Peter Kwong of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases in the U.S. will use an informatics-based approach to identify influenza virus epitopes that are especially suited to induce a strong and broad immune response, being conserved, accessible, and with a specific structural flexibility, and develop them as vaccine targets. Influenza is highly contagious and can cause severe illness, particularly among the young, elderly, and those with pre-existing conditions. Current vaccines are only partially effective, protect against single strains, and are generally ineffective against pandemic strains. Starting with three exposed influenza viral proteins, hemagglutinin (HA), neuraminidase (NA), and matrix protein 2 ectodomain (M2e), they will identify and rank candidate epitopes by determining their structural flexibility using all-atom molecular dynamic simulations, and by evaluating their conservation and surface accessibility, to promote recognition by the immune system and the generation of antibodies that target different viral strains. Candidate epitopes will be tested for antigenicity in vitro, and the best used to immunize mice to characterize the antibody response. After optimizing the vaccine regimen, they will ultimately evaluate the ability of the candidate vaccines to provide protection against diverse influenza strains in multiple animal models.

Jonah Sacha of the Oregon Health & Science University in the U.S. will explore a new approach to vaccine design by using a cytomegalovirus (CMV) vector expressing conserved influenza antigens to induce an effector memory T cell response that persists in the lungs and can provide lifelong immunity against influenza. The development of a universal influenza vaccine is a top global health priority: four pandemic outbreaks in the last 100 years killed tens of millions of people, and current antibody-mediated vaccines target highly variable antigenic proteins that are extremely strain-specific and unable to protect against future threats. Work on HIV and tuberculosis vaccines has shown that CMV-vectored vaccines can elicit and maintain effector memory T cells (T_EM) at high frequency in the lung. While T_EM don’t protect against infection, they restrict pathogen replication in the lung to the point that it is effectively eliminated. They will extend this work to influenza vaccine development, determining whether a CMV vaccine can protect cynomolgus macaque monkeys from the highly pathogenic 1918 influenza strain. After establishing the minimum lethal dose of the virus, they will vaccinate monkeys with a CMV vector expressing three highly conserved influenza viral proteins. They will characterize the subsequent cellular immune response, and then challenge the vaccinated animals with a low dose of 1918 influenza to evaluate the ability of the vaccine to protect them from infection.

Jonathan Heeney of the University of Cambridge in the United Kingdom will combine computational design with high-throughput synthetic biology to deliver an effective, universal influenza vaccine candidate for clinical trials in 24 months. Influenza infection impacts public health and the global economy, yet the high mutation rate of the virus has thwarted traditional approaches to develop a broadly effective vaccine. To address this, they developed a Digital Immune Optimized and selected Synthetic Vaccine (DioSynVax) technology platform, which has been successfully used for hemorrhagic fever vaccine development. They will now apply it to influenza vaccine development, by first analyzing structural and antibody-binding data to identify highly conserved antigens from three essential viral proteins: M2, neuraminidase (NA), and hemagglutinin (HA), which will ultimately result in broader and longer-lasting immune protection. These data will then be used to generate libraries of synthetic antigens for high-throughput screening to identify those that bind the most strongly to panels of broadly reactive monoclonal antibodies, and a subset will be tested for their ability to induce an antibody response in mice. The most promising candidate for each of the three viral proteins will then be combined and tested as a vaccine for protection against multiple influenza strains in ferrets.

David Aanensen from the University of Oxford and the Wellcome Sanger Institute in the United Kingdom and Maria van Kerkhove of the World Health Organization in Switzerland will combine next generation DNA sequencing technology with a simple, web-based data collection, processing, and distribution platform to better track the global spread of deadly infectious diseases including Middle East Respiratory Syndrome (MERS-CoV). MERS - also known as camel flu - is a viral disease that causes fever, cough, diarrhea, and shortness of breath, and is transmitted from camels to humans. One third of people diagnosed with the disease die. Next generation sequencing (NGS) technology allows rapid, inexpensive detection of pathogens as they spread. However, laboratories in different member states use different formats for sequencing data, and there is no mechanism for sharing it in real time. This limits the value of the technology for stopping outbreaks. To address this, they will establish routine sequencing protocols for both human and camel samples, and develop an interactive web platform on which the sequencing and epidemiological data can be shared. This will help develop more effective, real-time medical and non-medical interventions at local, national, and international levels. Once established, the protocols developed here may be applied to outbreaks of other diseases.

