Protecting Mankind against Global Infectious Diseases

Mankind has feared the coming of the four horsemen of the  apocalypse for millennia: war, famine, plague, and death. That  disease is feared as much as the horrors of war is no coincidence.  Infections can decimate just as many lives in a short space of time  as armed conflict – and they can develop into global pandemics in the same way as an assassin’s bullet can start a war.  

For instance, between 1347 and 1352, bubonic plague - the Black Death - accounted for the death of an estimated 25 million people, a third of the population of Europe [1] and, only 100 years ago, between 1918 and 1920, an estimated 50 million people around the globe succumbed to the 1918 H1N1 flu pandemic, sometimes referred to as the "Spanish flu" [2]. From the war-torn trenches of Europe and Native American villages to the mega-cities of the USA and  remote South Sea islands, countless victims died after infection with this aggressive and highly contagious form of the influenza virus. But it was not only weakened or older victims who were infected by the  virus. On the contrary, this insidious infection, generally causing  death by pneumonia, particularly affected young people between twenty and forty years of age.  

In addition, recent years have also seen repeated outbreaks of infectious diseases that have spread like wildfire. Since the 1980s, for example, HIV infection has led to almost 40 million deaths from AIDS-related illnesses [3]. The Ebola virus disease outbreak in West Africa in 2014-16  caused an epidemic that shook the world to its roots, causing more cases and deaths than all other outbreaks combined [4].

Just recently we all experienced just how quickly a new virus can reach all parts of the world. In December 2019, the novel coronavirus SARS-CoV-2- which causes Covid-19 – first emerged in Wuhan, China and then rapidly spread to all corners of the globe in a matter of weeks.

Crowded living conditions in major cities increase the danger of pandemics. Urban populations will probably grow by more than three billion people by 2050, above all in developing countries and emerging economies. In Africa, the problems are compounded by insufficient healthcare infrastructures[6]: In the Republic of Ghana, for instance, there are only two doctors per 10,000 inhabitants, while in the Democratic Republic of Congo, the figure is only 0.9 – in contrast, Germany has 42, the USA 26, and China currently has 18.

Another factor is global mobility: As around 80 million passengers board planes every week, a virus can strike almost anywhere on the planet within only a few days – and the number of passengers is expected to double within the next 20 years[4]. In view of increasing mobility and global population growth, there is also an increasing danger of contact with animals that may be carriers of viral pathogens – for instance birds, apes, and bats. There is also a growing catalog of new threats, ranging from bio-terrorism to the shifting of vegetation zones as a consequence of climate change: Tropical mosquitos that carry malaria, dengue fever, or yellow fever have already begun to spread into Europe. Stefan Oschmann (Chairman of the Executive Board and CEO of Merck KGaA, Darmstadt, Germany, 2016-2021) gets straight into the point by saying: “A global pandemic would be one of the major threats we face. Pandemic preparedness is a must. How well we are able to respond when the day comes depends on what we do today." (this quote was given during the award ceremony in July 2019, before the outbreak of Covid-19 happened)

So, what must we do? Merck KGaA, Darmstadt, Germany has added protection against pandemics to the categories of its grant program, known as the “Future Insight Prize,” that the company will be awarding annually for the next 35 years. The prize value is up to one million euros -  higher than that of the Nobel Prize. “With this, we are drafting a future vision for ambitious dream products that are important for humanity to have but cannot be realized with the current state of science and technology”, explains Ulrich Betz, the initiator of the Curious Future Insight Conference and the "Future Insight Prize". “With this research grant we encourage scientific work in the areas of health, nutrition, and energy that creates the required scientific and technological basis for a later realization of these visionary dream products.”

Due to the extreme urgency of the issue, a call for submissions to the first "Future Insight Prize" in the category “Pandemic Protector” was made and the research grant to fund future research was presented in the course of an award ceremony and expert discussion at the Innovation Center in Darmstadt on July 9^th, 2019. A jury of international experts from disciplines including tropical medicine, infectious diseases, vaccines and epidemiology, chose two leading researchers from the USA from the numerous submissions: Pardis Sabeti, Professor at the Broad Institute in Cambridge, Massachusetts, and James Crowe, Director of the Vanderbilt Vaccine Center at Vanderbilt University Medical Center in Nashville, Tennessee. “Their work underscores that science can be a force for good – that it can make a substantial and lasting contribution to human progress,” said Stefan Oschmann, honoring the recipients of the research grant. 

