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8th November 2022
With Omicron BA.2 (OBA2) giving rise to less severe infections, it is possible, suggests US researchers, that the COVID-19 virus is mutating to become milder.
In a study covering the period from October to December 2021 in South African, researchers concluded that infection with the Omicron COVID-19 variant led to a significantly reduced odds of hospitalisation. In fact, this was not an isolated finding and a Canadian study with 9,087 cases of Omicron, also found that infection with the variant was less severe. But as the virus mutated, an assessment of the severity of infections with one variant, OBA2, has produced conflicting results. For instance, one study found that all the Omicron variants investigated (including Omicron BA.2) led to a less severe infection compared to the Delta variant. In contrast, a French study showed that patients infected with the OBA2 variant were significantly more likely to be hospitalised and that the BA.2 variant was an independent risk factor for hospitalisation.
This led the US researchers to undertake a large, retrospective analysis of the severity of infection with the Omicron BA.2 lineage. They used data held within both inpatient and outpatient systems in New England and identified individuals infected with the Delta, Omicron B.1.1.529 and the Omicron BA.2 variants. Though genomic sequencing was not performed, infections were categorised as either Delta, Omicron or Omicron sub-variants according to the timing of the onset of disease detection. For example, infections between June and December 2021 were classed as Delta and cases between March and May 2022 as the Omicron BA.2 variant. The researchers included vaccination status, ethnicity and co-morbidities as covariates in their analysis and set the primary outcome as in-hospital death within 30 days of a positive COVID-19 test result. They also considered the need for invasive ventilation and intensive care unit admission as secondary outcomes.
Omicron BA.2 and COVID-19 outcomes
A total of 102,315 confirmed COVID-19 infections in patients with a mean age of 44.2 years (62% female) were included and of whom, 28,940 were classed as OBA2 and 65.9% of these individuals had been fully vaccinated and had a booster, compared to only 2.6% of those infected with the Delta variant.
The mortality rates were 0.7%, 0.4% and 0.3% for the Delta, Omicron and OB2 variants respectively. After adjustment for covariates, the risk of the primary outcome (i.e., mortality) was significantly higher for those infected with the Delta variant compared to OBA2, (Odds ratio, OR = 2.07, 95% CI 1.04 – 4.10) and for the original Omicron strain (OR = 2.20, 95% CI 1.56 – 3.11).
In subgroup analysis, there were also higher risks of hospitalisation, intensive care admissions and the need for mechanical ventilation, for Delta and original Omicron infections compared to OBA2.
The authors concluded that after having accounted for a variety of confounding factors, it seemed that the Omicron BA.2 sub-variant was intrinsically less severe than other variants.
Strasser ZH et al. Estimates of SARS-CoV-2 Omicron BA.2 Subvariant Severity in New England JAMA Netw Open 2022
24th December 2021
According to a preprint study by researchers from the Centre for Respiratory Diseases and Meningitis, Johannesburg, South Africa, Omicron infections appear to be associated with reduced risk of hospitalisation and after admission, less severe disease than the Delta variant.
While the Omicron COVID-19 variant was only identified in November 2021, there has been a flurry of research activity directed at trying to understand its transmissibility, the level of disease severity and effect on healthcare services. While initial laboratory studies have indicated that the variant can escape neutralisation by antibodies generated in fully vaccinated and boosted sera samples, these studies cannot foretell the clinical impact of the variant.
The South African researchers undertook a data linkage study of COVID-19 infections, case data and genomic information to establish whether an Omicron infection was associated with higher rates of hospitalisation and more severe disease among those who were hospitalised in comparison to the Delta COVID-19 variant. Although whole genome sequencing was not used, they utilised the presence of a S Gene Target Failure (SGTF), which serves as a proxy for Omicron and samples were examined between 1st October 2021 and 6th December 2021. Positive infections were therefore classified as either an SGTF or non-SGTF. The severity of an Omicron infection was assessed by comparison of SGTF and non-SGTF infections and to infections known to be caused by the Delta variant and regression models created and adjusted for several factors known to be associated with hospitalisation (e.g., age, sex, co-morbidities).
During the period of study there were 161,328 COVID-19 cases recorded and the proportion of SGTFs increased from 3% (early October 2021) to 98% (early December).
A total of 11,495 hospital admissions occurred with 2.5% due to an SGTF compared to 12.8% with a non-SGTF (p < 0.001). Multivariate analysis revealed that individuals with a SGTF had a lower odds of hospitalisation (adjusted odds ratio, aOR = 0.2, 95% CI 0.1 – 0.3, p < 0.001). In addition, once hospitalised, the odds of having severe disease were also reduced in those with SGTF although there was uncertainty over this estimate given the wide confidence intervals (aOR = 0.70, 95% CI 0.30 – 1.40).
Finally, the researchers found that compared to infection with the Delta variant, those with an SGTF had a significantly lower risk of severe disease (aOR = 0.30, 95% CI 0.20 – 0.50, p < 0.001).
The authors suggested that these data suggested that an Omicron infection was probably less severe than other variants such as Delta but recognised that this reduced severity might be accounted for by the higher levels of population immunity due to either natural infection and/or vaccination.
These results are broadly similar to those of a second recently published preprint from Scotland which found a nearly 70% reduced risk of hospitalisation (expected ratio = 0.32, 95% CI 0.19 – 0.52) for those with an Omicron infection. The study also found that giving a third or booster dose was associated with a 57% reduced risk of symptomatic infection.
Although both studies are preliminary, they do suggest the possibility that infection with the new variant is potentially less severe than other forms.
