First-ever safe, effective vaccine against Lassa fever

*NCDC, Innovative Biotech, Medigen others plan human clinical trials in Nigeria, says licensed product will be available by 2022
*Company sets 24 months timeline to manufacture as promising immunisations for diseases in poor countries are going to waste
Although Lassa fever has killed over 500 Nigerians and afflicted more than 5,000 in the last thirteen months, there is no licensed vaccine for the haemorrhagic fever in the world.Viral haemorrhagic fever is a general term for a severe illness, sometimes associated with bleeding, that may be caused by a number of viruses. Haemorrhagic fevers are viral infections; important examples are Ebola and Marburg haemorrhagic fevers, Crimean–Congo haemorrhagic fever (CCHF), Rift Valley fever (RVF), Lassa fever, Hantavirus diseases, dengue and yellow fever.

Lassa fever is endemic in Benin, Ghana, Guinea, Liberia, Mali, Sierra Leone, and Nigeria, but probably exists in other West African countries as well; annual outbreaks in several of these countries are usual.It is estimated that Lassa virus causes about 100,000 to 300,000 infections each year across West Africa and leading to more than 5,000 deaths. However, the burden of the disease is probably much higher than the current figures for Lassa fever cases and deaths.

However, scientists have developed the first-ever live ML29 vaccine that is safe and effective against Lassa fever in Nigeria and has advantages for containing outbreaks and large-scale epidemics of the virus.

The breakthrough study was presented last week at the first-ever Lassa Fever International Conference to celebrate the 50th anniversary of the discovery of the first case of the virus in Lassa, Borno State, tagged: “Rising To The Challenge.”The Nigeria Centre for Disease Control (NCDC) Abuja organized the conference.

The study is titled “Development of safe and effective Vaccine against Lassa Fever in Africa.” The researchers include: Simon Agwale of Innovative Biotech Nigeria; Igor Lukashevich of University of Louisville Kentucky, United States (U.S.); and Peter Pushko of Medigen Incorporated, US.

The lead researcher, Agwale, who presented the findings said plans are underway to manufacture Current Good Manufacturing Practice (cGMP) vaccine product and to launch a phase I clinical trial in Nigeria and in the US in partnership with the US and the Nigerian institutions.He said successful clinical development of this vaccine in Nigeria would result in the first vaccine against Lassa fever in the world.

Agwale, who is the Chief Executive Officer (CEO) of Innovative Biotech Nigeria told participants: “In collaboration with Medigen, Inc. (USA) and the University of Maryland we are developing safe and effective live ML29 vaccine expressing Lassa virus (LASV) glycoprotein (GPC) and nucleoprotein (NP) antigens. Live replicating vaccine has a unique advantage for preventing and containing LF epidemics because only a single vaccination is required.

“The vaccine so far has been successfully tested in the multiple animal models of LF including non-human primates. Remarkably, vaccination of SIV-infected rhesus macaques did not result in arenavirus infection symptoms and did not exacerbate SIV-induced disease.

“These results suggest the highest level of vaccine safety even in the immune-compromised vaccine recipients. Furthermore, vaccination of non-human primates and subsequent challenge with the wild-type pathogenic LASV resulted in complete protection. Finally, we have shown that our vaccine is the only known vaccine that provided protection against LASV variants currently circulating in Nigeria.”

Agwale in an exclusive interview with The Guardian said: “We have 24 months timeline to build a vaccine factory in Nigeria to start production. But for Lassa vaccines we have already created a cell line. We are now trying to raise the funds so that we can manufacture it. We can start the clinical trials before June 2019 if we have all the resources that we need.”

A foremost virologist and Head of the National Committee on Lassa fever, Prof. Oyewale Tomori told The Guardian that although there is currently no licensed vaccine that protects humans against Lassa Fever (LF), efforts are being made to conduct vaccine trials in human volunteers with LF vaccines that have been found to protect non-human primates from L F infection.

Tomori, who was also a former President of the Nigerian Academy of Science (NAS) and consultant to the World Health Organisation (WHO) said the WHO has given the highest priority for the development of LF vaccine predominantly targeting preventive use, with features allowing use for outbreak control.

