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1.
PLoS Pathog ; 18(6): e1010592, 2022 06.
Article in English | MEDLINE | ID: covidwho-1910702

ABSTRACT

Exposure histories to SARS-CoV-2 variants and vaccinations will shape the specificity of antibody responses. To understand the specificity of Delta-elicited antibody immunity, we characterize the polyclonal antibody response elicited by primary or mRNA vaccine-breakthrough Delta infections. Both types of infection elicit a neutralizing antibody response focused heavily on the receptor-binding domain (RBD). We use deep mutational scanning to show that mutations to the RBD's class 1 and class 2 epitopes, including sites 417, 478, and 484-486 often reduce binding of these Delta-elicited antibodies. The anti-Delta antibody response is more similar to that elicited by early 2020 viruses than the Beta variant, with mutations to the class 1 and 2, but not class 3 epitopes, having the largest effects on polyclonal antibody binding. In addition, mutations to the class 1 epitope (e.g., K417N) tend to have larger effects on antibody binding and neutralization in the Delta spike than in the D614G spike, both for vaccine- and Delta-infection-elicited antibodies. These results help elucidate how the antigenic impacts of SARS-CoV-2 mutations depend on exposure history.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Neutralizing , Antibodies, Viral , Antibody Formation , Epitopes , Humans , Neutralization Tests , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/metabolism , Vaccines, Synthetic , mRNA Vaccines
2.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-335252

ABSTRACT

The SARS-CoV-2 Omicron (B.1.1.529) variant first emerged as the BA.1 sub-lineage, with extensive escape from neutralizing immunity elicited by previous infection with other variants, vaccines, or combinations of both 1,2 . Two new sub-lineages, BA.4 and BA.5, are now emerging in South Africa with changes relative to BA.1, including L452R and F486V mutations in the spike receptor binding domain. We isolated live BA.4 and BA.5 viruses and tested them against neutralizing immunity elicited to BA.1 infection in participants who were Omicron/BA.1 infected but unvaccinated (n=24) and participants vaccinated with Pfizer BNT162b2 or Johnson and Johnson Ad26.CoV.2S with breakthrough Omicron/BA.1 infection (n=15). In unvaccinated individuals, FRNT 50 , the inverse of the dilution for 50% neutralization, declined from 275 for BA.1 to 36 for BA.4 and 37 for BA.5, a 7.6 and 7.5-fold drop, respectively. In vaccinated BA.1 breakthroughs, FRNT 50 declined from 507 for BA.1 to 158 for BA.4 (3.2-fold) and 198 for BA.5 (2.6-fold). Absolute BA.4 and BA.5 neutralization levels were about 5-fold higher in this group versus unvaccinated BA.1 infected participants. The observed escape of BA.4 and BA.5 from BA.1 elicited immunity is more moderate than of BA.1 against previous immunity 1,3 . However, the low absolute neutralization levels for BA.4 and BA.5, particularly in the unvaccinated group, are unlikely to protect well against symptomatic infection 4 .This may indicate that, based on neutralization escape, BA.4 and BA.5 have potential to result in a new infection wave.

3.
Nature ; 607(7918): 356-359, 2022 07.
Article in English | MEDLINE | ID: covidwho-1830078

ABSTRACT

The extent to which Omicron infection1-9, with or without previous vaccination, elicits protection against the previously dominant Delta (B.1.617.2) variant is unclear. Here we measured the neutralization capacity against variants of severe acute respiratory syndrome coronavirus 2 in 39 individuals in South Africa infected with the Omicron sublineage BA.1 starting at a median of 6 (interquartile range 3-9) days post symptom onset and continuing until last follow-up sample available, a median of 23 (interquartile range 19-27) days post symptoms to allow BA.1-elicited neutralizing immunity time to develop. Fifteen participants were vaccinated with Pfizer's BNT162b2 or Johnson & Johnson's Ad26.CoV2.S and had BA.1 breakthrough infections, and 24 were unvaccinated. BA.1 neutralization increased from a geometric mean 50% focus reduction neutralization test titre of 42 at enrolment to 575 at the last follow-up time point (13.6-fold) in vaccinated participants and from 46 to 272 (6.0-fold) in unvaccinated participants. Delta virus neutralization also increased, from 192 to 1,091 (5.7-fold) in vaccinated participants and from 28 to 91 (3.0-fold) in unvaccinated participants. At the last time point, unvaccinated individuals infected with BA.1 had low absolute levels of neutralization for the non-BA.1 viruses and 2.2-fold lower BA.1 neutralization, 12.0-fold lower Delta neutralization, 9.6-fold lower Beta variant neutralization, 17.9-fold lower ancestral virus neutralization and 4.8-fold lower Omicron sublineage BA.2 neutralization relative to vaccinated individuals infected with BA.1. These results indicate that hybrid immunity formed by vaccination and Omicron BA.1 infection should be protective against Delta and other variants. By contrast, infection with Omicron BA.1 alone offers limited cross-protection despite moderate enhancement.


Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , COVID-19 Vaccines , COVID-19 , Cross Protection , SARS-CoV-2 , Vaccination , Ad26COVS1/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , BNT162 Vaccine/immunology , COVID-19/immunology , COVID-19/prevention & control , COVID-19/virology , COVID-19 Vaccines/immunology , Cross Protection/immunology , Humans , SARS-CoV-2/classification , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Vaccination/statistics & numerical data
5.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-330150

ABSTRACT

Exposure histories to SARS-CoV-2 variants and vaccinations will shape the specificity of antibody responses. To understand the specificity of Delta-elicited antibody immunity, we characterize the polyclonal antibody response elicited by primary or mRNA vaccine-breakthrough Delta infections. Both types of infection elicit a neutralizing antibody response focused heavily on the receptor-binding domain (RBD). We use deep mutational scanning to show that mutations to the RBD's class 1 and class 2 epitopes, including sites 417, 478, and 484-486 often reduce binding of these Delta-elicited antibodies. The anti-Delta antibody response is more similar to that elicited by early 2020 viruses than the Beta variant, with mutations to the class 1 and 2, but not class 3 epitopes, having the largest effects on polyclonal antibody binding. In addition, mutations to the class 1 epitope (e.g., K417N) tend to have larger effects on antibody binding and neutralization in the Delta spike than in the D614G spike, both for vaccine- and Delta-infection-elicited antibodies. These results help elucidate how the antigenic impacts of SARS-CoV-2 mutations depend on exposure history.

6.
Cell Host Microbe ; 30(2): 154-162.e5, 2022 02 09.
Article in English | MEDLINE | ID: covidwho-1708092

ABSTRACT

Characterizing SARS-CoV-2 evolution in specific geographies may help predict properties of the variants that come from these regions. We mapped neutralization of a SARS-CoV-2 strain that evolved over 6 months from ancestral virus in a person with advanced HIV disease in South Africa; this person was infected prior to emergence of the Beta and Delta variants. We longitudinally tracked the evolved virus and tested it against self-plasma and convalescent plasma from ancestral, Beta, and Delta infections. Early virus was similar to ancestral, but it evolved a multitude of mutations found in Omicron and other variants. It showed substantial but incomplete Pfizer BNT162b2 escape, weak neutralization by self-plasma, and despite pre-dating Delta, it also showed extensive escape of Delta infection-elicited neutralization. This example is consistent with the notion that SARS-CoV-2 evolving in individual immune-compromised hosts, including those with advanced HIV disease, may gain immune escape of vaccines and enhanced escape of Delta immunity, and this has implications for vaccine breakthrough and reinfections.


Subject(s)
Antibodies, Neutralizing/blood , HIV Infections/pathology , Immune Evasion/immunology , Immunogenicity, Vaccine/immunology , SARS-CoV-2/immunology , Adult , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19 Vaccines/immunology , Cell Line , Chlorocebus aethiops , Female , HIV-1/immunology , Humans , Immunocompromised Host/immunology , Neutralization Tests , SARS-CoV-2/isolation & purification , South Africa , Vaccination , Vero Cells
7.
PLoS Pathog ; 18(2): e1010248, 2022 02.
Article in English | MEDLINE | ID: covidwho-1674026

