Search

BackgroundGlobally, the most significant risk factors for adverse COVID-19 outcome are increasing age and cardiometabolic comorbidities. However, underlying coinfections may modulate COVID-19 morbidity and mortality, particularly in regions with high prevalence of infectious diseases.MethodsWe retrospectively analyzed serum samples for IgG antibodies against the common circulating coronaviruses HCoV-NL63, HCoV-229E, HCoV-OC43 and HCoV-HKU1 from non-hospitalized and hospitalized confirmed COVID-19 patients recruited during the first (June-August 2020) and second (October 2020-June 2021) COVID-19 wave in Cape Town, South Africa. Patients were grouped according to COVID-19 disease severity: Group 1: previously SARS-CoV-2 infected with positive serology and no symptoms (n=94); Group 2: acutely SARS-CoV-2 infected, hospitalized for COVID-19 and severe symptoms (n=92).ResultsThe overall anti-HCoV IgG seroprevalence in the entire patient cohort was 60.8% (95% CI: 53.7 – 67.8), with 37.1% HCoV-NL63 (95% CI: 30 – 44), 30.6% HCoV-229E (95% CI: 24 – 37.3), 22.6% HCoV-HKU1 (95% CI: 16.6 – 28.6), and 21.0% HCoV-OC43 (95% CI: 15.1 – 26.8). We observed a significantly higher overall HCoV presence (72.3% versus 48.9%) and coinfection frequency (43.6% versus 19.6%) in group 1 compared to group 2 patients with significantly higher presentation of HCoV-NL63 (67.0% versus 6.6%) and HCoV-HKU1 (31.1% versus 14.1%). However, only antibody titers for HCoV-NL63 were significantly higher in group 1 compared to group 2 patients (p< 0.0001, 1.90 [95% CI: 0.62 – 2.45] versus 1.32 [95% CI: 0.30 – 2.01]) which was independent of the participants’ HIV status. Logistic regression analysis revealed significantly protective effects by previous exposure to HCoV-NL63 [p< 0.001, adjusted OR = 0.0176 (95% CI: 0.0039 – 0.0786)], while previous HCoV-229E exposure was associated with increased COVID-19 severity [p = 0.0051, adjusted OR = 7.3239 (95% CI: 1.8195–29.4800)].ConclusionWe conclude that previous exposure to multiple common coronaviruses, and particularly HCoV-NL63, might protect against severe COVID-19, while no previous HCoV exposure or single infection with HCoV-229E might enhance the risk for severe COVID-19. To our knowledge, this is the first report on HCoV seroprevalence in South Africa and its possible association with cross-protection against COVID-19 severity.

Few studies from Africa have described the clinical impact of co-infections on SARS-CoV-2 infection. Here, we investigate the presentation and outcome of SARS-CoV-2 infection in an African setting of high HIV-1 and tuberculosis prevalence by an observational case cohort of SARS-CoV-2 patients. A comparator group of non SARS-CoV-2 participants is included. The study includes 104 adults with SARS-CoV-2 infection of whom 29.8% are HIV-1 co-infected. Two or more co-morbidities are present in 57.7% of participants, including HIV-1 (30%) and active tuberculosis (14%). Amongst patients dually infected by tuberculosis and SARS-CoV-2, clinical features can be typical of either SARS-CoV-2 or tuberculosis: lymphopenia is exacerbated, and some markers of inflammation (D-dimer and ferritin) are further elevated (p < 0.05). Amongst HIV-1 co-infected participants those with low CD4 percentage strata exhibit reduced total, but not neutralising, anti-SARS-CoV-2 antibodies. SARS-CoV-2 specific CD8 T cell responses are present in 35.8% participants overall but undetectable in combined HIV-1 and tuberculosis. Death occurred in 30/104 (29%) of all COVID-19 patients and in 6/15 (40%) of patients with coincident SARS-CoV-2 and tuberculosis. This shows that in a high incidence setting, tuberculosis is a common co-morbidity in patients admitted to hospital with COVID-19. The immune response to SARS-CoV-2 is adversely affected by co-existent HIV-1 and tuberculosis.

