Immune #correlates of the #Thai #RV144 #HIV #vaccine regimen in South Africa (Sci Transl Med., abstract)

[Source: Science Translational Medicine, full page: (LINK). Abstract, edited.]

Immune correlates of the Thai RV144 HIV vaccine regimen in South Africa

Glenda E. Gray1,2,3,*, Ying Huang3, Nicole Grunenberg3, Fatima Laher1, Surita Roux4,†, Erica Andersen-Nissen3,5, Stephen C. De Rosa3, Britta Flach5, April K. Randhawa3, Ryan Jensen3, Edith M. Swann6, Linda-Gail Bekker4, Craig Innes7, Erica Lazarus1, Lynn Morris8, Nonhlanhla N. Mkhize8, Guido Ferrari9, David C. Montefiori9, Xiaoying Shen9, Sheetal Sawant9, Nicole Yates9, John Hural3, Abby Isaacs3, Sanjay Phogat10, Carlos A. DiazGranados10, Carter Lee11, Faruk Sinangil11, Nelson L. Michael12, Merlin L. Robb12, James G. Kublin3, Peter B. Gilbert3, M. Juliana McElrath3, Georgia D. Tomaras9 and Lawrence Corey3

1 Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 1864, South Africa. 2 South African Medical Research Council, Cape Town 7505, South Africa. 3 Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. 4 The Desmond Tutu HIV Centre, University of Cape Town, Cape Town 8001, South Africa. 5 Cape Town HVTN Immunology Laboratory, Hutchinson Centre Research Institute of South Africa, Cape Town 8001, South Africa. 6 Vaccine Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20852, USA. 7 The Aurum Institute, Klerksdorp 2570, South Africa. 8 National Institute for Communicable Diseases, National Health Laboratory Service, Sandringham, Johannesburg 2192, South Africa. 9 Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA. 10 Sanofi Pasteur, Swiftwater, PA 18370, USA. 11 Global Solutions for Infectious Diseases, South San Francisco, CA 94080, USA. 12 US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.

*Corresponding author. Email: glenda.gray@mrc.ac.za

† Present address: Synexus Clinical Research SA (Pty) Ltd., Somerset West, Cape Town, South Africa.

Science Translational Medicine  18 Sep 2019: Vol. 11, Issue 510, eaax1880 / DOI: 10.1126/scitranslmed.aax1880

 

Taking RV144 beyond Thailand

The RV144 vaccine trial in Thailand is the only HIV vaccine to show efficacy against HIV infection to date. Gray et al. designed the HVTN 097 trial to test this regimen in South Africa, where clade C HIV circulates; this clade is heterologous to the vaccine antigens. They intently examined immune protective responses previously identified in the RV144 trial and found that the vaccine seemed to be even more immunogenic in South Africans. CD4+ T cell responses were stronger and more common in HVTN 097, and the magnitude of protective antibody responses was greater compared to RV144. Their results indicate that the RV144 regimen or others like it could be protective in areas where HIV is endemic.

 

Abstract

One of the most successful HIV vaccines to date, the RV144 vaccine tested in Thailand, demonstrated correlates of protection including cross-clade V1V2 immunoglobulin G (IgG) breadth, Env-specific CD4+ T cell polyfunctionality, and antibody-dependent cellular cytotoxicity (ADCC) in vaccinees with low IgA binding. The HIV Vaccine Trials Network (HVTN) 097 trial evaluated this vaccine regimen in South Africa, where clade C HIV-1 predominates. We compared cellular and humoral responses at peak and durability immunogenicity time points in HVTN 097 and RV144 vaccinee samples, and evaluated vaccine-matched and cross-clade immune responses. At peak immunogenicity, HVTN 097 vaccinees exhibited significantly higher cellular and humoral immune responses than RV144 vaccinees. CD4+ T cell responses were more frequent in HVTN 097 irrespective of age and sex, and CD4+ T cell Env-specific functionality scores were higher in HVTN 097. Env-specific CD40L+ CD4+ T cells were more common in HVTN 097, with individuals having this pattern of expression demonstrating higher median antibody responses to HIV-1 Env. IgG and IgG3 binding antibody rates and response magnitude to gp120 vaccine– and V1V2 vaccine–matched antigens were higher or comparable in HVTN 097 than in RV144 ADCC, and ADCP functional antibody responses were elicited in HVTN 097. Env-specific IgG and CD4+ Env responses declined significantly over time in both trials. Overall, cross-clade immune responses associated with protection were better than expected in South Africa, suggesting wider applicability of this regimen.