The description of the dream product for protection against pandemics sounds deceptively simple: you start off with a sample from a person infected with  an unknown pathogen and use it to develop effective new ways to prevent or treat the disease. Speed is the key to success. It has been calculated that, if a strain of the influenza virus emerged today as contagious and deadly as the one that caused the 1918 pandemic, it would claim the lives of 250 million  people [10].  By October 2021, Covid-19 had so far caused over 4.7 million deaths worldwide and put health systems and economies under extreme  pressure [11]. 

This much-needed pandemic protector – thanks to Sabeti’s and Crowe's results – is now no longer merely a visionary idea, but instead a realistic possibility. Sabeti, who, together with her team, contributed to containing the Ebola outbreak in West Africa, is focusing on reading the nucleic acid sequences of  disease pathogens as quickly as possible to uncover its secrets. The development of new diagnostic methods is a vital step in containing an outbreak -  leading to tests that can quickly and accurately identify people who are infected with a viral pathogen - and track its spread and evolution. “New methods like CRISPR-Cas13, which is best known as a gene-editing tool are extremely helpful for this,” explains Sabeti. “This enables the development of a specific diagnosis methodology for viral diseases, while also making it easier to identify mutations arising in the viral genome. The method could even be used for the total destruction of an RNA virus - leading to new antiviral therapies.” 

Sabeti and her team have been at the forefront of employing these cutting-edge methods to develop and scale genomic surveillance, diagnostics, and  advanced analytics to improve our pandemic preparedness. They have also built a close partnership with the African Center of Excellence for Genomics of Infectious Diseases (ACEGID), which provides state-of-the-art infrastructure and research capacity for Nigeria and the wider continent.  

With the outbreak of Covid-19, Sabeti’s team accelerated their work on developing systems to rapidly sequence viral genomes and characterize important mutations early in the outbreak. They characterized the important role of superspreading events in propelling the pandemic. In tandem, her ACEGID partners sequenced the first SARS-CoV-2 genomes from Africa and became a continental World Health Organization (WHO) reference center. The team has also been interrogating genomic data to understand what parts of the virus are presented to the immune system during infection, and how this might influence vaccine development.  

In 2020, Sabeti and her team also continued their work into developing new capabilities for the detection of viral pathogens. They developed two groundbreaking diagnostic technologies: CARMEN, a CRISPR-based method for multiplexed viral detection in a laboratory setting and a complementary, field-deployable, point-of-care platform for SARS-CoV-2 detection called SHINE. These two techniques bridge urgent gaps in existing diagnostic capabilities, such as cost, sensitivity, and turnaround time.  

The Sabeti team is now using machine learning models to further improve and refine their viral diagnostics. Ultimately, Sabeti sees these as vital tools that  will help identify and contain new viral outbreaks early, with the goal of detecting high-priority viruses within an hour, any known human virus within a day, and previously unknown viruses within a week.  

Importantly, Crowe’s research complements this vision. He works with people who have already recovered from a viral disease and developed immunity. His team has developed a technology for extracting and replicating monoclonal antibodies (molecules produced by the immune system that target a specific  antigen on the virus) from the patient’s blood cells – an extremely effective antidote. “It may not offer lifelong protection, but a couple of months of  protection is enough to contain an epidemic,” explains Crowe. 

Antibodies that dock, lock onto and block important receptors on the viral surface have already been found for Marburg, Ebola and Zika viruses. “This  approach is he best way to combat these pathogens,” says Crowe, and points out the particular speed of the process: “In 2019, we showed in a simulated emergency exercise that we could progress in 78 days from blood sample to completed protection studies,” – that’s only a little over 11 weeks that his team needed to be ready to combat a new virus. “When Covid-19 occurred, we were ready to respond quickly. We isolated best-in-class human  monoclonal antibodies from survivor blood cells and passed the antibody combination on to a pharma partner in 25 days,” he adds. 

These antibodies formed the basis for AZD7442, a combination of two long-acting antibodies – tixagevimab and cilgavimab. A recent Phase III clinical trial showed that a single 300mg intramuscular dose of AZD7442 reduced the risk of developing symptomatic Covid-19 by 77% compared to a placebo [12].  

“We are grateful that Merck KGaA, Darmstadt, Germany set the vision for ‘Pandemic Protector’ in 2019 and supported our work to develop a protector platform. Little did we know that meeting this aspirational goal would occur during a real pandemic less than six months after the start of our Future Insight™ Prize supported work. The timing was amazing.” 

At the same time, the research scientist intends to play a role in preventive medicine with his AHEAD100 project. The aim is to develop monoclonal  antibodies for 100 known and dangerous virus types that are the most likely causes of future epidemics –so we can be much better prepared before a new outbreak occurs. It was launched formally on August 11, 2021, after an intense 6-month planning phase. 

