To date, the Western Cape Province of South Africa, has experienced four large waves of SARS-CoV-2 infections. The first wave caused by early ancestral clades of SARS-CoV-2 peaked in June 2020, the second wave with the Beta variant (B.1.351) peaked in December 2020, the third wave caused by the Delta variant (B.1.617.2) peaked in August 2021 and the fourth most recent wave was caused by the Omicron variant peaked in December 2021 ¹ .

Prior to the arrival of Omicron, Delta had been the dominant variant globally, its increased clinical severity particularly when compared to Alpha is well documented ^{2– 6} . Most of the severe disease in these studies occurred in those who were unvaccinated. The concern is that in these settings with well-established vaccination programmes, there are differences between the vaccinated and unvaccinated population, largely driven by socioeconomic disparities ⁷ , that might contribute to the clinical severity seen and confound the association between variant and disease severity. In addition, there is only limited data on Delta disease severity within a sub-Saharan African setting.

The start of the third wave of COVID-19 in the Western Cape Province was characterized by a rapid transition from the previously dominant Beta variant to Delta ⁸ . Using a novel proxy marker for Delta, namely RNA-dependent RNA polymerase (RdRp) target delay (RTD) in (polymerase chain reaction) PCR positive samples, our objective was to assess mortality associated with Delta, compared to Beta, in our population which had relatively low levels of vaccine coverage as well as a high prevalence of comorbidities, including HIV and tuberculosis.

The study was approved by the University of Cape Town Research Ethics Committee (HREC 460/2020).

We included 11,355 cases tested using the Seegene Allplex ^TM assay, which were 22% of all positive test results in the province in that time period ( Appendix Table 1). The median age was 43 years (interquartile range [IQR] 32-55) and 44% were male. RTD was present in 9106 (80%) of the cases included ( Table 1). Patient characteristics were similar in those with and without RTD. There was, however, a difference in Ct values (average of the E and N gene targets); those with RTD had lower median Ct values (26.1, IQR 22.2-30.9, vs 32.7 IQR 25.6-37.6).

Amongst the Seegene Allplex ^TM cases in our study, there were 700 deaths meeting the above definition for COVID-19-associatedness, with a case fatality rate of 6.3% in those with RTD, compared to 5.8% in those without. After adjusting for all covariates, we found that RTD was associated with death among cases (aOR 1.45 [95% CI 1.13-1.86]) and among those admitted to hospital (aOR 1.39 [95% CI 1.03-1.88]) ( Table 2).

Prior diagnosed infection with a first infection in the Beta dominated second wave (vs no prior diagnosed infection), was protective against death (aOR 0.32 [95% CI 0.11-0.92]), whereas prior diagnosed infection with a first infection in the first wave was not (aOR: 1.56 [95% CI 0.50-4.92]). Vaccination was protective against death. The aORs (95% CI) for partial and full vaccination were 0.59 (0.45-0.77) and 0.15 (0.03-0.62) respectively.

In a stratified analysis the association between RTD and death was similar in both those aged <50 and ≥50 years (aOR [95%CI] of 1.32 [0.77-2.26] and 1.44 [1.09-1.91] respectively).

RTD, a proxy marker for the Delta variant, was associated with an increased risk for death compared to presumptive Beta variant infection, while prior diagnosed infection (with first infection in the second wave) and vaccination were strongly protective. These findings are corroborated by a recent study from the Western Cape, which is the only other study to assess mortality with the Delta variant to compared to Beta. In that analysis, the wave itself was used as a proxy for variant, and the third wave (“Delta”: 26 May - 23 June 2021) had a higher aOR for mortality when compared to the second wave (“Beta”: 25 October - 21 November 2020) of 1.79 (95%CI 1.41-2.27) ¹³ , which is slightly higher than this analysis. Although the confidence intervals do overlap, the possible difference might be explained by the inclusion of cases after testing restrictions were in place in this analysis.

The increased transmissibility of Delta is well established, and may be due to its higher viral load ⁶ . In our analysis, specimens with RTD had lower Ct values than those without, suggesting a higher viral load. This, along with immune evasion by Delta, could contribute to the increased disease severity seen ¹⁴ . Nonetheless, our results need to be interpreted in the context of our setting where not all COVID-19 cases would have accessed testing. Delta often results in mild symptoms and during wave surges, as was the case from 15 June 2021 until the end of the analysis period, in the public sector only those aged ≥45 years or with comorbidities or requiring hospital admission would be eligible for all SARS-CoV-2 testing ¹⁵ . The interpretation of our results is therefore, that among those who access a PCR test, the Delta variant is associated with worse outcomes. While it is unclear if this finding can be extrapolated to all those with COVID-19 in our setting, similar findings from countries with more widespread testing support the increased clinical severity of Delta ^{2– 6} .

