Preparing for next pandemic, unknown pathogen X

For the first time during an ongoing Lassa fever outbreak, scientists have used rapid, portable genomic sequencing technology to identify viruses without prior knowledge of the cause of disease.

This enabled researchers to allay fears and direct the public health interventions to limit the spread of the virus and help to protect more people from disease.

Also, the technique holds promise for guiding public health response in the event of unknown Pathogen X, that international health organisations predict may be responsible for the next pandemic.

The research, conducted during the 2018 Lassa fever epidemic in Nigeria, was carried out by scientists from Public Health England (PHE) United Kingdom (UK), the Bernhard Nocht Institute for Tropical Medicine (BNITM) Germany and Irrua Specialist Teaching Hospital (ISTH) Nigeria, in collaboration with the Nigeria Centre for Disease Control (NCDC) and the World Health Organisation (WHO), was published in the journal Science on January 4, 2019.

A virus carried in the urine or faeces of infected rats cause Lassa fever. The virus causes fever, weakness, muscle pain and seizures, and is frequently fatal.

Lassa virus occurs endemically in West Africa and while it regularly causes small outbreaks, an outbreak of the virus in the area in early 2018 led to 376 confirmed cases within a few months– more than the combined total for the three previous years.

The sudden upsurge in cases raised concerns that a new, highly transmissible form of the virus had evolved, able to pass from person to person more effectively than previous strains.

In order to better understand the reasons for the heightened number of cases, the NCDC, together with the WHO, commissioned the research team to analyse patient samples to understand if the virus had an increased transmission potential. The research builds on work that was carried out by PHE and BNITM during the 2014-2016 Ebola outbreaks.

The team, working at the ISTH in Irrua, Edo State, used Oxford Nanopore Technology‘s portable device to rapidly sequence the genetic code of 120 virus samples.

Traditionally, genomic assays used in the field-required researchers to look at one genetic marker or virus strain at a time.

However, this time a different approach was used, in combination with DNA sequencing, and known as metagenomics, which enabled the team to test for multiple different variations of Lassa virus genome, which is known to be highly diverse– speeding up the process of identifying the strains responsible for causing illness in this outbreak.

The approach gives insights into the genetic material of an entire virus population at a specific point in time.

The researchers found that the strains in the samples weren’t all closely related, suggesting that there wasn’t a single source of the virus that then spread from person to person. Instead, there were lots of different strains, suggesting multiple different instances of contraction from rodents.

These early, rapid results allowed teams on the ground to continue focusing the public health response on community engagement around rodent control, environmental sanitation and safe food storage rather than shifting to solely focusing on addressing person-to-person spread.

The analysis revealed a great deal of diversity and indicated mixing with Lassa virus strains of the previous year’s outbreaks. “By using this technology to look at the Lassa virus family tree and comparing samples from this outbreak to those from previous years, we were able to exclude human-to-human transmission as the reason for the surge in cases” said Prof. Stephan Günther, head of the Virology Department at BNITM, explaining the results. “Instead, a frequent transmission from animals to humans seems to be the cause of the high case numbers.”

Professor Miles Carroll, Head of Research and Development of the National Infection Service at Public Health England, said: “Viruses are constantly changing, becoming more or less infectious and deadly over time. By studying their genetic code, we can better understand where the virus has come from and how it spreads.”

“Our previous tools to probe viral genomes took over a month to provide insights. Now, we can view results in as little as one day and in a field situation, guiding the public health interventions we deliver and ensuring we can act fast to stop more people becoming ill. Human-to-human transmission of viruses is something we always want to avoid, but in this instance the evidence indicated that we also needed to act in other areas for maximum impact.”

The Chief Medical Director of ISTH, Prof. Sylvanus Okogbenin, said: “The result of the sequencing reassured managing Clinicians in ISTH, the main centre for the diagnosis and treatment of Lassa fever in Nigeria. I would like to congratulate the team for the feat. The institution is very willing to collaborate further to ensure that on-site sequencing is a regular feature of its institute of Lassa fever research and control.”

Chief Executive Officer (CEO) and Director General of NCDC, Dr. Chikwe Ihekweazu, said: “The results from this study, which were made available to NCDC as they became available, were critical in enabling us provide answers to questions during the outbreak and focus response measures appropriately. We are proud that all the sequencing was done onsite in ISTH, and will work with our partners to increase capacity for metagenomics in Nigeria.”

