The pandemic has reached a grim milestone: one million people have now died of COVID-19, according to Worldometers.
On January 13, we published “Mystery China pneumonia outbreak likely caused by new human coronavirus” by Connor Bamford, a virologist at Queen’s University Belfast. Since then, we have published more than 3,500 articles on the now not-so-novel coronavirus, officially named Sars-CoV-2. Despite this huge output from the world’s leading experts, we have merely skimmed the surface of all there is to know about this perplexing pathogen. So much remains a mystery.
At this important juncture, we asked several experts from different fields what their burning question about the coronavirus is. Here is what they said:
How did Sars-CoV-2 enter the human population?
Connor Bamford, Research Fellow, Virology, Queen’s University Belfast
We must understand how Sars-CoV-2-like viruses jump into humans if we are to stop the next pandemic, as we do for influenza. Although originally thought to have emerged in the Huanan Seafood Wholesale Market in December 2019, the earliest patient had no link to the market suggesting the virus had emerged before then. How did this happen?
Since the original investigations into the beginnings of Sars coronaviruses in 2002, horseshoe bats in south-east Asia have been implicated as the reservoir hosts, and a virus (RmYN02) that is extremely similar to Sars-CoV-2 has already been found in bats. However, similar viruses have also been found in pangolins, raising the possibility that Sars-CoV-2 may not have jumped directly from a bat.
Also, Sars-CoV-2 has already spread to cats, dogs, tigers and mink, and for Sars-CoV-1 (the virus that caused the 2002-04 Sars epidemic), farmed civet cats and raccoon dogs acted as intermediate hosts, bringing a bat virus into proximity to humans. It is possible that Sars-CoV-2 is a generalist virus, capable of spreading through a wide range of species.
With the increase in contact between humans and wildlife, zoonoses are becoming an ever-growing threat. We must be vigilant. An important step now is to figure out the events that led Sars-CoV-2 to go from bat to human.
How can we tell if someone is protected from Sars-CoV-2?
Sarah Caddy, Clinical Research Fellow, Viral Immunology, University of Cambridge
The immune response to Sars-CoV-2 infection aims to eliminate the virus from the body. Many studies have carefully described the various stages of the immune response after initial infection, but we do not know which aspects of immunity are essential for preventing repeat infections. What are the relative roles of different types of antibodies, or the importance of different T cell subsets?
An important goal of Sars-CoV-2 immunological research is, therefore, to identify which immune component (or components) can show a person is protected from future infection. Such a marker would be termed a “correlate of protection”.
The ability to measure an accurate correlate of protection would be valuable for two reasons. First, it could tell us whether someone who has recovered from COVID-19 is likely to get re-infected. Second, identifying an easily measurable correlate of protection would be helpful for vaccine trials – it could speed up the evaluation of vaccine efficacy.
However, identifying good correlates of protection for other coronaviruses has proven notoriously difficult. Useful results have previously only been generated when volunteers were experimentally infected with viruses. The first human Sars-Cov-2 challenge studies are now due to begin early next year, so it is hoped that this will enable correlates of protection to be found more rapidly.
How can we explain the extreme geographical variation in COVID-19 mortality rates?
Derek Gatherer, Lecturer and Fellow of the Institute for Social Futures, Lancaster University
Cumulative deaths from COVID-19 per million of population (dpm), are very unevenly distributed across Europe (see map below) ranging from 7dpm in Slovakia to 856dpm in Belgium. A wedge of relatively lightly affected countries extends from Finland southwards to the northern Balkans.
There are similar pockets of low COVID-19 mortality on other continents, notably south-east Asian countries. Could the populations of low mortality countries have some cross-immunity to Sars-CoV-2 generated by recent exposure to another coronavirus – the obvious candidates being the milder “common cold” coronaviruses: 229E, NL63, OC43 or HKU1?
We urgently need more lab studies to understand how much cross-immunity coronaviruses confer on each other, while population studies are needed to determine the prevalence of coronavirus antibodies, not just to Sars-CoV-2 but also its milder yet potentially significant cousins.
Serology – the study of antibody prevalence – has long been the Cinderella of virology compared with the more glamorous world of genome sequencing, but its significance and the consequences of its neglect are now becoming apparent.
For a vaccine, what does success look like in the short versus long term?
Anne Moore, Senior Lecturer in Biochemistry and Cell Biology, University College Cork
The endgame to the COVID-19 pandemic requires the identification and manufacture of a safe and effective vaccine and a subsequent global immunisation campaign.
Candidate Sars-CoV-2 vaccines were rapidly developed based on years of vaccine development efforts. The unprecedented and significant input of global funding into this pandemic vaccine effort can only buy so much time for trials to succeed or fail. A successful trial needs the virus to be circulating in the community so we can determine how many vaccinated people (versus those receiving a placebo) become infected.
Short-term success will show that a safe vaccine will provide at least 50% protection. And if we see short-term success, what does long-term success look like?
The biggest question is, what is the duration of protection? If it is short-lived, then how do we boost immunity back to protective levels? How do we figure this out without relying on a traditional empirical approach? If there isn’t short-term success, then how do we ensure that global commitment is maintained to prevent Sars-CoV-2 vaccines from ending up in the same situation as terminated vaccine efforts for Sars? There will be another pandemic; we need a long-term vision and commitment to have short-term future success.
How can COVID-safe behaviour become embedded in people’s lives?
Susan Michie and Robert West, Professors of Health Psychology, UCL
It looks as though COVID-19 will be with us for the foreseeable future. We will all have to adopt a range of behaviours to keep ourselves from getting infected or infecting others. We know what these are: the question is how they can become embedded in our lives?