ABSTRACT

Many SARS-CoV-2 variants have mutations at key sites targeted by antibodies. However, it is unknown if antibodies elicited by infection with these variants target the same or different regions of the viral spike as antibodies elicited by earlier viral isolates. Here we compare the specificities of polyclonal antibodies produced by humans infected with early 2020 isolates versus the B.1.351 variant of concern (also known as Beta or 20H/501Y.V2), which contains mutations in multiple key spike epitopes. The serum neutralizing activity of antibodies elicited by infection with both early 2020 viruses and B.1.351 is heavily focused on the spike receptor-binding domain (RBD). However, within the RBD, B.1.351-elicited antibodies are more focused on the "class 3" epitope spanning sites 443 to 452, and neutralization by these antibodies is notably less affected by mutations at residue 484. Our results show that SARS-CoV-2 variants can elicit polyclonal antibodies with different immunodominance hierarchies.


Subject(s)
Antibodies, Viral/immunology , Antibody Formation/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacology , Antibodies, Neutralizing/immunology , COVID-19/drug therapy , Epitopes/immunology , Humans , Immunization, Passive/methods , Neutralization Tests , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism
8.
Nature ; 603(7901): 488-492, 2022 03.
Article in English | MEDLINE | ID: covidwho-1661968

ABSTRACT

The SARS-CoV-2 Omicron variant (B.1.1.529) has multiple spike protein mutations1,2 that contribute to viral escape from antibody neutralization3-6 and reduce vaccine protection from infection7,8. The extent to which other components of the adaptive response such as T cells may still target Omicron and contribute to protection from severe outcomes is unknown. Here we assessed the ability of T cells to react to Omicron spike protein in participants who were vaccinated with Ad26.CoV2.S or BNT162b2, or unvaccinated convalescent COVID-19 patients (n = 70). Between 70% and 80% of the CD4+ and CD8+ T cell response to spike was maintained across study groups. Moreover, the magnitude of Omicron cross-reactive T cells was similar for Beta (B.1.351) and Delta (B.1.617.2) variants, despite Omicron harbouring considerably more mutations. In patients who were hospitalized with Omicron infections (n = 19), there were comparable T cell responses to ancestral spike, nucleocapsid and membrane proteins to those in patients hospitalized in previous waves dominated by the ancestral, Beta or Delta variants (n = 49). Thus, despite extensive mutations and reduced susceptibility to neutralizing antibodies of Omicron, the majority of T cell responses induced by vaccination or infection cross-recognize the variant. It remains to be determined whether well-preserved T cell immunity to Omicron contributes to protection from severe COVID-19 and is linked to early clinical observations from South Africa and elsewhere9-12.


Subject(s)
COVID-19/immunology , COVID-19/virology , Cross Reactions/immunology , Immunity, Cellular , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/immunology , Adult , Aged , COVID-19 Vaccines/immunology , Convalescence , Hospitalization , Humans , Middle Aged , SARS-CoV-2/chemistry , SARS-CoV-2/classification
9.
Nature ; 602(7898): 654-656, 2022 02.
Article in English | MEDLINE | ID: covidwho-1616992

ABSTRACT

The emergence of the SARS-CoV-2 variant of concern Omicron (Pango lineage B.1.1.529), first identified in Botswana and South Africa, may compromise vaccine effectiveness and lead to re-infections1. Here we investigated Omicron escape from neutralization by antibodies from South African individuals vaccinated with Pfizer BNT162b2. We used blood samples taken soon after vaccination from individuals who were vaccinated and previously infected with SARS-CoV-2 or vaccinated with no evidence of previous infection. We isolated and sequence-confirmed live Omicron virus from an infected person and observed that Omicron requires the angiotensin-converting enzyme 2 (ACE2) receptor to infect cells. We compared plasma neutralization of Omicron relative to an ancestral SARS-CoV-2 strain and found that neutralization of ancestral virus was much higher in infected and vaccinated individuals compared with the vaccinated-only participants. However, both groups showed a 22-fold reduction in vaccine-elicited neutralization by the Omicron variant. Participants who were vaccinated and had previously been infected exhibited residual neutralization of Omicron similar to the level of neutralization of the ancestral virus observed in the vaccination-only group. These data support the notion that reasonable protection against Omicron may be maintained using vaccination approaches.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Immune Evasion/immunology , Neutralization Tests , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Animals , Cell Line , Chlorocebus aethiops , Humans , Mutation , SARS-CoV-2/classification , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism
10.
Clin Infect Dis ; 2021 Dec 10.
Article in English | MEDLINE | ID: covidwho-1566004

