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A report to the Director-General of WHO

The Independent Advisory Group on

Public Health Implications of Synthetic

Biology Technology Related to Smallpox

Geneva, Switzerland

29-30 June 2015

WHO/HSE/PED/2015.1

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Independent Advisory Group on Public Health Implications of Synthetic Biology Technology Related to Smallpox

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Contents

Executive summary ....................................................................................................... 5

Purpose .........................................................................................................................................................5

Background ...................................................................................................................................................5

Methodology ..................................................................................................................................................5

Implications ....................................................................................................................................................5

1. Background ............................................................................................................. 7

1.1 Objectives and process of the consultation ...........................................................................................7

1.2 Overview of smallpox .............................................................................................................................7

1.3 Report of the Scientific Working Group .................................................................................................8

2. Independent Advisory Group discussions ........................................................... 9

2.1 Methodology of scenario-based discussions .........................................................................................9

2.2 Discussion of the scenarios ...................................................................................................................9

2.2.1 Scenario 1: A remote area in a developing country ........................................................................... 9

2.2.2 Scenario 2: A densely populated city............................................................................................... 10

2.2.3 Scenario 3: A laboratory accident .................................................................................................... 10

2.2.4 Scenario 4: Individuals inject themselves with synthesized variola virus ........................................ 11

3. Implications ........................................................................................................... 12

3.1 Risk of smallpox .................................................................................................................................. 12

3.2 Implications for preparedness............................................................................................................. 12

3.3 Implications for research ..................................................................................................................... 13

4. Way forward........................................................................................................... 14

Annexes........................................................................................................................ 15

Annex 1. List of participants ....................................................................................................................... 15

Annex 2. Agenda ........................................................................................................................................ 16

Annex 3. Report of the Scientific Working Group Meeting on Synthetic Biology and Variola Virus

and Smallpox .............................................................................................................................. 17

Independent Advisory Group on Public Health Implications of Synthetic Biology Technology Related to Smallpox

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Independent Advisory Group on Public Health Implications of Synthetic Biology Technology Related to Smallpox

SUU, Alm.del - 2016-17 - Bilag 336: Henvendelse af 18/5-17 fra Bavarian Nordic vedr. det danske biologiske beredskab

Executive summary

Purpose

The purpose of the meeting was to provide guidance to the WHO Director-General on the public health

implications of synthetic biology technology as it relates to public health measures for smallpox preparedness

and control. The public health implications are for countries and for WHO, and include diagnostics, vaccines

and medicines and research related to the variola virus.

Background

At the Sixty-seventh World Health Assembly in May 2014, WHO was requested to undertake a consultation on

the use and potential impact of technologies for synthetic biology on smallpox preparedness and control, in

order to further inform the World Health Assembly in its discussions on the timing of the destruction of existing

variola virus stocks. As part of this consultative process a group of experts, the Independent Advisory Group

(IAG) on Public Health Implications of Synthetic Biology Technology Related to Smallpox, was convened at the

end of June 2015 in order to provide an assessment to the Director-General.

Prior to the meeting of the IAG, a Scientific Working Group (SWG) on Synthetic Biology and Variola Virus and

Smallpox was convened on 1617 April 2015 to review the evidence and inform the deliberations of the IAG.

The SWG addressed relevant scientific and technical questions around the re-creation of variola virus; the risks

and benefits of synthetic biology for variola virus research; and the guidance required from WHO regarding

distribution and handling of live variola virus maintained at the two designated WHO collaborating centres that

are authorized repositories of variola virus. The conclusions of the SWG were as follows:

“With the rapid advances in synthetic biology, there is now the

capability to recreate the variola virus, the

causative agent of smallpox. While recreating variola is quite complex, it is increasingly possible due to the

availability of genetic material and of machines for complex assembly, as well as increasing know-how

among a broad array of persons. Furthermore, the rapid rise in availability of genetic material from

commercial sources and the so-called

“grey market” is driving the cost of this material down, making

recreation

possible by multiple institutions and persons, including those with malicious intent. The “WHO

Recommendations concerning the distribution, handling and synthesis of variola virus DNA” should be

revised. Consideration should be given to adding a component or separate document on guidance to

commercial DNA providers for screening requests for DNA fragments.