The real-time, portable DNA sequencing technology used in this study has applications beyond Lassa fever.

By being able to look at lots of different pathogen sequences in one go, the technology could be applied to previously unknown pathogens.

This is important because international health agencies have predicted that an unknown ‘Pathogen X’ could cause the next major outbreak.

This new technology has the potential to enable scientists on the ground during an outbreak to rapidly study the pathogen genome without necessarily knowing what it is they are looking for.

The study is titled “Metagenomic Sequencing at the Epicenter of the Nigeria 2018 Lassa fever Outbreak.”

BNITM is Germany’s largest institution for research, services and training in the field of tropical diseases and emerging infections.

The current scientific focus is on malaria, haemorrhagic fever viruses, immunology, epidemiology, clinical research of tropical infections and mechanism of transmission of viruses by mosquitoes.

To study highly pathogenic viruses and infected insects, the institute is equipped with laboratories of the highest biosafety levels (BSL4) and a BSL3 insectary.

BNITM comprises the National Reference Centre for Tropical Pathogens and the WHO Collaborating Centre for Arbovirus and Haemorrhagic Fever Reference and Research.

Together with the Ghanaian Ministry of Health and the University of Kumasi, it runs a modern research and training centre in the West African rainforest, which is also available to external research groups.

Meanwhile, the NCDC and its partners will host the first Lassa Fever International Conference between January 16 and 17, 2019 in Abuja. This is to mark fifty years since the Lassa fever virus was first isolated, in a town in Nigeria.

The opportunity created by the ‘anniversary’ of the discovery of the virus, is being used to bring researchers and practitioners from across the world together, to share and appraise global efforts towards the control of the Lassa fever virus disease.

Plenary speakers at the conference include the Executive Governor of Nassarawa State – H.E. Umar Tanko Almakura, Chair National Lassa fever Steering Committee Nigeria – Professor Oyewale Tomori, Chief Medical Director Irrua Specialist Teaching Hospital Nigeria – Prof. Sylvanus Okogbenin, Technical Team Lead National Lassa Fever Working Group – Mrs. Elsie Ilori, Team lead – VHF World Health Organization (WHO) – Dr. Pierre Formenty, Head of Virology Bernard Nocht Institute for Tropical Medicine Germany – Prof. Stephan Gunther, Head of Virology Noguchi Memorial Institute for Medical Research University of Ghana Accra – Prof. William Kwabena Ampofo, Director UK Public Health Rapid Support Team – Prof. Daniel Bausch, Team Leader for Implementation Research Initiative for Vaccine Research WHO – Dr. Ana Maria Henao Restrepo, Director Africa Centre of Excellence for Genomics of Infectious Diseases Redeemers University – Prof. Christian Happi, and Chief Executive Officer of the Coalition for Epidemic Preparedness Innovations (CEPI) – Richard J. Hatchett, MD.

The first Lassa Fever International Conference is also an opportunity to increase global health focus on the disease, which is found mostly in West Africa.

Sierra Leone, Benin Republic, Liberia, Nigeria and Guinea continue to record cases and deaths from Lassa fever annually. As awareness and disease surveillance systems improve across these countries, mores cases are being detected.

This has created an increased sense of urgency for the global health community to do more through better prevention, disease detection, control and case management efforts.

In 2018, the World Health Organization launched its Research and Development blueprint, highlighting the potential of Lassa fever and a selected list of diseases to lead to public health emergencies.

This plan highlights the absence of efficacious drugs and/or vaccines, and further highlights the urgent need for accelerated research and development.

At the Lassa Fever International Conference, a global audience will learn about efforts towards new strategies to prevent transmission of the virus from rodents to human, new approaches to mitigating hospital transmission of the disease as well as new insights into the social context of Lassa transmission.

Current efforts on new Lassa fever vaccines, therapeutics and clinical treatment approaches will also be key highlights at the conference.

To prepare for the conference, NCDC called for scientific efforts into prevention, detection and control efforts to be showcased at the conference. This yielded over 500 abstracts from which 160 top quality papers were selected. In addition, travel scholarships were granted to 80 researchers from across Nigeria and West Africa.

The Lassa Fever International Conference brings stakeholders together for a meeting full of learning and exchange of ideas. With this, NCDC will work with partners to develop a strong reform agenda for Lassa fever control in Nigeria and globally.