ABSTRACT

BACKGROUND: People living with HIV (PLWH) have been reported to have a higher risk of more severe Covid-19 disease and death. We assessed the ability of the Ad26.CoV2.S vaccine to elicit neutralizing activity against the Delta variant in PLWH relative to HIV-negative individuals. We also examined effects of HIV status and suppression on Delta neutralization response in SARS-CoV-2 infected unvaccinated participants. METHODS: We enrolled participants who vaccinated through the SISONKE South African clinical trial of the Ad26.CoV2.S vaccine in health care workers (HCW). PLWH in this group had well controlled HIV infection. We also enrolled unvaccinated participants previously infected with SARS-CoV-2. Neutralization capacity was assessed by a live virus neutralization assay of the Delta variant. RESULTS: Majority of Ad26.CoV2.S vaccinated HCW were previously infected with SARS-CoV-2. In this group, Delta variant neutralization was 9-fold higher compared to the infected only group and 26-fold higher relative to the vaccinated only group. No decrease in Delta variant neutralization was observed in PLWH relative to HIV-negative participants. In contrast, SARS-CoV-2 infected, unvaccinated PLWH showed 7-fold lower neutralization and a higher frequency of non-responders, with the highest frequency of non-responders in people with HIV viremia. Vaccinated only participants showed low neutralization capacity. CONCLUSIONS: The neutralization response of the Delta variant following Ad26.CoV2.S vaccination in PLWH with well controlled HIV was not inferior to HIV-negative participants, irrespective of past SARS-CoV-2 infection. In SARS-CoV-2 infected and non-vaccinated participants, HIV infection reduced the neutralization response to SARS-CoV-2, with the strongest reduction in HIV viremic individuals.

11.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-295139

ABSTRACT

Summary Background People living with HIV (PLWH) have been reported to have an increased risk of more severe COVID-19 disease outcome and an increased risk of death relative to HIV-uninfected individuals. Here we assessed the ability of the Johnson and Johnson Ad26.CoV2.S vaccine to elicit neutralizing antibodies to the Delta variant in PLWH relative to HIV-uninfected individuals. We also compared the neutralization after vaccination to neutralization elicited by SARS-CoV-2 infection only in HIV-uninfected, suppressed HIV PLWH, and PLWH with detectable HIV viremia. Methods We enrolled 26 PLWH and 73 HIV-uninfected participants from the SISONKE phase 3b open label South African clinical trial of the Ad26.CoV2.S vaccine in health care workers (HCW). Enrollment was a median 56 days (range 19-98 days) post-vaccination and PLWH in this group had well controlled HIV infection. We also enrolled unvaccinated participants previously infected with SARS-CoV-2. This group consisted of 34 PLWH and 28 HIV-uninfected individuals. 10 of the 34 (29%) SARS-CoV-2 infected only PLWH had detectable HIV viremia. We used records of a positive SARS-CoV-2 qPCR result, or when a positive result was absent, testing for SARS-CoV-2 nucleocapsid antibodies, to determine which vaccinated participants were SARS-CoV-2 infected prior to vaccination. Neutralization capacity was assessed using participant plasma in a live virus neutralization assay of the Delta SARS-CoV-2 variant currently dominating infections in South Africa. This study was approved by the Biomedical Research Ethics Committee at the University of KwaZulu–Natal (reference BREC/00001275/2020). Findings The majority (68%) of Ad26.CoV2.S vaccinated HCW were found to be previously infected with SARS-CoV-2. In this group, Delta variant neutralization was 9-fold higher compared to the infected only group (GMT=306 versus 36, p<0.0001) and 26-fold higher relative to the vaccinated only group (GMT=12, p<0.0001). No significant difference in Delta variant neutralization capacity was observed in vaccinated and previously SARS-CoV-2 infected PLWH relative to vaccinated and previously SARS-CoV-2 infected, HIV-uninfected participants (GMT=307 for HIV-uninfected, 300 for PLWH, p=0.95). SARS-CoV-2 infected, unvaccinated PLWH showed 7-fold reduced neutralization of the Delta variant relative to HIV-uninfected participants (GMT=105 for HIV-uninfected, 15 for PLWH, p=0.001). There was a higher frequency of non-responders in PLWH relative to HIV-uninfected participants in the SARS-CoV-2 infected unvaccinated group (27% versus 0%, p=0.0029) and 60% of HIV viremic versus 13% of HIV suppressed PLWH were non-responders (p=0.0088). In contrast, the frequency of non-responders was low in the vaccinated/infected group, and similar between HIV-uninfected and PLWH. Vaccinated only participants showed a low neutralization of the Delta variant, with a stronger response in PLWH (GMT=6 for HIV-uninfected, 73 for PLWH, p=0.02). Interpretation The neutralization response of the Delta variant following Ad26.CoV2.S vaccination in PLWH with well controlled HIV was not inferior to HIV-uninfected study participants. In SARS-CoV-2 infected and non-vaccinated participants, the presence of HIV infection reduced the neutralization response to SARS-CoV-2 infection, and this effect was strongest in PLWH with detectable HIV viremia Funding South African Medical Research Council, The Bill & Melinda Gates Foundation.