Wolter N et al. Early assessment of the clinical severity of the SARS-CoV-2 Omicron variant in South Africa. MedRxiv 2021
22nd December 2021
Protection against severe COVID-19 from the Oxford vaccine (ChAdOx1) appears to wane as early as three months after the second dose according to a study by researchers from the MRC/CSO Social and Public Health Sciences Unit, University of Glasgow, UK.
Clinical trial data have shown that the currently available COVID-19 vaccines including ChAdOx1 provide a high level of protection against infection, however, evidence began to emerge of an increased incidence of infection among those who had been fully vaccinated. It was suggested that this might be due to either a waning of vaccine effectiveness or an increase in the dominance of new variants capable of immune escape. However, other data gathered over a 6 month period using the BNT162b2 vaccine found that its efficacy gradually reduced over this period of time.
For the present study, the UK team turned to data from Scotland and Brazil to examine the association between the time since the second vaccination with the Oxford vaccine (ChAdOx1) and the risk of severe COVID-19 outcomes. They chose Scotland and Brazil for comparative purposes because the Delta COVID-19 variant was the dominant strain in Scotland, whereas this was uncommon in Brazil. Consequently, if vaccine effectiveness reduced in both countries this would be unlikely to be because of the delta variant.
Using a retrospective design, the researchers linked data from the EAVE II study which provides COVID-19 data from 5.4 million people in Scotland and databases in Brazil to determine rates of infection, hospitalisation and deaths. They identified individuals from both countries aged 18 years and over who had received two doses of ChAdOx1 and set the primary outcome as the rate of severe COVID-19 outcomes, i.e., hospital admission or death, approximately two to three weeks after the second dose.
A total of 1972454 adults in Scotland and 42558839 in Brazil received two doses of ChAdOx1. However, an estimate of the vaccine effectiveness was based on a smaller cohort of 2534527 individuals with a mean age of 52 (49.9% male) in Scotland and 56013638 individuals in Brazil with a mean age of 48 years (47% male).
In Scotland the relative risk (RR) of severe COVID-19 was 2.01 (95% CI 1.54 – 2.62) 10 – 11 weeks after the second dose and increased further to 3.01 (after 14 – 15 weeks) and to 5.43 (after 18 – 19 weeks) compared with 2 – 3 weeks after the second dose. In Brazil there was a similar pattern at each time point, for example, the RR was 4.71 after 18 to 19 weeks.
The effectiveness of ChAdOx1 in Scotland decreased from 83.7% (95% CI 79.7 – 87) at weeks 2 – 3 to 63.7% (weeks 18 to 19). Similarly in Brazil vaccine efficacy reduced from 86.4% (2 – 3 weeks after second dose) to 42.2% (weeks 18 to 19).
Commenting on these findings, the authors noted how the similar drop in vaccine effectiveness was unlikely to be due to differences in circulating strains of the virus. They concluded on how these findings clearly illustrate how vaccine effectiveness reduces over time, highlighting the need for a booster vaccination dose.
Katikireddi SV et al. Two-dose ChAdOx1 nCoV-19 vaccine protection against COVID-19 hospital admissions and deaths over time: a retrospective, population-based cohort study in Scotland and Brazil. Lancet 2021
9th December 2021
RoActemra (tocilizumab) has received approval from the EMA for the treatment of adults with severe COVID-19 and who are in receipt of systemic treatment with corticosteroids and requiring supplemental oxygen or mechanical ventilation.
Until the COVID-19 approval, RoActemra was already approved for use in the management of inflammatory conditions including rheumatoid arthritis, systemic juvenile idiopathic arthritis, juvenile idiopathic polyarthritis, giant cell arteritis and cytokine release syndrome (CRS).
Tocilizumab is a monoclonal antibody that works by inhibiting the binding of interleukin-6 (IL-6) to its receptor and in doing so, Inhibits IL-6 signal transduction of inflammatory mediators in rheumatic diseases. However, emerging evidence has indicated a role for IL-6 signalling in patients hospitalised with severe COVID-19, especially those who are critically ill.
The approval for RoActemra was based on data from three phase III trials. In COVACTA, patients hospitalised with severe COVID-19 pneumonia were randomised, 2:1 to either a single intravenous infusion of tocilizumab (at a dose of 8mg per kilogram of body weight) or placebo. The primary outcome was clinical status at day 28 on an ordinal scale which ranged from 1 (discharged or ready for discharge) to 7 (death). In the published results of the trial, tocilizumab did not result in a significantly better clinical status or lower mortality than placebo at 28 days.
In EMPACTA, hospitalised patients with COVID-19 pneumonia, not receiving mechanical ventilation, were randomised to receive standard care plus one or two doses of either tocilizumab (8 mg per kilogram of body weight intravenously) or placebo. The primary outcome was mechanical ventilation or death by day 28 and the results showed that although tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or death, it did not improve survival.
In the REMDACTA study, patients were again randomised (2:1) to tocilizumab plus remdesivir or placebo plus remdesivir. The primary outcome was the time from randomisation to hospital discharge or “ready for discharge” (category 1 on a 7-category ordinal scale of clinical status) to day 28. As with the other trials, when published, the authors concluded that ‘tocilizumab plus remdesivir did not shorten time to hospital discharge or “ready for discharge” to day 28 compared with placebo plus remdesivir.’
However, despite these somewhat negative findings, a systemic review assessing the efficacy of IL-6 antagonists in patients hospitalised for COVID-19, in nearly 11,000 patients, concluded that ‘administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.’
Details of the revised indicated use in COVID-19 can be found in the summary of product characteristics.