Keywords: HIV/ADIS; Vaccines; South Africa.

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#Epidemiologic #Shift in #Candidemia Driven by #Candida auris, South Africa, [#ZA] 2016–2017 (Emerg Infect Dis., abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Volume 25, Number 9—September 2019 / Research

Epidemiologic Shift in Candidemia Driven by Candida auris, South Africa, 2016–2017

Erika van Schalkwyk2, Ruth S. Mpembe, Juno Thomas, Liliwe Shuping, Husna Ismail, Warren Lowman, Alan S. Karstaedt, Vindana Chibabhai, Jeannette Wadula, Theunis Avenant, Angeliki Messina, Chetna N. Govind, Krishnee Moodley, Halima Dawood, Praksha Ramjathan, Nelesh P. Govender2  , and for GERMS-SA

Author affiliations: National Institute for Communicable Diseases, Johannesburg, South Africa (E. van Schalkwyk, R.S. Mpembe, J. Thomas, L. Shuping, H. Ismail, N.P. Govender); Vermaak & Partners–Pathcare Pathologists, Johannesburg (W. Lowman); Wits Donald Gordon Medical Centre, Johannesburg (W. Lowman); University of the Witwatersrand, Johannesburg (W. Lowman, A.S. Karstaedt, V. Chibabhai, J. Wadula, A. Messina, N.P. Govender); University of Pretoria and Kalafong Provincial Tertiary Hospital, Pretoria, South Africa (T. Avenant); Netcare Hospitals Ltd, Johannesburg (A. Messina); Lancet Laboratories, Durban, South Africa (C.N. Govind, K. Moodley); University of KwaZulu-Natal, Durban (C.N. Govind, H. Dawood, P. Ramjathan); Grey’s Hospital, Pietermaritzburg, South Africa (H. Dawood); National Health Laboratory Service, Johannesburg (V. Chibabhai, J. Wadula, P. Ramjathan)

 

Abstract

Candida auris is an invasive healthcare-associated fungal pathogen. Cases of candidemia, defined as illness in patients with Candida cultured from blood, were detected through national laboratory-based surveillance in South Africa during 2016–2017. We identified viable isolates by using mass spectrometry and sequencing. Among 6,669 cases (5,876 with species identification) from 269 hospitals, 794 (14%) were caused by C. auris. The incidence risk for all candidemia at 133 hospitals was 83.8 (95% CI 81.2–86.4) cases/100,000 admissions. Prior systemic antifungal drug therapy was associated with a 40% increased adjusted odds of C. auris fungemia compared with bloodstream infection caused by other Candida species (adjusted odds ratio 1.4 [95% CI 0.8–2.3]). The crude in-hospital case-fatality ratio did not differ between Candida species and was 45% for C. auris candidemia, compared with 43% for non–C. auris candidemia. C. auris has caused a major epidemiologic shift in candidemia in South Africa.

Keywords: Candidemia; Candida auris; Nosocomial outbreaks; Drugs Resistance; South Africa.

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#Linezolid #resistance in patients with drug-resistant #TB and treatment failure in South Africa (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Linezolid resistance in patients with drug-resistant TB and treatment failure in South Africa

Sean Wasserman, Gail Louw, Limpho Ramangoaela, Garrick Barber, Cindy Hayes, Shaheed Vally Omar, Gary Maartens, Clifton Barry, III, Taeksun Song, Graeme Meintjes

Journal of Antimicrobial Chemotherapy, dkz206, https://doi.org/10.1093/jac/dkz206

Published: 12 May 2019

 

Abstract

Objectives

Limited data exist on clinical associations and genotypic correlates of linezolid resistance in Mycobacterium tuberculosis. We aimed to describe mutations and clinical factors associated with phenotypic linezolid resistance from patients with drug-resistant TB at two public sector facilities in South Africa.