Tomori who has also served as the Vice Chancellor of Redeemers University said recently, the Coalition for Epidemic Preparedness Innovations (CEPI) signed a deal worth up to $36 million to advance the development of a vaccine against LF, in partnership with Profectus BioSciences and Emergent BioSolutions. He said Lassa fever is one the of the four diseases that CEPI, a coalition of government and funding groups formed in 2017, has targeted for vaccine development.

Tomori said: “Last week, CEPI held a meeting in Abuja with NCDC, the National Agency for Food, Drug Administration and Control (NAFDAC) and vaccine manufacturers. There is a plan to conduct some of the human vaccine trials in Nigeria and the possibility that a human Lassa fever vaccine will be available by 2022/2023.

“ If Nigeria shows national commitment, LF vaccine may eventually be produced in Nigeria in co-development with upgrading our NAFDAC to the status of our National Regulatory Authority.”Agwale added: “We if you look at the data I presented based on small and higher animal models, the vaccine is 100 protective.

“Right now all these studies were done using private funds but this is the time now that there are various agencies that can fund the clinical trials like the CEPI as you see most of the products they are sponsoring. But we are also talking to the Federal Government to play a key role.“We have candidate Human Immuno-deficiency Virus (HIV) and Ebola vaccines. So with this factory coming into Nigeria, it will allow us to fast track the development of these products.”

One time Chief Epidemiologist of Nigeria and pioneer Director General of the NCDC, Prof. Abdulsalami Nasidi, told The Guardian: “Our concept is that we have a candidate Lassa fever vaccine and Nigeria should make all efforts to ensure that our own vaccine, which was gotten from our virus from here should be funded by the government and pushed. Not just the vaccines that were developed outside and just brought here to us for clinical trials. So we are also involved in vaccine development, we want to be involved in vaccine manufacturing. So Nigeria government should do whatever they need to do quickly to get that moving.”

Nasidi who was appointed in 2016 by the West Africa Health Organisation (WAHO) as the Acting Executive Director of the Economic Community of West African States (ECOWAS) Regional Surveillance and Disease Control Centre (RCDC) added: “We have upgraded ML29 to what we call RML29 that is the recombinant ML29. It is higher and easier to manufacture and can be manufactured in Nigeria.

“Well we are pushing and we are trying to see whether the government will come out and support it fully. We say from now to 24 months should get it all out.”However, there are fears that vaccine candidates for poor nations such as Nigeria are going to waste.

According to a study published in Nature journal, promising immunizations for diseases that affect mostly people in low- and middle-income countries need help getting to market.David C. Kaslow and colleagues noted that some 240 vaccine candidates are currently in the development pipeline for diseases such as malaria, tuberculosis and pneumonia — conditions that predominantly affect people in low- and middle-income countries (LMICs). Just two that made it through the pipeline in recent years are widely used in these nations: a conjugate vaccine for meningitis serogroup A diseases and a vaccine against Japanese encephalitis virus.

Drug developers must clear many barriers to get a vaccine licensed so it can be given to millions of people — whether in routine immunizations or during a disease outbreak. The initial phases of development entail evaluating candidates identified from basic research in proof-of-principle clinical trials, usually involving tens or hundreds of people (often called ‘the valley of death’ because so many candidates fail at this stage owing to a lack of resources).

Next, developers must invest in a manufacturing facility and test candidates in trials involving several thousand to tens of thousands of people (phase III). If regulators approve the vaccine for sale, vaccine manufacturers must then monitor safety in populations that have been vaccinated (known as post-marketing evaluation or phase IV studies).

Over the past decade, billions of dollars have been ploughed into academic laboratories, biotechnology firms and pharmaceutical companies to help them through the first phase of vaccine development for diseases that mainly affect emerging economies. The money has come from many organizations, including the US National Institutes of Health (NIH), the European Union, the Wellcome Trust in London and the Bill & Melinda Gates Foundation in Seattle, Washington. Numerous candidates are now in proof-of-principle trials, largely thanks to these investments and to advances in technology that span genomics to immunology. Several candidates are ready for late-stage clinical trials.