SARS-CoV-2 variants have emerged that escape neutralization and potentially impact vaccine efficacy. T cell responses play a role in protection from reinfection and severe disease, but the potential for spike mutations to affect T cell immunity is incompletely understood. We assessed neutralizing antibody and T cell responses in 44 South African COVID-19 patients infected either with the Beta variant (dominant from November 2020 to May 2021) or infected prior to its emergence (first wave, Wuhan strain), to provide an overall measure of immune evasion. We show that robust spike-specific CD4 and CD8 T cell responses were detectable in Beta-infected patients, similar to first wave patients. Using peptides spanning the Beta-mutated regions, we identified CD4 T cell responses targeting the wild type peptides in 12/22 first wave patients, all of whom failed to recognize corresponding Beta-mutated peptides. However, responses to mutated regions formed only a small proportion (15.7%) of the overall CD4 response, and few patients (3/44) mounted CD8 responses that targeted the mutated regions. Among the spike epitopes tested, we identified three epitopes containing the D215, L18, or D80 residues that were specifically recognized by CD4 T cells, and their mutated versions were associated with a loss of response. This study shows that in spite of loss of recognition of immunogenic CD4 epitopes, CD4 and CD8 T cell responses to Beta are preserved overall. These observations may explain why several vaccines have retained the ability to protect against severe COVID-19 even with substantial loss of neutralizing antibody activity against Beta.

In South Africa, the Coronavirus Disease 2019 (COVID-19) pandemic is occurring against the backdrop of high Human Immunodeficiency Virus (HIV), tuberculosis and non-communicable disease burdens as well as prevalent herpesviruses infections such as Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV). As part of an observational study of adults admitted to Groote Schuur Hospital, Cape Town, South Africa during the period June-August 2020 and assessed for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, we measured KSHV serology and KSHV and EBV viral load (VL) in peripheral blood in relation to COVID-19 severity and outcome. A total of 104 patients with PCR-confirmed SARS-CoV-2 infection were included in this study. 61% were men and 39% women with a median age of 53 years (range 21-86). 29.8% (95% CI: 21.7-39.1%) of the cohort was HIV positive and 41.1% (95% CI: 31.6-51.1%) were KSHV seropositive. EBV VL was detectable in 84.4% (95% CI: 76.1-84.4%) of the cohort while KSHV DNA was detected in 20.6% (95% CI: 13.6-29.2%), with dual EBV/KSHV infection in 17.7% (95% CI: 11.1-26.2%). On enrollment, 48 [46.2% (95% CI: 36.8-55.7%)] COVID-19 patients were classified as severe on the WHO ordinal scale reflecting oxygen therapy and supportive care requirements and 30 of these patients [28.8% (95% CI: 20.8-38.0%)] later died. In COVID-19 patients, detectable KSHV VL was associated with death after adjusting for age, sex, HIV status and detectable EBV VL [p = 0.036, adjusted OR = 3.17 (95% CI: 1.08-9.32)]. Furthermore, in HIV negative COVID-19 patients, there was a trend indicating that KSHV VL may be related to COVID-19 disease severity [p = 0.054, unstandardized co-efficient 0.86 (95% CI: -0.015-1.74)] in addition to death [p = 0.008, adjusted OR = 7.34 (95% CI: 1.69-31.49)]. While the design of our study cannot distinguish if disease synergy exists between COVID-19 and KSHV nor if either viral infection is indeed fueling the other, these data point to a potential contribution of KSHV infection to COVID-19 outcome, or SARS-CoV-2 infection to KSHV reactivation, particularly in the South African context of high disease burden, that warrants further investigation.

The reconstitution of Mycobacterium tuberculosis (Mtb)-antigen-specific CD4 T cells in a cohort of HIV-infected persons starting antiretroviral treatment (ART) in high TB endemic area is described. Restoration of the antigen-specific CD4 T cell subsets mirrored the overall CD4 T cell compartment. Activation (assessed by HLA-DR expression) decreased during ART but remained elevated compared to HIV-uninfected persons. Despite known Mtb sensitisation determined by IGRA, 12/23 participants had no Mtb-specific CD4 T cells detectable by flow cytometry, combined with overall elevated T cell activation and memory differentiation, suggesting heightened turnover. Our data suggest early ART initiation to maintain polyfunctional immune memory responses.

The reconstitution of Mycobacterium tuberculosis (Mtb)-antigen-specific CD4 T cells in a cohort of HIV-infected persons starting antiretroviral treatment (ART) in high TB endemic area is described. Restoration of the antigen-specific CD4 T cell subsets mirrored the overall CD4 T cell compartment. Activation (assessed by HLA-DR expression) decreased during ART but remained elevated compared to HIV-uninfected persons. Despite known Mtb sensitisation determined by IGRA, 12/23 participants had no Mtb-specific CD4 T cells detectable by flow cytometry, combined with overall elevated T cell activation and memory differentiation, suggesting heightened turnover. Our data suggest early ART initiation to maintain polyfunctional immune memory responses.