With the development of these technologies, public health agencies have to be aware that henceforth there

will always be the potential to recreate variola virus, and therefore the risk of smallpox re-emerging can

never be fully eradicated.”

Methodology

A scenario approach was chosen to foster discussion and debate on the implications of synthetic biology

among the members of the IAG. They were expected neither to comment on the likelihood of occurrence of the

scenarios nor to provide solutions or recommendations for them; rather the aim was to have illustrative events

to frame and guide the discussions.

The four scenarios described the following situations and were followed by discussions on the question of the

impact of synthetic biology on controlling the emergence of smallpox disease.



Scenario 1: the emergence of smallpox-like disease in a remote area in a developing country.

Scenario 2: the emergence of smallpox-like disease in a densely populated city.

Scenario 3: the emergence of smallpox-like disease following a laboratory accident.

Scenario 4: a situation in which a group of individuals inject themselves with synthesized variola virus.

Implications

Before synthetic biology was possible, two potential situations for re-emergence existed: (1) natural re-

emergence (e.g. by mutation of another poxvirus), and/or (2) a laboratory release (deliberate or accidental)

from one of the two WHO variola virus repositories or from unknown locations.

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Therefore, the risk of re-emergence is not new. However, it has increased as synthetic biology technologies to

recreate, and even modify, the virus continue to become cheaper and more easily accessible. Even if the live

virus stocks are destroyed, the act of destruction is not irrevocable.

Given that the risk has changed, the key questions facing the world now are:



Is the world prepared for this additional risk? If not, what should be done to become sufficiently

prepared?

What are the implications for (1) public health preparedness for re-emergence and (2) research around

this new risk?

Does the new, additional risk change the parameters of the discussion for the destruction of the variola

virus in the two repositories?

Based on recent reviews of the public health responses to the H1N1 pandemic and to the Ebola outbreak,

there is recognition of fundamental gaps in several areas of preparedness for any emerging disease outbreak,

including smallpox. Risk reduction strategies and preparedness need to be adapted to take into account this

new risk from synthetic biology in addition to the core capacities already required under the International Health

Regulations 2005 (IHR 2005), including:



Increased capacity for early detection and diagnostics:

clinical capacity to recognize and treat

smallpox; laboratory capacity, particularly at local level; development of simple diagnostic tests.

Increased capacity for disease control:

anticipation and preparedness of requirements for public

health countermeasures such as vaccines and antivirals; supplies and quantities of vaccines and

drugs needed for different scenarios; global expertise in specific epidemic diseases such as smallpox.

Increased biosecurity:

revised regulations for research on DNA fragments of variola virus and

synthesis of variola virus DNA by new technologic approaches;; increased biosafety and biosecurity in

laboratories, including stock inventories; strengthened regulatory frameworks and their

implementation; coordination between sectors including health, judiciary, law enforcement and

customs.

More effective risk communication:

acknowledgement of risk in the context of other infectious risks;

transparency regarding dangers and measures to prevent and avoid them; avoidance of attempts to

mislead the public; tracking of and responding to rumours; community engagement to detect and

manage disease and to assist in information sharing.



Synthetic biology goes beyond smallpox and should be considered in relation to the elimination and eradication

of other infectious diseases as well.

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1. Background

1.1 Objectives and process of the consultation

The Independent Advisory Group (IAG) on Public Health Implications of Synthetic Biology Technology Related

to Smallpox met at WHO headquarters on 2930 June 2015. The purpose of the meeting was to provide

guidance to WHO’s Director-General

on the public health implications of synthetic biology technology, as

related to public health smallpox preparedness and control. The implications reviewed were for countries and

for WHO, including diagnostics, vaccines and medicines and research related to the variola virus. The agenda

of the meeting is contained in Annex 1. A list of the members of the Independent Advisory Group and of the

resource persons who attended the meeting is contained in Annex 2.

The meeting was opened by Dr Keiji Fukuda who welcomed the participants. Dr Fukuda stressed the

importance of the meeting, noting that the matters to be discussed would be significant not only for smallpox

but also for other issues. Although the disease smallpox had been eradicated, Dr Fukuda noted that the virus

still exists in research laboratories. In addition, with the development of synthetic biology the recreation of

variola virus has become a possibility. He pointed out that the issue of the timing of the destruction of the

variola virus is a matter for discussion by WHO Member States.