The behaviours include keeping a greater physical distance from others; carrying a COVID kit (face mask, hand sanitiser and tissues) whenever we are outside the home; wearing a face mask properly in indoor public areas and storing or disposing of it safely; disinfecting hands and surfaces after possible contamination; catching coughs and sneezes in tissues; never touching our eyes, nose or mouth unless we know our hands are clean; avoiding or leaving unsafe situations, such as poorly ventilated indoor areas where there are lots of people; getting vaccinated; and staying at home and getting tested if we have symptoms.
The challenge is how to get these adopted at scale and maintained over time, in other words, embedded in people’s lives as routines and habits. This requires an understanding of what maintains and changes human behaviour. We need to equip people with the skills to develop routines that can become habits over time, provide the time and social and environmental support to achieve this and motivate them to use these opportunities.
What is the full spectrum of health consequences of COVID-19 infection?
David Hunter, Richard Doll Professor of Epidemiology and Medicine, University of Oxford
We now have good data on deaths from COVID-19 infection, showing an astonishing increase in risk of death with increasing age. This contrasts with the 2009 H1N1 flu epidemic, in which the aged were relatively less affected, and reminds us that we have a great deal more to learn about this virus.
While most of the focus has been on deaths, small studies of COVID-19 survivors discharged from hospital suggest that many do not return to their baseline health status. We know little about “long COVID” among those who did not require hospital admission, despite many individual reports of recurrent bouts of fever, fatigue, and a wide range of other symptoms.
Follow-up of COVID-19 patients suggest evidence of damage to the heart, lungs and other organs that may cause problems in the future, and there is some evidence that this may be true even among those with mild symptoms. Many viral infections can cause undiagnosed pathology, but severe long-term effects are relatively uncommon. If these effects are more common for COVID-19, however, then an exclusive focus on deaths means that we will not be considering the full costs of failing to control the epidemic, nor the full benefits of doing so.
Studies have started among patients after discharge from hospital. We urgently need well-controlled studies among the majority of those infected who did not need hospitalisation in case we are only seeing the tip of the COVID iceberg.
ABOUT THE AUTHORS
Sarah L Caddy is a vet and a Wellcome Trust Clinical Research Fellow at the new Cambridge Institute for Therapeutic Immunology and Infectious Disease (CITIID). Her research focuses on how antibodies can protect us from different virus infections. She is interested in viruses of all species, and hold a Diploma from the American College of Veterinary Microbiology.
Anne Moore is a Senior Lecturer in Biochemistry and Cell Biology, University College Cork. Dr. Moore graduated with a degree in Biochemistry University College Cork. She completed a PhD in HIV vaccine immunology with Professor Kingston Mills. Dr. Moore subsequently embarked upon post-doctoral work on defects in immune responses in HIV-infected individuals in the Wistar Institute in Philadelphia and further work on recombinant vaccines against viruses such as HIV and Ebola virus in Dr. Gary Nabel’s lab then at the University of Michigan. As a senior immunologist in Prof. Adrian Hill’s group in the University of Oxford, she developed several T cell inducing vaccine candidates against malaria and TB and was involved in clinical trials of these and other vaccine candidates in Oxford and malaria endemic areas in Africa. She was a Lecturer in Pharmacology, based in the School of Pharmacy, in early 2007. In 2016 she worked for 10 months with the vaccine biotech company, Vaxart, South San Francisco while on sabbatical. Here she worked on tablet-based oral vaccines for a range of therapeutic and prophylactic vaccine. In September 2018, she took a position as Senior Lecturer in Biochemistry and Cell Biology.
Connor Bamford is Research Fellow, Virology, Queen’s University Belfast. Connor is a virologist with over a decade of experience in studying how the immune system defends humans and other animals against disease-causing microbes like viruses, such as the hepatitis C virus, influenza virus and Zika virus. Connor recently moved to Queen’s University Belfast as a ‘Wellcome Trust Institutional Strategic Support Fund (ISSF) Early Career Research Fellow’ to continue his research into the human immune system and antiviral proteins called ‘interferons’. Connor obtained his PhD in 2014 in molecular virology studying the mumps virus before carrying out his postdoctoral research at the MRC-University of Glasgow Centre for Virus Research (CVR) in Scotland, UK.
David Hunter is the Richard Doll Professor of Epidemiology and Medicine, University of Oxford. Dr. Hunter trained as a medical doctor at the University of Sydney, Australia, then did doctoral training in Epidemiology at the Harvard TH Chan School of Public Health. He was on the faculty at Harvard for over 25 years doing research on HIV, cancer and genetic epidemiology. He was Dean for Academic Affairs and Acting Dean of the School, before moving to Oxford University as the Richard Doll Professor of Epidemiology and Medicine.
Derek Gatherer, Lecturer, Lancaster University is a Fellow of the Institute for Social Futures and currently researching assembly of Illumina and Nanopore sequences of Leishmania (Mundinia sub-genus) genomes.
Robert West is Professor of Health Psychology and Director of Tobacco Studies at UCL. Current research includes randomised trials of improved ways of helping smokers to stop, national and internal surveys and cohort studies of smoking behaviour, qualitative studies on the process of stopping smoking, laboratory studies on the acute effects of stopping smoking and how these can be mitigated by psychological and pharmacological interventions, and studies to assess and disseminate best practice in smoking cessation clinics.
Susan Michie, Professor of Health Psychology and Director of the UCL Centre for Behaviour Change, UCL. Susan Michie, FMedSci, FAcSS is Professor of Health Psychology and Director of the Centre for Behaviour Change at University College London. Professor Michie’s research focuses on behaviour change in relation to health: how to understand it theoretically and apply theory to intervention development, evaluation and implementation. She has developed innovative methods for characterising and reporting interventions and for synthesising evidence about the effectiveness of complex interventions, working across disciplines such as information science, environmental science, computer science and medicine.