Replacement dynamics and the pathogenesis of the Alpha, Delta and Omicron variants of SARS-CoV-2.

New SARS-CoV-2 variants causing COVID-19 are a major risk to public health worldwide due to the potential for phenotypic change and increases in pathogenicity, transmissibility and/or vaccine escape. Recognising signatures of new variants in terms of replacing growth and severity are key to informing the public health response. To assess this, we aimed to investigate key time periods in the course of infection, hospitalisation and death, by variant. We linked datasets on contact tracing (Contact Tracing Advisory Service), testing (the Second-Generation Surveillance System) and hospitalisation (the Admitted Patient Care dataset) for the entire length of contact tracing in the England - from March 2020 to March 2022. We modelled, for England, time delay distributions using a Bayesian doubly interval censored modelling approach for the SARS-CoV-2 variants Alpha, Delta, Delta Plus (AY.4.2), Omicron BA.1 and Omicron BA.2. This was conducted for the incubation period, the time from infection to hospitalisation and hospitalisation to death. We further modelled the growth of novel variant replacement using a generalised additive model with a negative binomial error structure and the relationship between incubation period length and the risk of a fatality using a Bernoulli generalised linear model with a logit link. The mean incubation periods for each variant were: Alpha 4.19 (95% credible interval (CrI) 4.13-4.26) days; Delta 3.87 (95% CrI 3.82-3.93) days; Delta Plus 3.92 (95% CrI 3.87-3.98) days; Omicron BA.1 3.67 (95% CrI 3.61-3.72) days and Omicron BA.2 3.48 (95% CrI 3.43-3.53) days. The mean time from infection to hospitalisation was for Alpha 11.31 (95% CrI 11.20-11.41) days, Delta 10.36 (95% CrI 10.26-10.45) days and Omicron BA.1 11.54 (95% CrI 11.38-11.70) days. The mean time from hospitalisation to death was, for Alpha 14.31 (95% CrI 14.00-14.62) days; Delta 12.81 (95% CrI 12.62-13.00) days and Omicron BA.2 16.02 (95% CrI 15.46-16.60) days. The 95th percentile of the incubation periods were: Alpha 11.19 (95% CrI 10.92-11.48) days; Delta 9.97 (95% CrI 9.73-10.21) days; Delta Plus 9.99 (95% CrI 9.78-10.24) days; Omicron BA.1 9.45 (95% CrI 9.23-9.67) days and Omicron BA.2 8.83 (95% CrI 8.62-9.05) days. Shorter incubation periods were associated with greater fatality risk when adjusted for age, sex, variant, vaccination status, vaccination manufacturer and time since last dose with an odds ratio of 0.83 (95% confidence interval 0.82-0.83) (P value < 0.05). Variants of SARS-CoV-2 that have replaced previously dominant variants have had shorter incubation periods. Conversely co-existing variants have had very similar and non-distinct incubation period distributions. Shorter incubation periods reflect generation time advantage, with a reduction in the time to the peak infectious period, and may be a significant factor in novel variant replacing growth. Shorter times for admission to hospital and death were associated with variant severity - the most severe variant, Delta, led to significantly earlier hospitalisation, and death. These measures are likely important for future risk assessment of new variants, and their potential impact on population health.

The real-time infection hospitalisation and fatality risk across the COVID-19 pandemic in England.

The COVID-19 pandemic led to 231,841 deaths and 940,243 hospitalisations in England, by the end of March 2023. This paper calculates the real-time infection hospitalisation risk (IHR) and infection fatality risk (IFR) using the Office for National Statistics Coronavirus Infection Survey (ONS CIS) and the Real-time Assessment of Community Transmission Survey between November 2020 to March 2023. The IHR and the IFR in England peaked in January 2021 at 3.39% (95% Credible Intervals (CrI): 2.79, 3.97) and 0.97% (95% CrI: 0.62, 1.36), respectively. After this time, there was a rapid decline in the severity from infection, with the lowest estimated IHR of 0.32% (95% CrI: 0.27, 0.39) in December 2022 and IFR of 0.06% (95% CrI: 0.04, 0.08) in April 2022. We found infection severity to vary more markedly between regions early in the pandemic however, the absolute heterogeneity has since reduced. The risk from infection of SARS-CoV-2 has changed substantially throughout the COVID-19 pandemic with a decline of 86.03% (80.86, 89.35) and 89.67% (80.18, 93.93) in the IHR and IFR, respectively, since early 2021. From April 2022 until March 2023, the end of the ONS CIS study, we found fluctuating patterns in the severity of infection with the resumption of more normative mixing, resurgent epidemic waves, patterns of waning immunity, and emerging variants that have shown signs of convergent evolution.

Growth, reproduction numbers and factors affecting the spread of SARS-CoV-2 novel variants of concern in the UK from October 2020 to July 2021: a modelling analysis.

