Fc effector activity and neutralization against SARS-CoV-2 BA.4 is compromised in convalescent sera, regardless of the infecting variant (preprint)

The SARS-CoV-2 Omicron BA.1 variant, which exhibits high level neutralization resistance, has since evolved into several sub-lineages including BA.4 and BA.5, which have dominated the fifth wave of infection in South Africa. Here we assessed the sensitivity of BA.4 to neutralization and antibody dependent cellular cytotoxicity (ADCC) in convalescent donors infected with four previous variants of SARS-CoV-2, as well as in post-vaccination breakthrough infections (BTIs) caused by Delta or BA.1. We confirm that BA.4 shows high level resistance to neutralization, regardless of the infecting variant. However, breakthrough infections, which trigger potent neutralization, retained activity against BA.4, albeit at reduced titers. Fold reduction of neutralization in BTIs was lower than that seen in unvaccinated convalescent donors, suggesting maturation of neutralizing responses to become more resilient against VOCs in hybrid immunity. BA.4 sensitivity to ADCC was reduced but remained detectable in both convalescent donors and in BTIs. Overall, the high neutralization resistance of BA.4, even to antibodies from BA.1 infections, provides an immunological mechanism for the rapid spread of BA.4 immediately after a BA.1-dominated wave. Furthermore, although ADCC activity against BA.4 was reduced, residual activity may nonetheless contribute to the protection from disease.

SARS-CoV-2 BA.4 infection triggers more cross-reactive neutralizing antibodies than BA.1 (preprint)

SARS-CoV-2 variants of concern (VOCs) differentially trigger neutralizing antibodies with variable cross-neutralizing capacity. Here we show that unlike SARS-CoV-2 Omicron BA.1, which triggered neutralizing antibodies with limited cross-reactivity, BA.4/5 infection triggers highly cross-reactive neutralizing antibodies. Cross-reactivity was observed both in the absence of prior vaccination and also in breakthrough infections following vaccination. This suggests that next-generation vaccines incorporating BA.4, which is spreading globally, might result in enhanced neutralization breadth.

COVID-19 severity and in-hospital mortality in an area with high HIV prevalence (preprint)

Background: HIV is moderate risk factor for developing severe COVID-19 and is associated with increased risk of COVID-19 mortality. HIV infection causes immune dysregulation characterised by progressive lymphopenia, chronic immune activation, immunological senescence, and T cell exhaustion. These changes are partly reversed by effective antiretroviral therapy (ART), which reduces morbidity and mortality in people living with HIV (PWH). We investigated the associations among clinical phenotypes, laboratory biomarkers, and hospitalisation outcomes in a cohort of people hospitalised with COVID-19 in a high HIV prevalence area. Methods: : We conducted a prospective observational cohort study in the Tshwane District Hospital complex in Pretoria, South Africa. We analysed data for patients admitted from April to November 2020, before the SARS-CoV-2 Beta variant-driven second wave. Respiratory disease severity was quantified using the respiratory oxygenation (ROX) score. Analysed biomarkers included full blood counts, differential white cell counts, C-reactive protein (CRP), ferritin, procalcitonin (PCT), D-dimer (DDIM), creatinine, alanine aminotransferase (ALT), CD4 T cell counts, and HIV-1 viral loads (HIVVL). Results: : The analysis included 558 patients, of whom 112 (21.7%) died during admission. The mean age of the cohort was 54 (SD ±16) years, and numbers of males (50.5%) and females (49.5%) were equivalent. A total of 82 (15%) were HIV-positive. PWH were younger (mean age 46 years) than HIV-negative people; most were on ART with a suppressed HIVVL (72%) and the median CD4 count was 159 (IQR 66-397) cells/µL at the time of admission. After adjusting for age, HIV was not associated with significantly increased risk of mortality during hospitalisation (aHR=1.1, 95% CI: 0.6-2.0). Levels of supportive care were similar in HIV-negative patients and PWH. Inflammatory biomarker levels were equivalent in PWH and HIV-negative patients. A total of 15 PWH had detectable HIVVLs (>1000 copies/mL). Detectable HIVVL was associated with higher ROX scores - indicating less severe respiratory disease. In PWH, mortality was associated with higher levels of CRP, ferritin, PCT and DDIM. When compared to HIV-negative patients who died, PWH who died were younger, had higher DDIM levels, and were more likely to have tuberculosis. Conclusions: : HIV per se was not associated with substantively increased risk of severe disease, or in-hospital mortality from COVID-19. Respiratory disease was less severe in PWH with detectable HIVVL. Inflammatory biomarker levels were equivalent in PWH and HIV-negative people, regardless of HIVVL. Increased levels of inflammatory biomarkers and DDIM were associated with in-hospital mortality irrespective of HIV status.

SARS-CoV-2 501Y.V2 (B.1.351) elicits cross-reactive neutralizing antibodies (preprint)

Neutralization escape by SARS-CoV-2 variants, as has been observed in the 501Y.V2 (B.1.351) variant, has impacted the efficacy of first generation COVID-19 vaccines. Here, the antibody response to the 501Y.V2 variant was examined in a cohort of patients hospitalized with COVID-19 in early 2021 - when over 90% of infections in South Africa were attributed to 501Y.V2. Robust binding and neutralizing antibody titers to the 501Y.V2 variant were detected and these binding antibodies showed high levels of cross-reactivity for the original variant, from the first wave. In contrast to an earlier study where sera from individuals infected with the original variant showed dramatically reduced potency against 501Y.V2, sera from 501Y.V2-infected patients maintained good cross-reactivity against viruses from the first wave. Furthermore, sera from 501Y.V2-infected patients also neutralized the 501Y.V3 (P.1) variant first described in Brazil, and now circulating globally. Collectively these data suggest that the antibody response in patients infected with 501Y.V2 has a broad specificity and that vaccines designed with the 501Y.V2 sequence may elicit more cross-reactive responses.

SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma (preprint)

SARS-CoV-2 501Y.V2, a novel lineage of the coronavirus causing COVID-19, contains multiple mutations within two immunodominant domains of the spike protein. Here we show that this lineage exhibits complete escape from three classes of therapeutically relevant monoclonal antibodies. Furthermore 501Y.V2 shows substantial or complete escape from neutralizing antibodies in COVID-19 convalescent plasma. These data highlight the prospect of reinfection with antigenically distinct variants and may foreshadow reduced efficacy of current spike-based vaccines.