Validation of laboratory developed serology assays for detection of IgG antibody to severe acute respiratory syndrome coronavirus 2 in the South African population.

Serological assays for detection of IgG, IgM or IgA against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) play an important role in surveillance, antibody persistence, vaccine coverage and infection rate. Serological assays, including both ELISA and rapid lateral flow assays, are available commercially but the cost limits their accessibility for low resource countries. Although serological assays based on mammalian-expressed SARS-CoV-2 spike protein have been previously described these assays need to be validated using samples from local populations within the continent, or country, in which they will be used. Interpretation of results could be influenced by differences in specificity and potential for pre-existing cross-reactive antibodies. In this study, we investigated two laboratory developed serological assays, an enzyme linked immunosorbent assay (ELISA) and an immunofluorescent assay (IFA), developed using recombinant SARS-CoV-2 spike protein, for use in South African populations. The tests were compared with commercially available and South Africa Health Products Regulatory Authority (SAPHRA) approved assays. A panel of 100 residual diagnostic serum samples, collected prior to the pandemic, were tested on three separate occasions to determine a suitable cut-off value for differentiation of positive from negative samples. Specificity of 96 % and 100 % for ELISA and IFA respectively was demonstrated. A total of 82/89 serum samples collected between days 2-94 after onset of illness from patients with a positive molecular result were positive for IgG antibody. The sensitivity of the laboratory developed assays on samples collected > one week after onset of illness was shown to be 100 % and 98.8 % for ELISA and IFA respectively. Positive predictive values were 92.1 % for ELISA and 91.0 % for IFA using characterization of samples as positive based on confirmation of infection using RT-PCR. Serum samples (n = 62) collected from RT-PCR positive patients infected with either ancestral, or emerging variants such as Beta or Delta, tested positive for IgG antibody (62/62) using the laboratory developed assays confirming application of the assays regardless of currently circulating variant during the time of evaluation. High concordance was demonstrated between the laboratory developed assays and the commercial immunoassay among samples collected from South African populations, although the small sample size, especially for the comparison with commercial assays, must be noted. If all quality assurance controls are in place, the use of local laboratory developed assays for high-throughput screening in resource-constrained environments is a realistic alternative option.

Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses (preprint)

It is unclear whether prior endemic coronavirus infections affect COVID-19 severity. Here, we show that in cases of fatal COVID-19, antibody responses to the SARS-COV-2 spike are directed against epitopes shared with endemic beta-coronaviruses in the S2 subunit of the SARS-CoV-2 spike protein. This immune response is associated with the compromised production of a de novo SARS-CoV-2 spike response among individuals with fatal COVID-19 outcomes.

Potential impact of individual exposure histories to endemic human coronaviruses on age-dependence in severity of COVID-19 (preprint)

Cross-reactivity to SARS-CoV-2 from previous exposure to endemic coronaviruses (eHCoV) is gaining increasing attention as a possible driver of both protection against infection and severity of COVID-19 disease. Here, we use a stochastic individual-based model to show that heterogeneities in individual exposure histories to endemic coronaviruses are able to explain observed age patterns of hospitalisation due to COVID-19 in EU/EEA countries and the UK, provided there is (i) a decrease in cross-protection to SARS-CoV-2 with the number of eHCoV exposures and (ii) an increase in potential disease severity with number of eHCoV exposures or as a result of immune senescence. We also show that variation in health care capacity and testing efforts is compatible with country-specific differences in hospitalisation rates. Our findings call for further research on the role of cross-reactivity to endemic coronaviruses and highlight potential challenges arising from heterogeneous health care capacity and testing.

The impact of host resistance on cumulative mortality and the threshold of herd immunity for SARS-CoV-2 (preprint)

It is widely believed that the herd immunity threshold (HIT) required to prevent a resurgence of SARS-CoV-2 is in excess of 50% for any epidemiological setting. Here, we demonstrate that HIT may be greatly reduced if a fraction of the population is unable to transmit the virus due to innate resistance or cross-protection from exposure to seasonal coronaviruses. The drop in HIT is proportional to the fraction of the population resistant only when that fraction is effectively segregated from the general population; however, when mixing is random, the drop in HIT is more precipitous. Significant reductions in expected mortality can also be observed in settings where a fraction of the population is resistant to infection. These results help to explain the large degree of regional variation observed in seroprevalence and cumulative deaths and suggest that sufficient herd-immunity may already be in place to substantially mitigate a potential second wave.