The topic was being addressed because the World Health Assembly in 2014 had asked about the significance

of synthetic virology in relation to smallpox. The Director-General

would respond to the Health Assembly’s

question and the meeting of the Independent Advisory Group would be a major part of preparing that response.

The Director-General would consider the advice given by the IAG and would decide how to disseminate the

report.

The meeting was attended by members of the IAG as well as four internationally renowned experts on variola

virus and smallpox. All participants were asked to treat the discussions as confidential.

1.2 Overview of smallpox

Dr Sylvie Briand gave an introduction to smallpox disease which has been a cause of fear for centuries and for

which the first ever

vaccine was developed in 1796. WHO’s smallpox eradication

programme was started in

1966, and the last natural case of the disease was reported in 1977 in Somalia. The World Health Assembly

declared smallpox eradicated in 1980. However, the variola virus has not been eradicated, as it was decided at

that time to maintain stocks in the Soviet Union and the United States. The live virus is today maintained at two

WHO Collaborating Centres: the Centres for Disease Control and Prevention, Atlanta, USA (CDC), and the

State Research Centre of Virology and Biotechnology, Novosibirsk, Russian Federation (VECTOR).

Humans were the only reservoir for the disease. The disease course has a long incubation period of 717

days. People are infectious only from the onset of rash and remain infectious until disappearance of the last

scab. Transmission is through large and small particle aerosols, and direct contact with body fluids. The

disease is also spread by fomites. In its last decades the disease was chiefly spread in households and health-

care settings. In a susceptible population the average number of cases of smallpox generated by an infected

person is 36 (while for measles it is 1218).

The symptoms of the disease can be confused with other diseases such as monkeypox and even chickenpox.

Various vaccines and diagnostics are available, and antivirals are being developed. In addition there is VIG

(Vaccinia Immune Globulin) which is made from the blood of individuals who have been vaccinated with the

smallpox vaccine. Given the research of recent decades there are more interventions available now than there

were in the pre-eradication period.

During the Smallpox Eradication Programme, the vaccine used had serious adverse reactions (5-10 in one

million vaccinees), and 1-2 in one million died. However, vaccination was carried out because the risk from the

vaccine was less than the risk from the disease. Today the vaccine could not be used in certain populations,

such as persons with HIV. Although attenuated, safer vaccines are available, there is uncertainty about their

effectiveness and safety in mass campaigns.

It is highly likely that an outbreak of smallpox will lead to similar challenges to those posed by the recent Ebola

outbreak in West Africa or MERS-CoV outbreak in the Republic of Korea. Major priorities in such an outbreak

would be fear management, risk communication and community engagement to promote compliance with

control measures and reduction of stigma. If several countries are infected there will need to be rapid delivery

of vaccines, and countries would be expected to want more than they need. The global emergency stockpile of

smallpox vaccine is 2.4 million doses in Switzerland, plus 32 million doses donated and available in other

countries. The overall quantity of vaccine available is estimated to be around 700 million doses. There is a lack

of clarity about the length of immunity after vaccination, and the only certain lifetime protection comes from

having already had smallpox once.

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The main concern in an outbreak of smallpox would be that no one under 40 years of age (around 3.6 billion

people) has been vaccinated, thus leading to an increasingly susceptible population. There would be delays in

diagnosis since the disease is unknown by many health workers, and a global panic can be anticipated even

with only a small number of cases.

There would be a major economic impact

–

the 2015 outbreak of Middle East Respiratory Syndrome

Coronavirus (MERS-CoV) in the Republic of Korea is estimated to have cost the Korean economy many

billions of dollars. .

Meeting participants noted that little is known about potential hidden stocks of variola viruses. At the same

time, the development of synthetic biology reduces our confidence in eradication. If the disease were to

reappear, whether naturally or due to a synthetic virus, we would have 14 days (maximum incubation period) to

vaccinate contacts. However, given the intensity of international travel, the disease would potentially spread

rapidly and, since health systems in developing countries are often under-resourced, delays in diagnostics can

be anticipated.

