Predictions on the path that COVID-19 will next take are common in the media, but there is a great deal that unknown at this point. Professor Martin Michaelis and Dr Mark Wass of Kent’s School of Biosciences explain why it is not possible to make reliable predictions:
‘In the current situation, it is impossible to predict how the COVID-19 pandemic will develop in the next months or years, because our knowledge is still too limited. Here are some reasons for this:
1) We do not know how many individuals have been infected.
‘Currently, we have no accurate way to measure how many people have been infected with SARS-CoV-2 (the coronavirus that causes COVID-19). To determine this, we need reliable antibody tests that will show whether individuals have developed antibodies against SARS-CoV-2 as part of their immune response. Once we have, we can investigate whether only a small proportion of individuals have been infected, as it is currently estimated, or if a larger part of the population has been in contact with the coronavirus; this will be a critical piece of information.
‘If the proportion of people with anti-SARS-CoV-2 antibodies is low, the virus may be more deadly than we have assumed so far. If there are many more individuals with anti-SARS-CoV-2 antibodies than expected, the disease may be generally milder than we have thought.
2) We do not know whether individuals are immune after they have been infected.
‘Although it may be common that the immune response associated with an infection results in immunity, this is not always the case. Hence, we do not know whether individuals who have been in contact with the virus are immune to COVID-19 (even if we have reliable antibody tests). If they are immune, then we do not know for how long. If the immunity is short-lived (e.g. for few months or years) it will not provide long-term protection or herd immunity against further SARS-CoV-2 waves.
‘For certain viruses, such as Dengue virus, the opposite has been observed. In Dengue virus infection, the first infection is usually mild, but subsequent infections are typically associated with severe, life-threatening disease. This was discovered during vaccine studies, when vaccinated individuals had a dramatically increased risk of becoming critically ill. The processes underlying this phenomenon is called “antibody-dependent enhancement”. However, antibody-dependent enhancement has been described in animal models for other coronaviruses including SARS-CoV, which caused SARS in 2002/ 2003 and is closely related to the currently circulating SARS-CoV-2, and MERS-CoV, which has so far infected almost 2,500 individuals predominantly in the Middle East and with a death rate of about a third. Hence, we cannot be sure that an infection with SARS-CoV-2 results in immunity.
3) We do not know whether it will be possible to develop a vaccine.
‘This aspect is closely related to the previous on immunity. If natural infection does not result in lasting immunity, it may be difficult to develop a vaccine that does. If antibody-dependent enhancement is a problem, a vaccine may make the situation worse. Notably, there are a number of viruses for which it has not been possible to develop effective vaccines so far, including the closely related SARS-CoV but also, for example, HIV and hepatitis C virus.
4) We do not know whether the virus may change.
‘Currently, we know very little about coronavirus and its behaviour. This is why there is such breadth of different predictions and regular change in advice. Even if some of the current predictions turn out to be correct, the virus may change over time, which makes reliable predictions impossible. The genomes of viruses such as SARS-CoV-2 are much less stable than, for example, human genomes. There is not the same level of proofreading during genome replication, so the mutation rate is higher and new variants with changed properties may emerge at any time. This could mean that new variants may be able to emerge quickly, that can bypass pre-existing immunity caused by previous infections or vaccines.
‘This is, for example, the case for influenza viruses and the reason why there is a new influenza vaccine every year. New variants may be associated with both milder and more aggressive disease. Since we have little experience with this virus, we will have to learn more about the capacity of SARS-CoV-2 to produce novel variants over time.
5) We do not know whether SARS-CoV-2 is here to stay.
‘SARS-CoV disappeared after a bit more than six months. How can we know that it will not be the same for SARS-CoV-2? The honest answer is, we cannot, but it seems very unlikely. SARS patients were only infectious and could spread the virus, when they were already ill. In this case, it is relatively easy to contain a virus by isolation and quarantine. For the same reason, the Ebola virus outbreak in West Africa (2013-2016) could eventually be stopped. Ebola virus disease patients are only contagious when they are ill and only via direct contact. In contrast, COVID-19 is spread by individuals who have yet to develop any symptoms and even by those who may never develop symptoms.
‘Therefore, it is much less likely that SARS-CoV-2 may disappear as SARS-CoV did in 2003.
‘If SARS-CoV-2 infection results in sustainable immunity, an effective vaccine can be developed and if the capacity of the virus to change is limited, there may be a chance to get rid of it. However, if one of these prerequisites is not met, it may be likely here to stay. This would mean that we could expect a resurgence of SARS-CoV-2, as we consistently do for influenza viruses.
‘Moreover, it must be considered that SARS-CoV-2 has been transmitted from an animal reservoir to humans. Therefore, it is possible that there will be further animal-to-human transmissions, even if the current variant could be eradicated in the human population. New reports of a case in France from December may suggest that such transmissions may be more common than previously anticipated.
6) We do not know how to use antiviral drugs, even if we have them.
‘The treatment of diseases like COVID-19 is complicated, because the damage is caused by two processes:
1) The direct damage caused by the virus when it replicates and destroys cells
2) An overshooting immune response (also called ‘cytokine storm‘).
‘This means that antiviral drugs would be needed to control virus replication and also immunosuppressive drugs to control the immune response. However, these drugs cannot be simply combined, because the antiviral drugs may not be effective without the support of the immune system. Remdesivir, the antiviral drug that has recently received preliminary approval from the US Food and Drug Administration (FDA), seems to have shown mixed effects in different trials. Recently, it was described in a placebo-controlled trial carried out by the US National Institutes of Health to reduce recovery time from 15 to 11 days in seriously ill COVID-19 patients. There is hope that earlier application of remdesivir to patients before they develop severe disease may control the virus and prevent an overshooting immune response. If this does not work, then therapy success may depend on complex treatment regimens that combine antiviral and immunomodulatory drugs.
‘Taken together, based on the currently available data there is no certainty with regard to the further development of the COVID-19 pandemic. It is in the same way possible to draw up plausible scenarios that are relatively mild or those that result in the deaths of millions.’
Professor Martin Michaelis and Dr Mark Wass, School of Biosciences, University of Kent
Professor Michaelis and Dr Wass run a joint computational/wet laboratory. Dr Wass is a computational biologist with expertise in structural biology and big data analysis. Professor Michaelis’ research is focused on the identification and investigation of drugs and their mechanisms of action, with a focus on cancer and viruses.
With regard to viruses, Professor Michaelis and Dr Wass work on virus-host cell interactions and antiviral drug targets. In the cancer field, they investigate drug resistance in cancer. In collaboration with Professor Jindrich Cinatl (Goethe-University, Frankfurt am Main), they manage and develop the Resistant Cancer Cell Line (RCCL) Collection, a unique collection of 2,000 cancer cell lines with acquired resistance to anti-cancer drugs. They are also interested in meta-research that investigates research practices in the life sciences.
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