Neutralising antibodies to SARS coronavirus 2 in Scottish blood donors - a pilot study of the value of serology to determine population exposure (preprint)

BackgroundThe progression and geographical distribution of SARS coronavirus 2 (SARS-CoV-2) infection in the UK and elsewhere is unknown because typically only symptomatic individuals are diagnosed. We performed a serological study of blood donors in Scotland between the 17th of March and the 18th of May to detect neutralising antibodies to SARS-CoV-2 as a marker of past infection and epidemic progression. AimTo determine if sera from blood bank donors can be used to track the emergence and progression of the SARS-CoV-2 epidemic. MethodsA pseudotyped SARS-CoV-2 virus microneutralisation assay was used to detect neutralising antibodies to SARS-CoV-2. The study group comprised samples from 3,500 blood donors collected in Scotland between the 17th of March and 19th of May, 2020. Controls were collected from 100 donors in Scotland during 2019. ResultsAll samples collected on the 17th March, 2020 (n=500) were negative in the pseudotyped SARS-CoV-2 virus microneutralisation assay. Neutralising antibodies were detected in 6/500 donors from the 23th-26th of March. The number of samples containing neutralising antibodies did not significantly rise after the 5th-6th April until the end of the study on the 18th of May. We find that infections are concentrated in certain postcodes indicating that outbreaks of infection are extremely localised. In contrast, other areas remain comparatively untouched by the epidemic. ConclusionThese data indicate that sero-surveys of blood banks can serve as a useful tool for tracking the emergence and progression of an epidemic like the current SARS-CoV-2 outbreak.

Fundamental principles of epidemic spread highlight the immediate need forlarge-scale serological surveys to assess the stage of the SARS-CoV-2 epidemic (preprint)

The spread of a novel pathogenic infectious agent eliciting protective immunity is typically characterised by three distinct phases: (I) an initial phase of slow accumulation of new infections (often undetectable), (II) a second phase of rapid growth in cases of infection, disease and death, and (III) an eventual slow down of transmission due to the depletion of susceptible individuals, typically leading to the termination of the (first) epidemic wave. Before the implementation of control measures (e.g. social distancing, travel bans, etc) and under the assumption that infection elicits protective immunity, epidemiological theory indicates that the ongoing epidemic of SARS-CoV-2 will conform to this pattern. Here, we calibrate a susceptible-infected-recovered (SIR) model to data on cumulative reported SARS-CoV-2 associated deaths from the United Kingdom (UK) and Italy under the assumption that such deaths are well reported events that occur only in a vulnerable fraction of the population. We focus on model solutions which take into consideration previous estimates of critical epidemiological parameters such as the basic reproduction number (R0), probability of death in the vulnerable fraction of the population, infectious period and time from infection to death, with the intention of exploring the sensitivity of the system to the actual fraction of the population vulnerable to severe disease and death. Our simulations are in agreement with other studies that the current epidemic wave in the UK and Italy in the absence of interventions should have an approximate duration of 2-3 months, with numbers of deaths lagging behind in time relative to overall infections. Importantly, the results we present here suggest the ongoing epidemics in the UK and Italy started at least a month before the first reported death and have already led to the accumulation of significant levels of herd immunity in both countries. There is an inverse relationship between the proportion currently immune and the fraction of the population vulnerable to severe disease. This relationship can be used to determine how many people will require hospitalisation (and possibly die) in the coming weeks if we are able to accurately determine current levels of herd immunity. There is thus an urgent need for investment in technologies such as virus (or viral pseudotype) neutralization assays and other robust assays which provide reliable read-outs of protective immunity, and for the provision of open access to valuable data sources such as blood banks and paired samples of acute and convalescent sera from confirmed cases of SARS-CoV-2 to validate these. Urgent development and assessment of such tests should be followed by rapid implementation at scale to provide real-time data. These data will be critical to the proper assessment of the effects of social distancing and other measures currently being adopted to slow down the case incidence and for informing future policy direction.