1.3 Report of the Scientific Working Group

In April 2015 WHO convened a meeting of a Scientific Working Group (SWG) on Synthetic Biology and Variola

Virus and Smallpox. The report of the SWG, which was presented to the Independent Advisory Group by

Professor Geoffrey Smith, is attached as Annex 3. The aim of the SWG was to provide scientific background

information on synthetic biology technology with regard to the variola virus.

The SWG concluded that, with the increasing availability of DNA fragments that can be synthesized from

simple chemicals, it would be possible to recreate variola virus, and that this could be done by a skilled

laboratory technician or by undergraduate students working with viruses in a relatively simple laboratory. To

recreate the variola virus by synthesizing the DNA and then relinking the parts is theoretically possible but is

considered to be highly unlikely to happen accidentally since the variola genome is large and complex. It was

therefore felt that synthesis would require a deliberate and sustained effort.

Over 45 genomes of the variola virus have been sequenced and the sequence is in the public domain, and

other orthopox viruses (which have similar DNA) have been recreated. Recreating variola virus is prohibited by

under the World Health Assembly (WHA) resolutions, though anyone trying to do this may not know or care

about WHO’s rules.

Someone recreating the virus could, either by accident or deliberately, introduce elements

to enhance its virulence or make it resistant to existing medicines and vaccines.

The SWG noted that, although a recreated variola virus could be useful for research on vaccines and

diagnostic tests, there are serious concerns regarding modifications of the virus by institutions or individuals

with malicious intent. Members of the SWG concluded that the WHO recommendations concerning the

distribution, handling and synthesis of variola virus DNA should be revised. Additionally, consideration should

be given to the addition of a component or separate document on guidance to commercial DNA providers

regarding screening of requests for DNA fragments. The SWG further concluded that, given the ability to

recreate the variola virus using synthetic biology techniques, the destruction of the remaining stocks of variola

virus at the two WHO Collaborating Centres would not irrevocably destroy the virus. After destruction of the

stocks, the variola virus could still be recreated.

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2. Independent Advisory Group discussions

2.1 Methodology of scenario-based discussions

A scenario approach was used to foster discussion among the members of the IAG on the impact of synthetic

biology on smallpox preparedness and control. Participants were asked to discuss what would be the

implications of synthetic biology in the following fictional scenarios, where the re-emergence of smallpox would

be suspected.



Scenario 1 described the emergence of smallpox-like disease in a remote area in a developing

country.

Scenario 2 described the emergence of smallpox-like disease in a densely populated city.

Scenario 3 described the emergence of smallpox-like disease following a laboratory accident.

Scenario 4 described a situation in which a group of individuals inject themselves with synthesized

variola virus.



The purpose of discussions was not to comment on the likelihood of each scenario happening, but rather to

focus on what would be likely to happen if such a situation occurred and the role of synthetic biology. The

ensuing discussion for each scenario is summarized in the next section.

2.2 Discussion of the scenarios

2.2.1 Scenario 1: A remote area in a developing country

Summary



Challenges in recognizing the clinical symptoms of the disease.



Challenges in laboratory diagnosis and confirmation (at least 8 weeks) requiring a reference

laboratory.



Limited use of synthetic biology for the rapid development of control measures.

Members of the IAG agreed that the emergence of smallpox in a remote area in a developing country raised a

number of specific issues related to the poor state of the health system and the remoteness of the event.

Remoteness meant that the virus was unlikely to spread as rapidly as in an urban environment, and could

probably be contained in the area without international spread. However, it would also delay the arrival of

outbreak investigators to the area and, once there, they may not suspect smallpox. Local laboratories would

have no possibility to diagnose the disease. A national reference laboratory would find it was a poxvirus but this

was likely to mislead the authorities into thinking it was monkeypox or another poxvirus. Monkeypox is endemic

in the Democratic Republic of the Congo and appears to be increasing; it probably also exists in other tropical

countries. Only after a WHO collaborating centre examined samples would it be possible to identify smallpox,

by which time almost eight weeks would have passed.

Possible solutions in this scenario could include mobile telephone apps that recognize the nature of disease

from a photograph, or dipstick-like diagnostics. The latter are already being developed by CDC to be orthopox-

sensitive and variola-specific.