Hospital admission was more likely with Delta compared to Alpha in England (aHR 2.26 [95%CI 1.32-3.89]) ² and Denmark (RR 2.83 [95%CI 2.02-3.98]) ³ . In Singapore, infection with Delta and Beta vs. wild-type SARS-CoV-2 were both associated with a composite outcome of oxygen use, intensive care admission and death (aOR 4.9 [95%CI 1.43-30.78] and 1.69 [95%CI 0.19-14.69] respectively) ⁴ . Similarly, a recent study from Qatar found that Delta compared to Beta had an aOR of 3.61 (1.65-7.91) for severe-critical disease, which was defined as intensive care unit admission, use of high-flow oxygen, mechanical ventilation, or death ¹⁶ . Delta (vs wild-type) was associated with mortality in Canada (aOR 2.32 [95% CI 1.47-3.30]) as were N501Y-positive variants (Alpha, Beta, Gamma) (aOR 1.51 [95%CI 1.30-1.74]) ⁵ .

However, most of these countries had relatively high COVID-19 vaccination coverage rates by the time the Delta variant became dominant there ¹⁷ . Since most severe COVID-19 cases would be in unvaccinated people, differences between the vaccinated and the unvaccinated population might confound associations with variant infection and disease severity. By contrast in the Western Cape by 31 July 2021, only 5.0% of all adults, mostly in older age groups, were fully vaccinated ¹⁷ . In addition, most of these studies compared the outcomes of Delta to Alpha. The Alpha variant has been shown to have worse clinical outcomes compared to wild-type, with an aHR for death of 1.73 (95%CI 1.41 - 2.13) ¹⁸ .

Despite Delta no longer being the dominant variant, it continues to circulate globally and understanding and quantifying the disease severity associated with it and its spectrum of mutations remains critical. A Delta resurgence cannot be excluded, particularly with the recent emergence of the Omicron-Delta recombinant strain (BA.1 x AY.4) that the World Health Organisation has declared to be a variant under monitoring ¹⁹ . In addition, disease severity of dominant circulating variants is often calculated relative to the previously dominant variants ²⁰ . The Omicron variant, for instance, has been found to cause less disease than the Delta variant, but this has to be understood in the context of the Delta variant already being associated with more severe disease compared to Alpha or Beta, hence quantifying the clinical severity of different variants is important for such comparisons ^{10, 13} .

This study has several limitations. First, we could only include cases tested on the Seegene Allplex ^TM 2019-nCoV assay, excluding cases diagnosed by other PCR methods or antigen testing. However, the included cases are mostly representative of all diagnosed PCR cases in the Western Cape ( Appendix Table 1). Patients tested on this assay were similar in age, sex, known comorbidities, prior diagnosed infection and vaccination status to those who tested positive using other PCR assays. As different laboratories service different geographical regions there was a difference, however, in the district of residence. Patients who tested positive on antigen tests tended to be younger, have fewer comorbidities and fewer were admitted to hospital. This is in accordance with the Western Cape’s testing guidelines where PCR was preferred for hospital patients, while antigen testing was promoted at primary health care facilities ¹⁵ .

Second, while RTD is a reliable proxy marker for Delta, it is not as accurate as whole genome sequencing, and misclassification may have diluted the effect of Delta. Third, we could only assess the effect of prior laboratory-confirmed COVID-19 infection and seroprevalence studies suggest considerably higher numbers were infected, even after the first wave, and that prior infection prevalence differed by sub-district of residence ²¹ . While we did adjust for sub-district, the absence of a protective effect of prior infection in the first wave may be due to insufficient numbers of those infections being diagnosed. Fourth, the inclusion of cases after testing restrictions were introduced is likely to result in an underestimate of Delta disease severity. However, in the stratified analysis, those younger than 50 years, who would be more likely to be affected by the testing restrictions, still had a similar findings to those >50 years. Fifth, although we adjusted for COVID-19 hospital admissions to account for escalating service pressure during the wave surge, we could not adjust for non-COVID-19 admissions that might have added to pressure on facilities and contributed to mortality.

And finally, there are innate limitations in using observational data from surveillance and routine health records to assess variant disease severity, particularly as potential biases around testing patterns cannot always be fully adjusted for 20.

In this study we found that RTD, a useful proxy for infection with the Delta variant, is associated with an increased risk of mortality amongst those who were tested for COVID-19 in our setting. This suggests that the Delta variant is associated with an increased risk of mortality when compared with other variants, and the Beta variant in particular.

The Western Cape Provincial Health Data Centre collates all available electronic health data on public sector patients in the province for operational service use. The underlying data in this study are routinely collected patient records that have been de-identified and pseudo-anonymised in accordance with research ethics requirements. The patients have not consented to these data being part of publicly accessible repositories considering the inherent risks of re-identification. The Western Cape Department of Health and Wellness evaluates research proposals for all research in the public health sector in the province, subject to standard research ethics, government approval and data governance prescripts. This includes those that draw on routine datasets like the current study. For more information on conducting research in health services or on data managed by the Western Cape Government Department of Health and Wellness (WCGHW), please email health.research@westerncape.gov.za.