Erica Ollmann Saphire was a 2018-19 US-UK Fulbright Scholar to the Medical Research Council Laboratory of Molecular Biology, a research institute in Cambridge, UK and is a Professor at La Jolla Institute for Immunology.
Here, she shares details of her current work as Director of a collaborative effort funded by the Bill & Melinda Gates Foundation that brings together more than 50 labs to advance antibody therapies against COVID-19.
The novel coronavirus, SARS-CoV-2, which causes COVID-19, is a powerful demonstration that emergence of a pathogen in one location, even if far away, can rapidly upend lives and livelihoods all over the planet. In the face of this and other escalating pandemics, the scientific community must unite. We must work together, and with focus, speed and innovation to develop both rapid responses and more permanent solutions to this and future outbreaks of disease.
My laboratory uses cryo-electron microscopy and x-ray crystallography, a process which generates three-dimensional structures of proteins from deadly viruses like SARS-CoV-2, Ebola virus, Lassa virus and measles. The Fulbright fellowship enabled me to work at the MRC Laboratory for Molecular Biology to gain expertise in cryo-electron tomography. This technique involves collecting a series of images from frozen samples of cells or viruses. Individual molecular assemblies of interest can be reconstructed from these images into a 3D picture of how the virus functions and how therapeutics inhibit it.
This structural information helps us understand, at a molecular level, vulnerabilities in viruses that can be exploited by therapeutics that prevent or treat virus infections. SARS-CoV-2, like most viruses, is coated with glycoproteins that facilitate cell attachment and infections. These glycoproteins are also prime targets of antibodies produced by our immune system that block or “neutralize” virus infection.
Antibody treatment
Antibodies are molecules made by your immune system in response to surviving an infection or receiving a vaccine. Antibodies become your immune system’s “sentries” to rapidly detect and destroy the pathogen the next time you are exposed. Antibodies from survivors can also be used to immediately protect other people. Antivenom is one example with which you are familiar: a mixture of antibodies against the toxins in snake venom can rapidly neutralize those toxins and save a recipient’s life.
An immune response against a virus can produce millions of different antibodies that have different potencies. Instead of delivering an uncharacterized mixture of antibodies, we can examine the array of antibodies in the blood of a survivor, and identify the one or two that are most potent and most active against the infection: the one or two needles in the haystack. We can then manufacture large amounts of these individual antibodies at high purity to produce a highly specific, potent drug. Antibody therapies are now available against several cancers, autoimmune diseases, and infectious diseases alike.
A collaborative effort
Such antibody therapies were needed for Ebola virus, but researchers around the world were faced with a puzzle: some antibodies neutralized virus infection in test tubes, but didn’t protect living things from disease. Other antibodies protected living things, but didn’t apparently function well in test tubes. We needed information about what other features of antibodies contribute to protection and what laboratory assays best forecasted protection in living things. To get that information, in 2013, I secured funding from the National Institutes of Health and brought together researchers from across the Ebola virus field to contribute their expertise to a global, multidisciplinary effort, the Viral Hemorrhagic Fever Immunotherapeutic Consortium (VIC).
VIC partners conducted side-by-side, multidisciplinary analyses of antibodies against Ebola and Lassa virus glycoproteins, to determine which features of antibodies allowed them to protect living things from disease. The VIC found which experiments were most predictive, identified new ways of measuring and forecasting immune protection, and ultimately helped advance safe and effective antibody-based therapies for both Ebola virus and Lassa virus.
Antibody therapy for these and other diseases provides a critical option for protection for people who have not been vaccinated, haven’t yet been vaccinated, or for whom a vaccine isn’t an option (infants, some pregnant women, those with underlying conditions). Yet antibody therapy is typically more expensive than a vaccine, and we don't want individuals in low and middle-income countries to be priced out of lifesaving therapy. Even once a vaccine is available, it won’t be in all places at all times. Failure to control SARS-CoV-2 anywhere on the planet can send the virus surging back to other locations as people travel.
The Coronavirus Immunotherapeutics Consortium
This year, with funding from the Bill & Melinda Gates Foundation, we are using the successful model of the VIC to form the Coronavirus Immunotherapeutics Consortium (CoVIC). At least fifty different academic and industrial labs are discovering and advancing antibody therapies against the novel coronavirus. Through CoVIC, they may share their samples to build a broader, deeper dataset. Together, we will better understand the landscape of antibodies that protect against the novel virus and may identify novel combinations of ideal synergy, not possible through any individual effort alone.
The goal of this consortium is to identify one or more antibody therapies of sufficient potency and durability to lower the cost of goods and achieve delivery anywhere in the world. To protect the intellectual property of participating investigators, contributed antibodies will be anonymized through the assignment of code names. Code-named samples will be sent to CoVIC partner labs for structural analyses and parallel, standardized assays to determine antibody affinity and avidity, epitope and neutralization activity. Data from the anonymized panel will be cataloged real-time in a publicly available database that can provide guidance on selection of therapeutic candidates to advance for clinical and prophylactic use. The work of CoVIC will be further supported by a $100,000 grant we recently received through the Emergent Ventures Fast Grants program, funding which we used to purchase incubators needed to produce molecules of vaccine development as well as antibodies from human cells.
My Fulbright experience of developing novel tools and international collaborations to enhance therapeutic development is behind this effort. Together, the CoVIC seeks to provide cost-effective antibody treatments to ensure that no one is left behind in the race to prevent and cure COVID-19. Please join me, my colleagues and the Bill & Melinda Gates Foundation in supporting the CoVIC. Visit the CoVIC website to learn more.
Assembly of the incredibly powerful, 11-foot tall Titan Krios microscope, which Dr. Erica Ollmann Saphire and her team will use to examine the virus at a molecular level. Video courtesy of the La Jolla Institute for Immunology.