It was felt that most public health laboratories in Africa would be able to identify a virus as an orthopox, but a

reference laboratory would be required to identify variola.

It would be beneficial to have a reference standard against which to measure a circulating virus; thus, if there

was no live variola virus in the repositories, a new one could be created as a reference using synthetic biology.

However, this would take months or years with the current technologies. One could use only the new isolate,

which would be quicker, but this would not provide the same level of certainty.

A possible solution discussed by the IAG would be to supply the live variola virus to local or regional reference

laboratories to help in diagnosis. However, it was acknowledged that this requires consideration of the risk of

unintentional or intentional release of the virus relative to required biosafety and biosecurity measures for a

virus which has been kept under tight security since 1980.

The general opinion was that synthetic biology has had little impact on the work of the collaborating centres on

variola virus. Synthetic biology has been used partly to develop some of the proteins on the surface of the

virus. If a new strain of variola virus with different characteristic than the current live variola virus were

developed and released, it is highly unlikely that synthetic biology could be used to develop an effective

vaccine quickly.

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2.2.2 Scenario 2: A densely populated city

Summary



Transmission will be faster in densely populated areas and contact tracing will be extremely

difficult.



Rapid scale-up of laboratory diagnostic capacity will be required in many places in the case

of re-emergence.

The IAG again raised the issue of the capability of the health system to detect the virus, coupled again with

delays in identification due to a complete lack of familiarity with it. After all, no one looks for an illness that has

been eradicated. The crowded environment in a city increases the chance of spread, and the fact that patients

can easily visit several doctors and hospitals also increases the risk of further infections. Contract tracing would

be a major undertaking. While persons with infectious smallpox are usually so sick that they will not travel, the

fact that the cities are usually close to ports and/or airports, means that the chance of spread to other areas

and countries is enhanced.

While this scenario had a shorter timeline from detection to diagnosis than the first one, the scale of potential

infection is also much greater. Some members felt, however, that making the diagnosis of smallpox within 20

days would be very optimistic, as the likelihood would be that a zoonotic illness would be suspected and

searching for this would take time. On the issue of diagnosis, the view was expressed that, if we know we are

not able to eliminate the risk of smallpox definitely, we should not destroy the tools and experience we have,

and hands-on experience will be very important, at least for the next 30 years. However, a contrary view was

that there will continue to be a great deal of genetic research in the coming years and much of this will apply to

variola virus, so expertise in this area is likely to increase rather than diminish.

Asked how viable it would be for the collaborating centres to supply primers to laboratories elsewhere at the

request of WHO, VECTOR said it would send the primers and assay kits within a week. CDC noted it would

take longer due to approvals but they would do it, and they would want to do proficiency testing to ensure that

the primers work in a different environment.

2.2.3 Scenario 3: A laboratory accident

Summary



A laboratory accident is always possible but the risk can be minimized by training of

laboratory staff and strict application of biosecurity norms.



The risk of accident is higher in illicit and unregulated laboratories.

In this scenario of a laboratory accident, it was noted that a national microbiological institute should not

possess variola virus. In a recent case (US National Institutes of Health (NIH), USA 2014), where unlabelled

vials of variola virus were discovered, the contents were presumably thought to be old, but safe, material. In

that situation it was fortunate that the person who handled the vials did so carefully and according to training,

and appropriate biosafety procedures were followed upon discovery. In the USA the discovery of these old

variola vials led to NIH, CDC and others carrying out a full stocktake and catalogue of all stored materials.

Members of the IAG said the scenario showed the need for training and strict compliance with procedures to

avoid such an accident. However, it was felt that this kind of accident is always possible

–

not only in amateur

laboratories but even in high-level ones. Procedures would probably be much less strict in a laboratory doing

illicit research with variola virus

Some members felt that in the first three scenarios it was astonishing that someone would ever consider that

the cause might be a poxvirus. In reality, it would generally take a very long time to come to that conclusion. It

was also noted that to distinguish a natural virus from a newly recreated one would require genome sequence

determination and comparison, and if these were identical, the viruses could not be distinguished.