12.
Elife ; 102021 10 05.
Article in English | MEDLINE | ID: covidwho-1450948

ABSTRACT

There are conflicting reports on the effects of HIV on COVID-19. Here, we analyzed disease severity and immune cell changes during and after SARS-CoV-2 infection in 236 participants from South Africa, of which 39% were people living with HIV (PLWH), during the first and second (Beta dominated) infection waves. The second wave had more PLWH requiring supplemental oxygen relative to HIV-negative participants. Higher disease severity was associated with low CD4 T cell counts and higher neutrophil to lymphocyte ratios (NLR). Yet, CD4 counts recovered and NLR stabilized after SARS-CoV-2 clearance in wave 2 infected PLWH, arguing for an interaction between SARS-CoV-2 and HIV infection leading to low CD4 and high NLR. The first infection wave, where severity in HIV negative and PLWH was similar, still showed some HIV modulation of SARS-CoV-2 immune responses. Therefore, HIV infection can synergize with the SARS-CoV-2 variant to change COVID-19 outcomes.


Subject(s)
COVID-19/complications , COVID-19/immunology , HIV Infections/complications , HIV Infections/immunology , Immunity, Cellular , Severity of Illness Index , Adult , Aged , CD4 Lymphocyte Count , Female , Humans , Male , Middle Aged , SARS-CoV-2 , South Africa
13.
J Biol Chem ; 297(2): 100925, 2021 08.
Article in English | MEDLINE | ID: covidwho-1336599

ABSTRACT

Apart from prevention using vaccinations, the management options for COVID-19 remain limited. In retrospective cohort studies, use of famotidine, a specific oral H2 receptor antagonist (antihistamine), has been associated with reduced risk of intubation and death in patients hospitalized with COVID-19. In a case series, nonhospitalized patients with COVID-19 experienced rapid symptom resolution after taking famotidine, but the molecular basis of these observations remains elusive. Here we show using biochemical, cellular, and functional assays that famotidine has no effect on viral replication or viral protease activity. However, famotidine can affect histamine-induced signaling processes in infected Caco2 cells. Specifically, famotidine treatment inhibits histamine-induced expression of Toll-like receptor 3 (TLR3) in SARS-CoV-2 infected cells and can reduce TLR3-dependent signaling processes that culminate in activation of IRF3 and the NF-κB pathway, subsequently controlling antiviral and inflammatory responses. SARS-CoV-2-infected cells treated with famotidine demonstrate reduced expression levels of the inflammatory mediators CCL-2 and IL6, drivers of the cytokine release syndrome that precipitates poor outcome for patients with COVID-19. Given that pharmacokinetic studies indicate that famotidine can reach concentrations in blood that suffice to antagonize histamine H2 receptors expressed in mast cells, neutrophils, and eosinophils, these observations explain how famotidine may contribute to the reduced histamine-induced inflammation and cytokine release, thereby improving the outcome for patients with COVID-19.