This important initiative has been launched by a large public-private consortium with support from county and state governments, CEPI, the Bill and  Melinda Gates Foundation, academic institutions, and many commercial partners.

Despite these successes, there remains a lot to be done to assure protection against a pandemic in an emergency, emphasized both the research grant recipients and the international experts during the presentation of the Future Insight Prize. In the opinion of Pardis Sabeti, the analysis of pathogens on the spot and fast development of vaccines is not enough: “It is also essential that knowledge is disseminated widely and quickly, and that the people affected are involved in order to gain their trust and to empower them on the front lines.”

This has only seen partial success in the battle against Ebola. The rVSV-ZEBOV vaccine[10],  already under development for a long time, offered practically complete protection against infection, but only came into play in West Africa after a year - much too late - but, nevertheless: a fast ring vaccination was successful when the next outbreak came. Here, healthcare staff and initial contacts of infected patients and their immediate contacts were vaccinated. This enabled a new epidemic to be contained.

So far, this approach has failed in the case of the current outbreak in the Democratic Republic of Congo - despite the availability of several hundred thousand doses of the vaccine. As a consequence of armed conflict in the country, patients and their contact persons cannot be reached. What makes things worse is that rebel forces are reportedly destroying treatment centers and spreading rumors about how Ebola is being spread – adding the challenge of education as well as the delivery of vaccines. 

So, what must we do? We have added protection against pandemics to the categories of our grant program, known as the “Future Insight Prize", that the company will be awarding annually for the next 35 years. The prize value is up to one million euros -  higher than that of the Nobel Prize. “With this, we are drafting a future vision for ambitious dream products
 that are important for humanity to have but cannot be realized with the current state of science and technology” explains Ulrich Betz, the initiator of the Curious Future Insight Conference and the "Future Insight Prize". “With this research grant we encourage scientific work in the areas of health, nutrition, and energy that creates the required scientific and technological basis for a later realization of these visionary dream products.”

Due to the extreme urgency of the issue, a call for submissions to the first "Future Insight Prize" in the category “Pandemic Protector” was made and the research grant to fund future research was presented in the course of an award ceremony and expert discussion at our Innovation Center in Darmstadt, Germany on July 9^th, 2019. A jury of international experts from disciplines including tropical medicine, infectious diseases, vaccines and epidemiology, chose two leading researchers from the USA from the numerous submissions: Pardis Sabeti, Professor at the Broad Institute in Cambridge, Massachusetts, and James Crowe, Director of the Vanderbilt Vaccine Center at Vanderbilt University Medical Center in Nashville, Tennessee. “Their work underscores that science can be a force for good – that it can make a substantial and lasting contribution to human progress,” said Stefan Oschmann, honoring the recipients of the research grant. 2

• Future Insight Prize: http://futureinsightprize.emdgroup.com
• Lab of Pardis Sabeti: https://www.sabetilab.org/ 
• Lab of James E. Crowe: https://www.vumc.org/crowe-lab/ 
• Coalition for Epidemic Preparedness Innovations (CEPI): https://cepi.net/ 
• Future Insight Conference: http://curious2020.com

_{[1] https://www.nationalgeographic.com/science/article/the-plague
[2] https://www.cdc.gov/flu/pandemic-resources/reconstruction-1918-virus.html
[3] https://www.unaids.org/en/resources/fact-sheet
[4] https://www.who.int/health-topics/ebola#tab=tab_1
[5] https://www.diffen.com/difference/World_War_I_vs_World_War_II
[6] https://www.statista.com/statistics/564717/airline-industry-passenger-traffic-globally/
[7] https://ourworldindata.org/urbanization#how-many-people-will-live-in-urban-areas-in-the-future
[8] https://www.who.int/data/gho/data/indicators/indicator-details/GHO/medical-doctors-(per-10-000-population)
[9] https://www.eurekalert.org/news-releases/861125
[10] https://www.bbc.com/future/article/20181120-what-if-a-deadly-influenza-pandemic-broke-out-today
[11] https://www.statista.com/statistics/1093256/novel-coronavirus-2019ncov-deaths-worldwide-by-country/
[12] https://www.astrazeneca.com/media-centre/press-releases/2021/azd7442-prophylaxis-trial-met-primary-endpoint.html
[13] Published by James E. Crowe, Jr Vanderbilt University Med Center Nashville, TN, USA during his speech during the award ceremony of the Future Insight Prize 2019 on July 9, 2019 in Darmstadt, Germany}