OBJECTIVES: Importations of novel variants of concern (VOC), particularly B.1.617.2, have become the impetus behind recent outbreaks of SARS-CoV-2. Concerns around the impact on vaccine effectiveness, transmissibility and severity are now driving the public health response to these variants. This paper analyses the patterns of growth in hospitalisations and confirmed cases for novel VOCs by age groups, geography and ethnicity in the context of changing behaviour, non-pharmaceutical interventions (NPIs) and the UK vaccination programme. We seek to highlight where strategies have been effective and periods that have facilitated the establishment of new variants. DESIGN: We have algorithmically linked the most complete testing and hospitalisation data in England to create a data set of confirmed infections and hospitalisations by SARS-CoV-2 genomic variant. We have used these linked data sets to analyse temporal, geographic and demographic distinctions. SETTING AND PARTICIPANTS: The setting is England from October 2020 to July 2021. Participants included all COVID-19 tests that included RT-PCR CT gene target data or underwent sequencing and hospitalisations that could be linked to these tests. METHODS: To calculate the instantaneous growth rate for VOCs we have developed a generalised additive model fit to multiple splines and varying day of the week effects. We have further modelled the instantaneous reproduction number Rt for the B.1.1.7 and B.1.617.2 variants and included a doubly interval censored model to temporally adjust the confirmed variant cases. RESULTS: We observed a clear replacement of the predominant B.1.1.7 by the B.1.617.2 variant without observing sustained exponential growth in other novel variants. Modelled exponential growth of RT PCR gene target triple-positive cases was initially detected in the youngest age groups, although we now observe across all ages a very small doubling time of 10.7 (95% CI 9.1 to 13.2) days and 8 (95% CI 6.9 to 9.1) days for cases and hospitalisations, respectively. We observe that growth in RT PCR gene target triple-positive cases was first detected in the Indian ethnicity group in late February, with a peak of 0.06 (95% CI 0.07 to 0.05) in the instantaneous growth rate, but is now maintained by the white ethnicity groups, observing a doubling time of 6.8 (95% CI 4.9 to 11) days. Rt analysis indicates a reproduction number advantage of 0.45 for B.1.617.2 relative to B.1.1.7, with the Rt value peaking at 1.85 for B.1.617.2. CONCLUSIONS: Our results illustrate a clear transmission advantage for the B.1.617.2 variant and the growth in hospitalisations illustrates that this variant is able to maintain exponential growth within age groups that are largely doubly vaccinated. There are concerning signs of intermittent growth in the B.1.351 variant, reaching a 28-day doubling time peak in March 2021, although this variant is presently not showing any evidence of a transmission advantage over B.1.617.2. Step 1b of the UK national lockdown easing was sufficient to precipitate exponential growth in B.1.617.2 cases for most regions and younger adult age groups. The final stages of NPI easing appeared to have a negligible impact on the growth of B.1.617.2 with every region experiencing sustained exponential growth from step 2. Nonetheless, early targeted local NPIs appeared to markedly reduced growth of B.1.617.2. Later localised interventions, at a time of higher prevalence and greater geographic dispersion of this variant, appeared to have a negligible impact on growth.

Raf-mediated cardiac hypertrophy in adult Drosophila.

In response to stress and extracellular signals, the heart undergoes a process called cardiac hypertrophy during which cardiomyocytes increase in size. If untreated, cardiac hypertrophy can progress to overt heart failure that causes significant morbidity and mortality. The identification of molecular signals that cause or modify cardiomyopathies is necessary to understand how the normal heart progresses to cardiac hypertrophy and heart failure. Receptor tyrosine kinase (RTK) signaling is essential for normal human cardiac function, and the inhibition of RTKs can cause dilated cardiomyopathies. However, neither investigations of activated RTK signaling pathways nor the characterization of hypertrophic cardiomyopathy in the adult fly heart has been previously described. Therefore, we developed strategies using Drosophila as a model to circumvent some of the complexities associated with mammalian models of cardiovascular disease. Transgenes encoding activated EGFR(A887T), Ras85D(V12) and Ras85D(V12S35), which preferentially signal to Raf, or constitutively active human or fly Raf caused hypertrophic cardiomyopathy as determined by decreased end diastolic lumen dimensions, abnormal cardiomyocyte fiber morphology and increased heart wall thicknesses. There were no changes in cardiomyocyte cell numbers. Additionally, activated Raf also induced an increase in cardiomyocyte ploidy compared with control hearts. However, preventing increases in cardiomyocyte ploidy using fizzy-related (Fzr) RNAi did not rescue Raf-mediated cardiac hypertrophy, suggesting that Raf-mediated polyploidization is not required for cardiac hypertrophy. Similar to mammals, the cardiac-specific expression of RNAi directed against MEK or ERK rescued Raf-mediated cardiac hypertrophy. However, the cardiac-specific expression of activated ERK(D334N), which promotes hyperplasia in non-cardiac tissues, did not cause myocyte hypertrophy. These results suggest that ERK is necessary, but not sufficient, for Raf-mediated cardiac hypertrophy.