Subject(s)
Famotidine/pharmacology , Histamine Antagonists/pharmacology , SARS-CoV-2/drug effects , Toll-Like Receptor 3/metabolism , A549 Cells , Binding Sites , Caco-2 Cells , Chemokine CCL2/metabolism , Coronavirus 3C Proteases/metabolism , HeLa Cells , Humans , Interferon Regulatory Factor-3/metabolism , Interleukin-6/metabolism , Molecular Docking Simulation , NF-kappa B/metabolism , Protein Binding , SARS-CoV-2/physiology , Signal Transduction , Toll-Like Receptor 3/chemistry , Virus Replication
14.
Lancet Glob Health ; 9(7): e967-e976, 2021 07.
Article in English | MEDLINE | ID: covidwho-1271838

ABSTRACT

BACKGROUND: There has been remarkable progress in the treatment of HIV throughout sub-Saharan Africa, but there are few data on the prevalence and overlap of other significant causes of disease in HIV endemic populations. Our aim was to identify the prevalence and overlap of infectious and non-communicable diseases in such a population in rural South Africa. METHODS: We did a cross-sectional study of eligible adolescents and adults from the Africa Health Research Institute demographic surveillance area in the uMkhanyakude district of KwaZulu-Natal, South Africa. The participants, who were 15 years or older, were invited to participate at a mobile health camp. Medical history for HIV, tuberculosis, hypertension, and diabetes was established through a questionnaire. Blood pressure measurements, chest x-rays, and tests of blood and sputum were taken to estimate the population prevalence and geospatial distribution of HIV, active and lifetime tuberculosis, elevated blood glucose, elevated blood pressure, and combinations of these. FINDINGS: 17 118 adolescents and adults were recruited from May 25, 2018, to Nov 28, 2019, and assessed. Overall, 52·1% (95% CI 51·3-52·9) had at least one active disease. 34·2% (33·5-34·9) had HIV, 1·4% (1·2-1·6) had active tuberculosis, 21·8% (21·2-22·4) had lifetime tuberculosis, 8·5% (8·1-8·9) had elevated blood glucose, and 23·0% (22·4-23·6) had elevated blood pressure. Appropriate treatment and optimal disease control was highest for HIV (78·1%), and lower for elevated blood pressure (42·5%), active tuberculosis (29·6%), and elevated blood glucose (7·1%). Disease prevalence differed notably by sex, across age groups, and geospatially: men had a higher prevalence of active and lifetime tuberculosis, whereas women had a substantially high prevalence of HIV at 30-49 years and an increasing prevalence of multiple and poorly controlled non-communicable diseases when older than 50 years. INTERPRETATION: We found a convergence of infectious and non-communicable disease epidemics in a rural South African population, with HIV well treated relative to all other diseases, but tuberculosis, elevated blood glucose, and elevated blood pressure poorly diagnosed and treated. A public health response that expands the successes of the HIV testing and treatment programme to provide multidisease care targeted to specific populations is required to optimise health in such settings in sub-Saharan Africa. FUNDING: Wellcome Trust, Bill & Melinda Gates Foundation, the South African Department of Science and Innovation, South African Medical Research Council, and South African Population Research Infrastructure Network. TRANSLATION: For the isiZulu translation of the abstract see Supplementary Materials section.


