Host or pathogen-related factors in COVID-19 severity? – Authors' reply
Authors: Lucy C Okell, Robert Verity, Aris Katzourakis, Erik M Volz, Oliver J Watson, Swapnil Mishra, Patrick Walker, Charlie Whittaker, Christl A Donnelly, Steven Riley, Azra C Ghani, Axel Gandy, Seth Flaxman, Neil M Ferguson, Samir Bhatt
Journal: The Lancet (2020)

Christian Gortázar and colleagues, in their response to our Correspondence about herd immunity in COVID-19,1Okell LC Verity R Watson OJ et al.Have deaths from COVID-19 in Europe plateaued due to herd immunity?.Lancet. 2020; 395: e110-e111Summary Full Text Full Text PDF PubMed Scopus (48) Google Scholar suggest that the mutation of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might provide an alternative explanation for the observed decline in deaths in Europe. As evidence, they highlight the observation that the SARS-CoV-2 virus has mutated,2Kim JS Jang JH Kim JM Chung YS Yoo CK Han MG Genome-wide identification and characterization of point mutations in the SARS-CoV-2 genome.Osong Public Health Res Perspect. 2020; 11: 101-111Crossref PubMed Scopus (72) Google Scholar, 3Zhang L Jackson CB Mou H et al.The D614G mutation in the SARS-CoV-2 spike protein reduces S1 shedding and increases infectivity.bioRxiv. 2020; (published online June 12.) (preprint)https://doi.org/10.1101/2020.06.12.148726Google Scholar alongside their own report arguing that the severity of COVID-19 has decreased over time.4Gortazar C Rodríguez del Río F Hervás D Dominguez L de la Fuente J COVID-19 severity declines over time.Authorea. 2020; (published online June 10.) (preprint)https://doi.org/10.22541/au.159181137.78287140Google Scholar Unfortunately, their own study appears to have ended before many recoveries could have occurred, severely undermining the main conclusion. There are, however, other data that could be interpreted as declining severity—for example, in Europe and parts of the USA from August to September, 2020, the number of cases have been rising without the expected spike in deaths shortly thereafter. The question is whether mutation can provide a parsimonious explanation for these trends. When thinking about viral evolution it is useful to make a distinction between transmissibility (chance of onward infection) and virulence (severity of disease). The D614G mutation, noted by Gortázar and colleagues, has been found to increase transmissibility,3Zhang L Jackson CB Mou H et al.The D614G mutation in the SARS-CoV-2 spike protein reduces S1 shedding and increases infectivity.bioRxiv. 2020; (published online June 12.) (preprint)https://doi.org/10.1101/2020.06.12.148726Google Scholar but large, well powered studies have not detected a link between this genetic variant and COVID-19 mortality.5Volz EM Hill V McCrone JT et al.Evaluating the effects of SARS-CoV-2 Spike mutation D614G on transmissibility and pathogenicity.medRxiv. 2020; (published online August 4.) (preprint)https://doi.org/10.1101/2020.07.31.20166082Google Scholar Furthermore, the increasing prevalence of the D614G variant largely predates the observed changes in COVID-19 mortality. Other SARS-CoV-2 mutations, such as Δ382, have been found to confer reduced virulence, but with no data showing increased transmissibility.6Young BE Fong S-W Chan Y-H et al.Effects of a major deletion in the SARS-CoV-2 genome on the severity of infection and the inflammatory response: an observational cohort study.Lancet. 2020; 396: 603-611Summary Full Text Full Text PDF Scopus (282) Google Scholar Crucially, neither of these mutations, nor any other mutation identified to date, can explain the sudden and large scale drop in deaths observed in many European countries following lockdown. Furthermore, the mutation hypothesis still offers no explanation as to why countries that enforced lockdown earlier should have had fewer deaths in subsequent weeks. Hence, we strongly disagree that mutation offers an alternative explanation for the trends described in our original Correspondence.What about the current trend of increasing cases without subsequent deaths? We think it is less plausible to be because of genetic factors, and basic epidemiological explanations should be first ruled out. Foremost among these explanations is that testing has increased, and might have been applied to a previously under-represented subset of the population. Cases might be concentrated in young people who are known to have a better prognosis. Treatment7Horby P Lim WS Emberson J et al.Effect of dexamethasone in hospitalized patients with COVID-19: preliminary report.medRxiv. 2020; (published online June 22.) (preprint)https://doi.org/10.1101/2020.06.22.20137273Google Scholar and clinical management have improved, alongside increased hospital capacity and response speed. SARS-CoV-2 will continue to evolve, and a gradual change in disease severity and transmissibility should be anticipated, but there is currently no evidence to support an evolutionary trend towards greater or lesser virulence. Competing epidemiological data must first be dismissed alongside more genetic evidence before it can be concluded that mutation has rendered COVID-19 a reduced threat to public health. We declare no competing interests. LCO, RV, NMF, and SB contributed equally. Have deaths from COVID-19 in Europe plateaued due to herd immunity?Transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently in marked decline in many countries in Europe, North America, and parts of Asia, following unprecedented governmental interventions aiming to substantially reduce travel and physical contact between individuals. There are two possible and very different explanations for this decline. Full-Text PDF Host or pathogen-related factors in COVID-19 severity?Lucy Okell and colleagues1 observed that the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently in marked decline in many countries. Okell and colleagues suggest two possible explanations for this decline, namely the effect of lockdowns, physical distancing, and other interventions; or, alternatively, herd immunity. After analysing trends in cumulative deaths over time in many European countries that went into lockdown at different stages of their epidemic, and data obtained from serology studies on the proportion of the population that had the infection previously, Okell and colleagues found few data to support an explanation that relies on herd immunity. Full-Text PDF