Asked the question whether, if all the current samples were destroyed, they could be recreated after

destruction of the originals, both CDC and VECTOR replied that WHO recommendations prohibit them from

doing so. Not all samples have been sequenced so a number of them could not be recreated anyway, though

CDC reported it had been asked to sequence all samples and had partly done so. Professor Smith said there

was no need to work with the live variola virus in order to be able to respond to a future possible smallpox

outbreak. One could use other orthopox viruses to maintain this skill set in a trained staff under containment

conditions.

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2.2.4 Scenario 4: Individuals inject themselves with synthesized variola virus

Summary



Re-emergence of smallpox will create fear and panic which can have an impact far worse

than that of the disease itself.



Rapid confirmation of suspected cases will be essential; thus the rapid increase of

diagnostic capacity will be critical.

In this scenario, the IAG felt that the major issue to be faced was widespread fear and panic. Services would

soon be overwhelmed and emergency stocks of vaccines would be insufficient.

Advisory Group members were agreed that this was a nightmare scenario that would go beyond the health

sector and would be an issue of the highest order in every country. There would be insufficient vaccines, test

kits, capacity and everything else, and the widespread public panic would be complicated by politics.

Communication is important, but the entire system of communication would likely be disrupted. Rumours would

spread on social media and the authorities would spend their time responding to problems rather than

anticipating and preparing for them.

As for research and diagnostic capacity, CDC has five persons working on live variola virus and some others

who are trained to do so; through the various US services, diagnostic capacity could be scaled up fairly quickly.

However, in this scenario, it could be possible, if WHO so decided and Member States were in agreement, to

downgrade the pathogen to Biosecurity Level 3 so that many more laboratories could be allowed to work on

diagnosis. VECTOR reported having only a few persons trained to work on the live virus. In general there is a

need for laboratory surge capacity that would need to be addressed.

The WHO stockpile of smallpox vaccine would, as in the case of other vaccines, be available within a week. It

was noted that SAGE (Strategic Advisory Group of Experts on Immunization) judged that vaccination would be

targeted to specific groups and not the entire population. Ensuring equitable and timely access to suitable

medical interventions would be challenging in the case of very high demand. One expert mentioned that

sanctions in Iran prevented the country from purchasing reference kits or other equipment for diagnostics, thus

reducing preparedness capacity.

In a more general discussion, members of the IAG commented that the maintenance of the virus stocks after

1980 had led to today’s

situation in which the virus DNA has been sequenced and the sequence has been

published. Consequently, as the SWG concluded, even if the virus stocks are destroyed today, the virus could

potentially be recreated.

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3. Implications

3.1 Risk of smallpox

Much of the discussion focused on the issue of risk. The nature of the risk of smallpox re-emergence has

changed significantly over the past several decades. The IAG concluded that:



The risk of variola virus re-emerging from natural sources is not likely to be greater today than in 1980,

though it cannot be excluded.

Following the eradication of smallpox in 1980, the risk of the disease re-emerging is likely to be from

accidental or deliberate release of the virus from one or both of the two repositories or from other

unknown locations.

Additionally, the variola virus can now be recreated with synthetic biology and even modified. Many

facilities worldwide

–

including some poorly regulated or unregulated laboratories

–

are thought to have

the knowledge and expertise to do this. The nature of risk is evolving and is linked to the reduced cost

of technology and ease of access to use it.

3.2 Implications for preparedness

Given the evolution in the risk from variola virus, the IAG concluded that preparedness and response must also

change and that strategies are needed for risk reduction.

In theory smallpox is easy to control. However, experience has taught us that the control of epidemic diseases

and the implementation of simple measures such as infection prevention and control can be challenging. In

addition, the element of fear leads people to behave in irrational ways.

Emphasizing the importance of the core capacities required by the International Health Regulations (2005), the

IAG agreed that smallpox risk reduction strategies should include:



Increased capacity for early detection

−

increased clinical capacity to recognize and treat smallpox (e.g. develop and disseminate mobile

telephone applications for photo recognition of skin diseases);

−

increased laboratory capacity, particularly at local level;

−

simple rapid diagnostic tests (such as dipstick diagnostics) for countries with low diagnostic

capacity.