Achim Hoerauf of IMMP in Germany will apply artificial intelligence (AI) to speed the development of treatments for onchocerciasis, which is an infectious disease commonly known as River Blindness caused by a parasitic worm. The parasites are spread by affected blackflies, and the worm larvae accumulate in the skin and eyes, causing irritation and sometimes blindness. Nearly 21 million cases occur each year, and 99% of affected people live in Africa. The drug currently used for treatment kills only worm larvae, and studies are ongoing to identify more effective drugs that target adult worms. However, evaluating these drug candidates requires manual analysis using microscopy of samples of irritated skin from patients after treatment. This process is time consuming and slows drug development. To address this, they will use samples that have already been manually annotated to train an AI system to automatically analyze future samples to recognize worm body parts, gender, vitality, and stage of development. Once established, the AI system will be tested with samples from a new clinical trial - tissues from patients treated with the new drug will be analyzed in parallel by human and computer. Once optimized, the AI system will take over the analysis, and the much slower human analysis will only be needed as a quality control system.

Alain Labrique of Johns Hopkins Bloomberg School of Public Health in the U.S. and Meghan Azad of the University of Manitoba in Canada will study the impact of prelacteals - fluids or solids given before breastfeeding is established - on the populations of bacteria in the newborn gut (the microbiome), and how it may affect development. Immediate and exclusive breastfeeding helps maintain healthy growth in infants and protects them against infections, which are also influenced by their gut microbiome. However, in Bangladesh and many other low-resource countries, it is common practice to give newborns ritual foods, like honey or sugar water, before breastfeeding begins, which may impede development. They hypothesize a link between prelacteal use and newborn development mediated by the gut microbiome. To test this, they will use an ongoing population-based study in rural Bangladesh and compare the types and amounts of bacteria in the gut using stool samples of 300 prelacteal-fed and exclusively breastfed infants at 7 days, 28 days and 3 months of life. They will also analyze the composition of the prelacteals being used, including the presence of any toxic contaminants, and of the breastmilk of the mothers, for correlating with any changes in gut microbial populations. The study will enable them to quantify the potentially negative impact of this widespread cultural practice, common to over a billion people across the Gangetic floodplain.

Ruth Müller of the Institute of Tropical Medicine in Belgium and Meghnath Dhimal of the Nepal Health Research Council will provide entomological training for health science students and medical professionals and increase community awareness of vector-borne diseases (VBDs) in Nepal to better equip the population to deal with disease outbreaks. VBDs like those caused by the dengue, zika, or chikungunya viruses cause more than 700,000 deaths annually, mostly in poor countries with limited public health resources and tropical climates. Climate change has expanded the affected areas as warmer temperatures facilitate survival of the insect vectors. They will establish the EntoCAP team to enhance entomological capacity to fight these diseases. The team will hold five-day workshops for 300 health science students and health care professionals on surveillance and control of vector populations, and monitoring of disease outbreaks. They will also increase community interest in VBDs by hosting science labs for children to teach them how to recognize mosquitoes at various developmental stages and understand the dangers of VBDs. In addition, they will begin building a reference collection using DNA barcoding technology to catalog insect vectors by species for studying biodiversity and microevolution of disease vectors.

Eric Ochomo of the Kenya Medical Research Institute (KEMRI) in Kenya and Luc Djogbenou of the University of Abomey (UAC) in Benin will develop a curriculum to teach African scientists how to use genetic approaches to combat insecticide resistance in the fight against malaria. Malaria is a disease that kills almost 500,000 people annually, most in sub-Saharan Africa. People become infected when bitten by mosquitoes that transmit the disease-causing parasites. Insecticide treatment of bed nets and indoor areas are effective methods of disease control, but mosquitoes are becoming resistant. Varying the types of insecticides used and applying them in different combinations can help fight resistance, but it's difficult to know the most effective approach before resistance develops without the help of genetic markers. They will teach African scientists techniques to identify genetic resistance markers including sample collection and preservation, transcriptomic and whole-genome sequencing, and bioinformatics using online and hands-on approaches. This will ensure timely changes to insecticide application to better combat resistance. They will also encourage local scientists to establish industry partnerships to ensure that resistance monitoring can continue long-term.