Methods

Adults and adolescents with treatment failure (culture positivity ≥4 months) on a linezolid-containing regimen were retrospectively identified. Phenotypic resistance, as defined by a linezolid MIC >1 mg/L, was assessed for retrieved isolates using broth microdilution. Targeted sequencing of rrl and rplC was performed, irrespective of growth on subculture.

Results

Thirty-nine patients with linezolid-based treatment failure were identified, 13 (33%) of whom had phenotypic or genotypic linezolid resistance after a median duration of 22 months (range = 7–32) of linezolid therapy. Paired MIC testing and genotyping was performed on 55 unique isolates. All isolates with phenotypic resistance (n = 16) were associated with known resistance mutations, most frequently due to the T460C substitution in rplC (n = 10); rrlmutations included G2814T, G2270C/T and A2810C. No mutations were detected in isolates with MICs at or below the critical concentration.

Conclusions

Linezolid resistance occurred in a third of patients with drug-resistant TB and treatment failure. Resistance occurred late and was predicted by a limited number of mutations in rrl and rplC. Screening for genotypic resistance should be considered for patients with a positive culture after 4 months of linezolid therapy in order to optimize treatment and avoid the toxicity of ineffective linezolid therapy.

Topic: phenotype – mutation – south africa – treatment failure – linezolid
– drug-resistant tuberculosis

Issue Section:  ORIGINAL RESEARCH

Keywords: Antibiotics; Drugs Resistance; Linezolid; Tuberculosis; S. Africa.

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#Klebsiella pneumoniae ST307 with #blaOXA-181, #SouthAfrica, 2014–2016 (Emerg Infect Dis., abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Volume 25, Number 4—April 2019 / Research

Klebsiella pneumoniae ST307 with blaOXA-181, South Africa, 2014–2016

Michelle Lowe1, Marleen M. Kock, Jennifer Coetzee, Ebrahim Hoosien, Gisele Peirano, Kathy-Ann Strydom, Marthie M. Ehlers, Nontombi M. Mbelle, Elena Shashkina, David B. Haslam, Puneet Dhawan, Robert J. Donnelly, Liang Chen1, Barry N. Kreiswirth, and Johann D.D. Pitout

Author affiliations: University of Pretoria, Pretoria, South Africa (M. Lowe, M.M. Kock, K.-A. Strydom, M.M. Ehlers, N.M. Mbelle, J.D.D. Pitout); National Health Laboratory Service, Pretoria (M. Lowe, M.M. Kock, K.-A. Strydom, M.M. Ehlers, N.M. Mbelle); Ampath Laboratories, Pretoria (J. Coetzee, E. Hoosien); Calgary Laboratory Services, Calgary, Alberta, Canada (G. Peirano, J.D.D. Pitout); University of Calgary, Calgary (G. Peirano, J.D.D. Pitout); Rutgers University, Newark, New Jersey, USA (E. Shashkina, L. Chen, B.N. Kreiswirth); Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA (D.B. Haslam); New Jersey Medical School, Newark (P. Dhawan, R.J. Donnelly)

 

Abstract

Klebsiella pneumoniae sequence type (ST) 307 is an emerging global antimicrobial drug–resistant clone. We used whole-genome sequencing and PCR to characterize K. pneumoniae ST307 with oxacillinase (OXA) 181 carbapenemase across several private hospitals in South Africa during 2014–16. The South Africa ST307 belonged to a different clade (clade VI) with unique genomic characteristics when compared with global ST307 (clades I–V). Bayesian evolution analysis showed that clade VI emerged around March 2013 in Gauteng Province, South Africa, and then evolved during 2014 into 2 distinct lineages. K. pneumoniae ST307 clade VI with OXA-181 disseminated over a 15-month period within 42 hospitals in 23 cities across 6 northeastern provinces, affecting 350 patients. The rapid expansion of ST307 was most likely due to intrahospital, interhospital, intercity, and interprovince movements of patients. This study highlights the importance of molecular surveillance for tracking emerging antimicrobial clones.