Increased capacity for disease control

−

more public health countermeasures such as vaccines and antivirals;

−

reconsideration of the quantity of vaccines, diagnostics and antivirals likely to be needed in

different scenarios; and

−

increased global preparedness against specific epidemic diseases such as smallpox.

Increased biosecurity

−

revised regulations for research on DNA fragments of variola virus;

−

increased biosafety and biosecurity in all laboratories, including regular inventories of stocks;

−

strengthening of existing regulatory frameworks to ensure that they are applied correctly; and

−

coordination between sectors such as health, judiciary, law enforcement and the customs service.

More effective risk communication

−

risk communication that acknowledges risk honestly, but puts it into perspective in comparison

with other infectious risks;

−

transparency regarding dangers and what is being done to avoid or protect against them;

−

avoidance of attempts to mislead the public;

−

tracking of rumours (especially on social media) and responding to them quickly with factual

information; and

−

community engagement in support of activities to detect and manage disease and to assist in

sharing information.



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3.3 Implications for research

A summary of the work of the WHO Advisory Committee on Variola Virus Research (ACVVR) was presented

by its chair, Professor Geoffrey Smith of the University of Cambridge. After the declaration of smallpox

eradication in 1980, the WHO Ad Hoc Committee on Orthopox Virus Infections recommended that live variola

virus stocks should be destroyed. This resolution was passed by the World Health Assembly in 1996 and

destruction was set for 1999. However, destruction was postponed so that essential research for public health

benefit could be undertaken, under the oversight of the WHO ACVVR. There are only two WHO‐sanctioned

repositories of live variola virus in the world, CDC and VECTOR. Besides undertaking research with live variola

virus, these institutions provide fragments of the virus to other laboratories that are governed by WHA

resolutions. Reports of the ACVVR are provided regularly

to WHO’s governing bodies.

The research conducted under the auspices of the ACVVR has special importance. A number of IAG members

urged that the research scope and terms of reference of the ACVVR should be reviewed to ensure that they

take account of the new situation. They should also potentially be enlarged to include research on the efficacy

of current vaccines and resistance to antivirals, biosafety and biosecurity, forensics in case of an outbreak, and

scientific survey/monitoring. Professor Smith responded that any proposals for further research should be

specific rather than general, and that the ACVVR scope is already sufficiently broad to take account of these

issues.

WHO’s recommendations on research with the live variola virus should be strengthened

and given more

emphasis. Some members even suggested that the recommendations against unauthorized use should be

backed by sanctions. The IAG felt it was unlikely that any WHO Member State has adopted laws on the basis

of the WHO recommendations so there is no effective sanction if they are contravened. Many persons in

laboratories around the world may not even know of these recommendations.

There should be consideration of whether the risk of a smallpox outbreak is reduced by limiting variola

research to only the two specialized WHO collaborating centre laboratories or whether risk would be further

reduced by permitting live variola virus research in more laboratories. This would require increasing expertise

and capacities, in addition to instituting appropriate regulations and regulatory mechanisms, especially by

national authorities.

Some members felt that, despite the presence of resource persons, there was a lack of clarity regarding the

types of research activities that require the live virus (i.e. in the WHO collaborating centres) and what activities

can be done elsewhere or with non-live virus or DNA fragments. All variola research so far has been on the live

virus or DNA fragments, so if we are to move to recommending research without the live virus we need to

understand what this would involve and what the risks are.

Key points



Adapted rules and regulations for manipulating and synthesizing variola virus genomes are

necessary.



There should be consideration of future research models, including the number of research sites

and expertise development at global level.



National public health laws should back WHO’s

recommendations concerning the distribution,

handling and synthesis of variola virus DNA.

Independent Advisory Group on Public Health Implications of Synthetic Biology Technology Related to Smallpox

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4. Way forward

Recognizing that the risk of smallpox re-emergence has increased with the low cost and widespread availability

of technology to synthesize genomes, the IAG concluded that the WHO recommendations concerning

synthesis and use of variola virus DNA fragments should be revised urgently.

The impact of synthetic biology goes beyond smallpox and could (some members felt “should”) be considered

in relation to the eradication or elimination of other infectious diseases. Several members argued that, if there

was a refusal to destroy the variola virus, there would be no destruction of any dangerous pathogen in the

future. There was a call for a common policy for all diseases slated for eradication.

