influence a process, Weir mentioned a few challenges that still remain in vaccine development for the influenza virus. In general, for the seasonal strain selection and the preparation of pandemic vaccine strains, the major challenge is the existence of very large gaps in our knowledge of how genotype sequences relate to phenotypic changes.
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From page 40... ...
When this ExoN was inactivated, the CoV mutation rate was increased by 20-fold. Normally, mutations allow tremendous variation in viral populations and presumably increase adaptation, fitness, virulence, and therefore public health risks.
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From page 41... ...
Inglesby asked Dormitzer whether the annual process of production of flu vaccine relies on research using highly transmissible and highly virulent strains. Dormitzer responded that this is not the case and that the goal is quite opposite to take a strain found in nature and transform -- it into something that can be manufactured efficiently by increasing its growth rate in cell culture or eggs.
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From page 42... ...
There is potential for GoF research to improve vaccine production, but it is not today except for limited instances; it has long-term potential for this purpose as long as the work can be done without inordinate risk. Denison asked whether any "bad" GoF experiments were performed to discover the polybasic cleavage site associated with high virulence.
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From page 43... ...
He believes that whatever the question asked, whether about replication or virulence and transmissibility, the science should be the same and should follow an iterative process that incorporates risks, milestones, and points to change along the way. As a follow-up from Relman's question on transmissibility in MERS and SARS animal models, Koblentz asked Baric to clarify which set of experiments he would use to study transmissibility.
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From page 44... ...
Denison agreed that on a case-by-case basis, if it is possible, then a safer approach is always preferred, but that it depends on the genetic background of the strain of interest. As an example, Denison explained that sometimes a certain type of loss- or gain-of-function experiment is undertaken on BSL-2 strains that are 90 percent identical to more virulent strains, but that the small genetic background differences and therefore structure can greatly influence the outcome of the experiment.
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From page 45... ...
Baric agreed with those comments and affirmed the importance of reverse genetics and GoF research in understanding viral pathogenesis as well as vaccine and therapeutic design. NIH should be very careful about delineating the boundaries of the restrictions to be placed on the research community because there could be dire consequences if these restrictions are too broad.
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