Subject(s)
Diabetes Mellitus/epidemiology , Epidemics , HIV Infections/epidemiology , Hypertension/epidemiology , Rural Health/statistics & numerical data , Tuberculosis/epidemiology , Adolescent , Adult , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Multimorbidity , Prevalence , South Africa/epidemiology
15.
ACS Cent Sci ; 7(5): 792-802, 2021 May 26.
Article in English | MEDLINE | ID: covidwho-1225483

ABSTRACT

The outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global threat to human health. Using a multidisciplinary approach, we identified and validated the hepatitis C virus (HCV) protease inhibitor simeprevir as an especially promising repurposable drug for treating COVID-19. Simeprevir potently reduces SARS-CoV-2 viral load by multiple orders of magnitude and synergizes with remdesivir in vitro. Mechanistically, we showed that simeprevir not only inhibits the main protease (Mpro) and unexpectedly the RNA-dependent RNA polymerase (RdRp) but also modulates host immune responses. Our results thus reveal the possible anti-SARS-CoV-2 mechanism of simeprevir and highlight the translational potential of optimizing simeprevir as a therapeutic agent for managing COVID-19 and future outbreaks of CoV.

16.
Nature ; 593(7857): 142-146, 2021 05.
Article in English | MEDLINE | ID: covidwho-1155700

ABSTRACT

SARS-CoV-2 variants of concern (VOC) have arisen independently at multiple locations1,2 and may reduce the efficacy of current vaccines that target the spike glycoprotein of SARS-CoV-23. Here, using a live-virus neutralization assay, we compared the neutralization of a non-VOC variant with the 501Y.V2 VOC (also known as B.1.351) using plasma collected from adults who were hospitalized with COVID-19 during the two waves of infection in South Africa, the second wave of which was dominated by infections with the 501Y.V2 variant. Sequencing demonstrated that infections of plasma donors from the first wave were with viruses that did not contain the mutations associated with 501Y.V2, except for one infection that contained the E484K substitution in the receptor-binding domain. The 501Y.V2 virus variant was effectively neutralized by plasma from individuals who were infected during the second wave. The first-wave virus variant was effectively neutralized by plasma from first-wave infections. However, the 501Y.V2 variant was poorly cross-neutralized by plasma from individuals with first-wave infections; the efficacy was reduced by 15.1-fold relative to neutralization of 501Y.V2 by plasma from individuals infected in the second wave. By contrast, cross-neutralization of first-wave virus variants using plasma from individuals with second-wave infections was more effective, showing only a 2.3-fold decrease relative to neutralization of first-wave virus variants by plasma from individuals infected in the first wave. Although we tested only one plasma sample from an individual infected with a SARS-CoV-2 variant with only the E484K substitution, this plasma sample potently neutralized both variants. The observed effective neutralization of first-wave virus by plasma from individuals infected with 501Y.V2 provides preliminary evidence that vaccines based on VOC sequences could retain activity against other circulating SARS-CoV-2 lineages.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/therapy , COVID-19/virology , Immune Evasion/immunology , Mutation , SARS-CoV-2/immunology , Animals , Antibodies, Neutralizing/biosynthesis , Antibodies, Viral/biosynthesis , COVID-19/epidemiology , Cell Line , Chlorocebus aethiops , Humans , Immune Evasion/genetics , Immunization, Passive , Neutralization Tests , SARS-CoV-2/genetics , South Africa/epidemiology , Time Factors , Vero Cells
18.
Trends Biochem Sci ; 46(5): 351-365, 2021 05.
Article in English | MEDLINE | ID: covidwho-947467

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently creating a global health emergency. This crisis is driving a worldwide effort to develop effective vaccines, prophylactics, and therapeutics. Nucleic acid (NA)-based treatments hold great potential to combat outbreaks of coronaviruses (CoVs) due to their rapid development, high target specificity, and the capacity to increase druggability. Here, we review key anti-CoV NA-based technologies, including antisense oligonucleotides (ASOs), siRNAs, RNA-targeting clustered regularly interspaced short palindromic repeats-CRISPR-associated protein (CRISPR-Cas), and mRNA vaccines, and discuss improved delivery methods and combination therapies with other antiviral drugs.


Subject(s)
COVID-19 Vaccines , CRISPR-Cas Systems , RNA, Messenger , RNA, Viral , SARS-CoV-2 , COVID-19/genetics , COVID-19/immunology , COVID-19/metabolism , COVID-19/therapy , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , Humans , RNA, Messenger/genetics , RNA, Messenger/immunology , RNA, Messenger/metabolism , RNA, Viral/genetics , RNA, Viral/immunology , RNA, Viral/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/immunology , SARS-CoV-2/metabolism
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