Genomic analysis offers insight into 2018 Nigeria Lassa fever outbreak

A surge in Lassa fever cases in Nigeria in 2018 does not appear to be linked to a single virus strain or increased human-to-human transmission, according to a genomic analysis published in The New England Journal of Medicine.

Scanning electron micrograph of Lassa virus budding off a Vero cell. NIAID

Multiple institutions collaborated on the report, including the African Center of Excellence for Genomics of Infectious Diseases at Redeemer’s University in Ede, Nigeria; the Broad Institute of MIT and Harvard in Cambridge, Massachusetts; the Scripps Research Institute in La Jolla, California; and Tulane University in New Orleans, among others.

The research was supported in part by the National Institute of Allergy and Infectious Diseases (NIAID), the National Human Genome Research Institute (NHGRI), and the NIH Common Fund’s Human Heredity and Health in Africa Program, all components of the National Institutes of Health (NIH).

The Nigeria Centre for Disease Control (NCDC) reported an unusually large increase in Lassa fever cases in 2018, with 523 laboratory-confirmed cases and 135 deaths from January 1 through October 7.

Lassa fever is endemic to West Africa, where Mastomys natalensis rodents, a primary animal reservoir of Lassa virus, are common. The rodent is often found in or around human habitats, and people become infected with Lassa virus through direct contact with rodent urine and stool. People with Lassa fever also can transmit the virus to other people through close contact, although experts believe this is rare. About 15 to 20 percent of people hospitalized with Lassa fever die from the disease, but only 1 percent of all Lassa virus infections result in death, according to the U.S. Centers for Disease Control and Prevention.

Public health officials were concerned that the Lassa fever outbreak in Nigeria in 2018 might be driven by a previously unknown factor, such as a new or more virulent Lassa virus strain, according to the authors. This prompted the research team to analyze Lassa virus genomes from patient samples to determine if genomic data signatures could explain the surge in cases.

The authors analyzed Lassa virus genomes of 129 patients from the 2017-2018 outbreak and from 91 patients from the 2015-2017 seasons. They discovered that Lassa genomes from 2018 were drawn from a diverse range of viruses previously observed in Nigeria rather than from a single dominant strain. This indicates that a single virus strain was not driving the surge in cases in 2018. Additionally, dating of the most recent ancestors of samples from 2018 showed limited support for human-to-human transmission. Rather, the dataset had features consistent with many, independent zoonotic transmissions (humans becoming infected through contact with rodent feces or urine).

The research team reported their findings in real time to the NCDC and local health authorities to support the public health response to the outbreak. The research serves as a model for investigating infectious disease emergencies by combining genomic information with traditional epidemiological data to inform response strategies, the authors note.

Scientists develop novel vaccine for Lassa fever and rabies

A novel vaccine designed to protect people from both Lassa fever and rabies showed promise in preclinical testing, according to new research published in Nature Communications.

This transmission electron microscopic (TEM) image depicts Lassa virus virions adjacent to some cell debris. CDC/ C. S. Goldsmith

The investigational vaccine, called LASSARAB, was developed and tested by scientists at Thomas Jefferson University in Philadelphia; the University of Minho in Braga, Portugal; the University of California, San Diego; and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

The inactivated recombinant vaccine candidate uses a weakened rabies virus vector, or carrier. The research team inserted genetic material from Lassa virus into the rabies virus vector so the vaccine expresses surface proteins from both the Lassa virus and the rabies virus. These surface proteins prompt an immune response against both Lassa and rabies viruses. The recombinant vaccine was then inactivated to “kill” the live rabies virus used to make the carrier.

There are currently no approved Lassa fever vaccines. Although Lassa fever is often a mild illness, some people experience serious symptoms, such as hemorrhage (severe bleeding) and shock. The overall Lassa virus infection case-fatality rate is about 1 percent, according to the World Health Organization (WHO), but that rate rises to 15 percent for patients hospitalized with severe cases of Lassa fever. People contract Lassa virus through contact with infected Mastomys rats and through exposure to an infected person’s bodily fluids. Lassa fever is endemic to West Africa where these rats are common. In 2018, Nigeria experienced its largest-ever Lassa fever outbreak, with 514 confirmed cases and 134 deaths from Jan. 1 through Sept. 30, according to the Nigeria Centre for Disease Control(link is external).

Africa is also at high risk for human rabies. The WHO estimates that 95 percent of the estimated 59,000 human rabies deaths per year occur in Africa and Asia(link is external). Nearly all human rabies deaths are caused by bites or scratches from infected dogs. Effective rabies vaccines and post-exposure shots are available, but many deaths still occur in resource-limited countries(link is external), according to the Centers for Disease Control and Prevention.