A comment was made that the history of epidemics shows that they are usually shaped by human activity

–

such as trade, travel, colonization, population movements etc. Synthetic biology is a new human activity and

may result in its own spate of epidemics.

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Annexes

Annex 1. List of participants

ADVISERS

Dr Marc Sprenger (Chair)

Principal Advisor Dutch Government

Ministry of Interior and Kingdom Relations

Saltsjobaden, Stockholm

SWEDEN

Dr Maryam Abousaber

Expert On Biologicals

Food and Drug Organization

Ministry of Health and Education

Tehran

ISLAMIC REPUBLIC OF IRAN

Dr Clarissa Damaso

Head, Virus Laboratory Biophysics Institute

Federal University of Rio de Janeiro

Rio de Janeiro

BRAZIL

Prof. Lawrence O. Gostin

University Professor

Founding O'Neill Chair in Global Health Law

Georgetown Law

Washington, DC

UNITED STATES OF AMERICA

Prof. Mohammed Hassar

Clinical Pharmacologist and Director Emeritus

Institut Pasteur du Maroc

Rabat

MOROCCO

Prof. Didier Houssin

Président du Haut Conseil de l’évalutation de la

recherché et de l’enseignement

supérieur (HCERES)

Président du Conseil d’administration de l’Agence

Nationale de sécurité sanitaire

de l’alimentation, de

l’environnement et du travail (ANSES)

Paris

FRANCE

Prof. Jean-Jacques Muyembe-Tamfum

Director

Institut National de Recherche Bio-Médicale (INRB)

Kinshasa

DEMOCRATIC REPUBLIC OF THE CONGO

Prof. Li Ruan

Professor

Biotech Center for Viral Disease Emergency

National Institute for Viral Disease Control and

Prevention

Chinese Center for Disease Control and Prevention

Beijing

CHINA

Dr Amadou Alpha Sall

Institut Pasteur de Dakar

Dakar

SENEGAL

Dr Lars Schaade

Vice President

Head of the Centre for Biological Threats and Special

Pathogens

Robert Koch Institute

Berlin

GERMANY

RESOURCE PERSONS

Prof. Mark Buller

Molecular Microbiology & Immunology

Saint Louis University School of Medicine

St. Louis

UNITED STATES OF AMERICA

Dr Inger K. Damon

Director

Division of High Consequence Pathogens and

Pathology

United States Centers for Disease Control and

Prevention

Atlanta

UNITED STATES OF AMERICA

Dr Rinat Maksiutov

Head

Diagnostics Laboratory on Smallpox Virus

State Research Center of Virology (SRC VB VECTOR)

Koltsovo, Novosibirsk

RUSSIAN FEDERATION

Prof. Geoffrey L. Smith

Wellcome Trust Principal Research Fellow

Head, Department of Pathology

University of Cambridge

Cambridge

UNITED KINGDOM

WHO STAFF

Dr Keiji Fukuda,

ADG/HSE

Dr Sylvie Briand,

Director, PED

Mr Alejandro Costa,

Scientist, PED/CED

Ms Ramesh Shademani,

Senior Project Lead, PED

Ms Anaïs Legand,

Technical Officer, PED

Mr David Bramley,

Rapporteur, PED/CED

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Annex 2. Agenda

Consultation on the Public Health Implications

of Synthetic Biology Technology Related to Smallpox

2930 June 2015, World Health Organization, Geneva

Day 1, 29 June 2015

9:00

–

9:30

Introduction of members

Context and purpose of the consultation

Nomination of the Chair

Approval of the agenda

Dr K. Fukuda, WHO

9:30

–

9:35

–

10:45

Declaration of Interests

Ms R. Shademani, WHO

Session 1: Current situation

- Overview of key concerns and issues including

Dr S. Briand, WHO

current approaches to preparedness and control

(10 min)

Prof G. Smith, Chair of SWG

- Summary of the Scientific Working Group (SWG)

report (10 min)

- Discussion

Coffee break

Session 2

- Scenario-based discussion of implications of

synthetic biology

Lunch

Session 2 - continued

- Continued discussion

Coffee break

Continued discussion related to research