Yet much of this promising pipeline could go to waste. No single organization or group is striving to support the formidably challenging second phase of vaccine development for diseases that mainly affect emerging economies.Taking a vaccine candidate from a discovery at the lab bench to widespread deployment is complex, lengthy and expensive.

CEO of CEPI, Richard Hatchett, told participants that the company’s Lassa fever response programme is designed to address diagnostic gaps and strengthen Nigeria’s ability to respond to future outbreaks.He said CEPI will support the expansion of the Foundation for Innovative New Diagnostics (FIND’s) ongoing Lassa fever response programme, including evaluation of diagnostic tests, validated diagnostics within clinical trial site development, and sample collection and archiving. These activities will build diagnostic capacity that is crucial for improved patient care and for the development and targeted deployment of vaccines and medicines.

Funded by the German government and now CEPI, FIND is working in partnership with the Bernhard Nocht Institute for Tropical Medicine (BNITM), the NCDC, and the World Health Organization (WHO).

Hatchett said the CEPI-supported expansion of the programme would cover:
• Evaluation of serological assays for laboratory-based diagnosis and for assessment of disease prevalence (immunoglobulin G, immunoglobulin M, enzyme-linked immunosorbent assays)
• Clinical trial site development: establishment of one fully accredited clinical trial and two–three sites in Nigeria with minimal levels of Good Clinical Laboratory Practice compliance for reliable diagnosis of Lassa fever cases, supporting future trials of vaccines.
• Expanded sample collection and archiving: accelerating the research and development and regulatory approvals for new diagnostics and vaccines through the establishment of a sample archive.

Director of Vaccine Science, CEPI, Gunnstein Norheim, said: “The role of diagnostics in the development of vaccines is crucial, and we see the need for a robust increase in funding to enable access to validated tests for affected populations. “Such tests are needed to guide treatment, enable reliable estimates of disease burden, and as tools for verifying cases in field trials to test vaccine efficacy. FIND and WHO’s concerted efforts on Lassa diagnostics are pivotal to the development of an effective Lassa vaccine.”

CEO, FIND, Catharina Boehme, said: “While diagnostics are essential for tracking disease patterns and identifying outbreaks, diagnostic intelligence is also critical to the development of new drugs and vaccines, as well as pinpointing where and when these should be used. “We welcome this collaboration with CEPI to strengthen diagnostic capacity in Nigeria that will improve the overall Lassa fever response and minimize – hopefully even prevent – the terrible impact to communities of these regular disease outbreaks.”

Meanwhile, Hatchett said work streams in this project expansion are expected to take place over two years, with the majority of the product development work being completed in 2019 and the overall FIND Lassa fever response programme will run until 2020.He said CEPI funding for this project complements support from the German government (Federal Ministry for Education and Research [BMBF] and KfW) for the Lassa fever response programme in three countries, including Nigeria.

FIND is a global non-profit organization that drives innovation in the development and delivery of diagnostics to combat major diseases affecting the world’s poorest populations. CEPI is an innovative partnership between public, private, philanthropic, and civil organisations launched in Davos in 2017 to develop vaccines to stop future epidemics. CEPI has received multi-year funding from Norway, Germany, Japan, Canada, the Bill & Melinda Gates Foundation, and Wellcome. CEPI has also received single-year investments from the governments of Australia and Belgium. The European Commission foresees substantial financial contributions to support relevant projects through EC mechanisms. CEPI has reached over US$ 740 million of its $1 billion funding target.

Since its launch in January 2017, CEPI has announced three calls for proposals. The first call was for candidate vaccines against Lassa virus, Middle East Respiratory Syndrome coronavirus (MERS-CoV), and Nipah virus—to date, CEPI has invested over $270 million to develop five vaccine candidates against Lassa virus, four against MERS- CoV, and two against Nipah virus. The second call was for the development of platforms that can be used for rapid vaccine development against unknown pathogens. The third call is for candidate vaccines against Rift Valley fever and Chikungunya viruses.