The newly published findings show that LASSARAB, when administered with GLA-SE adjuvant (an immune response-stimulating protein), elicits antibodies against Lassa virus and rabies virus in mouse and guinea pig models. The vaccine also protected guinea pigs from Lassa fever after being exposed to the virus 58 days after vaccination.

Prior research indicated that an antibody-mediated immune response is not correlated with protection from Lassa fever, the authors note. However, the new findings show that high levels of non-neutralizing immunoglobulin G (IgG) antibodies that bind to the Lassa virus surface protein correlate with protection against Lassa virus. Levels of this type of antibody could potentially be a Lassa fever correlate of protection used to determine vaccine efficacy, according to the authors. They note the next step is to evaluate the experimental vaccine in nonhuman primates before advancing to human clinical trials.

Strong Clinical Research Capacity in At-Risk Countries Key to Global Epidemic Prevention

New report outlines urgent need and opportunities in low- and middle-income countries where disease outbreaks most often strike

Robust clinical research capacity in low- and middle-income countries is key to stemming the spread of epidemics, according to a new report from the International Vaccines Task Force (IVTF).

The report, entitled Money and Microbes: Strengthening Research Capacity to Prevent Epidemics, lays out how to develop the political support, financing and coordination required to build this capacity as a crucial component of global epidemic preparedness. The IVTF was convened by the World Bank Group (WBG) and the Coalition for Epidemic Preparedness Innovations (CEPI) in October 2017.

There have been many global and country-level efforts to strengthen pandemic preparedness and response since the deadly West African Ebola outbreak in 2014-2015 that killed 11,000 people—and the last few weeks have provided evidence of this.

During the current Ebola outbreak in the Democratic Republic of Congo (DRC) with 49 total cases and 26 deaths so far, the government of DRC has approved the use for trials starting this week of a new, as-yet unlicensed Ebola vaccine, the rVSV-ZEBOV. The vaccine has proven highly effective in a clinical trial conducted in Guinea in 2015. Nigeria had its worst Lassa Fever outbreak on record earlier this year, and also pushed forward with conducting clinical trials as the outbreak unfolded.

“Times of crisis present the opportunity to focus capabilities and energy on solving important problems,” said Marie-Paule Kieny, Director of Research at INSERM and co-chair of IVTF. “Robust clinical research capacity is the only way to ensure that we don’t face future outbreaks with the same knowledge gaps over and over again.”

Of the 96 countries that have conducted vaccine trials in the past 20 years, 56 have conducted only between 1 and 10 trials, according to a registry maintained by the World Health Organization (WHO). This is insufficient to advance promising new vaccines, therapeutics and diagnostics for epidemic infectious diseases at the scale that is needed. The report recommends building capacity at a national or regional level that can flexibly scale up to run clinical trials during outbreaks, and focus on ongoing high-priority disease research based on local needs in between outbreaks.

“There are now more robustly trained local researchers working in better equipped facilities in low- and middle-income countries, but their numbers remain far too limited,” said Richard Sezibera, Member of the Senate, Rwanda, and Co-chair of the IVTF. “We must urgently prioritize clinical research both to save lives in low-income settings, and to generate valuable information that is a global public good.”

Besides improving health outcomes, clinical research offers a strong return on investment—publicly-funded research and innovation delivers about a 20 percent annual return on investment, compared with an average of 6.8 percent for the S&P 500, which includes the 500 largest companies listed on the U.S. stock market, according to Science Business.

“Investment in strong clinical research capability is a win-win, paying for itself many times over,” said Tim Evans, Senior Director and head of the Health, Nutrition and Population Global Practice at the World Bank Group. “It saves lives and improves health, drives innovation, and creates high-quality jobs, and also builds global health security from the ground up, making us all safer.”

The IVTF recommends that low- and middle-income countries commit domestic financing to this agenda, building political support and a research-friendly culture. It recommends that WHO develops a global tool and robust indicators for assessing country research capacity, and that the WBG creates an investment framework for national and regional clinical research capacity, using many of its unique financing mechanisms to link clinical research to its overall investments in pandemic preparedness. IVTF also recommends strong private sector engagement through transfer of skills and expertise as well as financing.

“Closing the clinical research gap is essential to ensure that we have the capacity that can be mobilized quickly and effectively whenever and wherever it is needed during outbreaks,” said Richard Hatchett, CEO of CEPI. “Without this, we will not be better prepared for and able to response to current and future epidemic threats.”