Cambria Finegold, Richard Shaw and Roger Day of the Centre for Agriculture and Bioscience International in collaboration with Katherine Derby of the University of York and Sarah Gurr of the University of Exeter all in the United Kingdom, will design a platform - GBCrop - to collect, analyze and disseminate data on the global impact of crop pests and disease. The fact that 40% of crops are lost to pests impacts both the global food supply and local economies. Despite this, little is known about why and how crop pests and diseases occur. The extent of the problem was acknowledged by the UN declaring 2020 the Year of the Plant. They will design GBCrop to collect large quantities of high-quality data and apply advanced analytical methods to generate results that can then be used to direct research and policy development, and to predict the impact of emerging diseases. The program is modeled after Global Burden of Disease, which has transformed health policy agendas over the last 25 years. They will begin by consulting with key experts, and then include policy makers, private industry representatives, government organizations, potential funders and scientific experts. Together they will decide what data to collect and how it can best be used to accurately predict the impact of emerging crop diseases. They will launch their plan-of-action in the Year of the Plant and aim to make their first recommendations in 2023 on how to maximize crop gains.

Iruka Okeke of the University of Ibadan, College of Medicine in Nigeria and Kat Holt of Monash University in Australia will set-up a remote laboratory that uses nanopore sequencing as a low-cost, portable method to monitor the spread of antimicrobial resistance in rural areas of Africa and combine it with genome editing tools for more rapid diagnosis and improved treatment. Antimicrobial resistance (AMR) occurs when pathogens are able to survive treatments that previously would have killed them. Infection persists in these patients and spreads to others in the community, increasing both the risk of serious complications and the economic costs. To combat AMR, it needs to be tracked locally and quickly enough to inform treatment. However, traditional tracking methods are slow, and difficult to use in rural settings because of limited resources. Nanopore sequencing technology is a highly portable method of sequencing DNA that is suitable for resource-poor settings. They will setup a prototype minimal bacterial genomics lab at a provincial hospital laboratory in Africa, and use nanopore sequencing to catalog pathogens collected from patients and monitor AMR. They will also combine the sequencing with a genome editing tool - CRISPR-Cas - to enrich for known resistant pathogens and enable much faster diagnosis directly from blood or stool samples. Once optimized in the initial location, the remote lab can be recreated in other areas of Africa.

Pia Wintermark of McGill University in Canada and Cally Tann of the London School of Hygiene & Tropical Medicine in the United Kingdom will establish a pilot cohort in Uganda of term newborns who suffered from asphyxia at birth, which means that their brain and other organs did not receive enough blood or oxygen, and conduct a clinical test of a novel neurorestorative agent (i.e., to repair brain injuries) to see if it can improve early brain development in this setting. Birth asphyxia and the resulting neonatal encephalopathy is the third leading cause of mortality in infants under five and leads to significant brain damage and long-term neurodevelopmental morbidities. In a rat model of term neonatal brain damage, they found that a compound, sildenafil, reduced brain damage and inflammation, and increased nerve cell growth. This compound has already proven safe for use in humans for other purposes. They will first assemble a pilot cohort of 100 neonates with neonatal encephalopathy in Uganda, and clinically evaluate them over the first three months of age to better characterize the disease in this setting. From this cohort, 30 newborns will be selected to test whether daily treatment of sildenafil from day 2 to day 9 of life can improve brain growth and development and is a feasible and acceptable neurorestorative treatment strategy in this setting.

Anne CC Lee and Mandy Brown Belfort of Brigham and Women's Hospital in the U.S. along with Stéphane Sizonenko and Petra Huppi of the University of Geneva in Switzerland will test whether lactoferrin, a breast milk nutrient, can promote growth and reduce injury in the developing infant brain. Of the 15 million annual preterm births, almost a million of the surviving babies have severe neurological defects such as cerebral palsy. However, there are limited treatments available. Breast milk has a positive effect on the infant brain, but the mechanisms for this are unclear. Their preliminary data showed that lactoferrin, a glycoprotein found in breast milk, has a neuroprotective effect in several rat models of neonatal brain injury. They will build on this to study the effect of different concentrations of lactoferrin in the rat models, as well as assaying candidate inflammation, cell death, and neurotrophic factors to identify the molecular mechanisms involved. They will perform a human observational study to associate the different levels of lactoferrin found in breast milk samples from a cohort of mothers of preterm infants at Brigham and Women's Hospital with the infant's brain development as assessed by magnetic resonance imaging. They will also measure lactoferrin levels in samples collected from 100 mothers in Bangladesh to see how they compare. Together, they will generate essential data on lactoferrin for future human clinical trials in low- to middle-income countries.