Keywords: Antibiotics; Drugs Resistance; Carbapenem; Oxacillin; Klebsiella pneumoniae; South Africa.

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Experimental #infection of racing #pigeons (Columba livia domestica) with highly pathogenic Clade 2.3.4.4 sub-group B #H5N8 #avian #influenza virus (Vet Microbiol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Vet Microbiol. 2018 Dec;227:127-132. doi: 10.1016/j.vetmic.2018.10.028. Epub 2018 Nov 2.

Experimental infection of racing pigeons (Columba livia domestica) with highly pathogenic Clade 2.3.4.4 sub-group B H5N8 avian influenza virus.

Abolnik C1, Stutchbury S2, Hartman MJ3.

Author information: 1 Department of Production Animal Studies, Faculty of Veterinary Science, University of Pretoria, Private Bag X04, 0110, South Africa. Electronic address: celia.abolnik@up.ac.za. 2 Department of Production Animal Studies, Faculty of Veterinary Science, University of Pretoria, Private Bag X04, 0110, South Africa. 3 Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria, Private Bag X04, Onderstepoort, 0110, South Africa.

 

Abstract

Reported mass mortalities in wild pigeons and doves during the 2017/2018 Clade 2.3.4.4 HPAI H5N8 outbreaks in South Africa necessitated an investigation of healthy racing pigeons for their susceptibility and ability to transmit a Clade 2.3.4.4 sub-group B virus of South African origin. Pigeons challenged with medium (104.5 EID50) and high doses (106 EID50) but not a low dose (103 EID50) of virus, shed virus in low levels of <103 EID50/ml from the oropharynx and cloaca for up to eight days, with peak shedding around 4 days post challenge. Challenged pigeons were able to transmit the virus to contact pigeons, but not contact chickens. Neither pigeons nor chickens presented clinical disease, and only two pigeons in the group that received the high challenge dose developed influenza A-virus specific antibodies. The levels of virus shed by the racing pigeons were well below the published bird infectious dose 50 values for most poultry, especially chickens, therefore the risk that racing pigeons could act as propagators and disseminators through excretion of Clade 2.3.4.4 HPAI H5N8 strains remains negligible.

Copyright © 2018 Elsevier B.V. All rights reserved.

KEYWORDS: Chickens; Clade 2.3.4.4; Highly pathogenic avian influenza; Pigeons

PMID: 30473343 DOI: 10.1016/j.vetmic.2018.10.028 [Indexed for MEDLINE]

Keywords: Avian Influenza; H5N8; Poultry; South Africa.

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Analysis of a subacute sclerosing #panencephalitis (SSPE) Genotype B3 virus from the 2009/10 South African #measles #epidemic shows hyperfusogenic F proteins contribute to measles virus infection in the #brain (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

Analysis of a subacute sclerosing panencephalitis (SSPE) Genotype B3 virus from the 2009/10 South African measles epidemic shows hyperfusogenic F proteins contribute to measles virus infection in the brain.

Fabrizio Angius, Heidi Smuts, Ksenia Rybkina, Debora Stelitano, Brian Eley, Jo Wilmshurst, Marion Ferren, Alexandre Lalande, Cyrille Mathieu, Anne Moscona, Branka Horvat,Takao Hashiguchi, Matteo Porotto, Diana Hardie

DOI: 10.1128/JVI.01700-18

 

ABSTRACT

During a measles virus (MeV) epidemic in 2009 in South Africa, measles inclusion body encephalitis (MIBE) was identified in several HIV-infected patients. Years later, children are presenting with subacute sclerosing panencephalitis (SSPE). To investigate the features of established MeV neuronal infections, viral sequences were analysed from brain tissue samples of a single SSPE case and compared with MIBE sequences previously obtained from patients infected during the same epidemic. Both the SSPE and the MIBE viruses had amino acid substitutions in the ectodomain of the F protein that confer enhanced fusion properties. Functional analysis of the fusion complexes confirmed that both MIBE and SSPE F protein mutations promoted fusion with less dependence on interaction by the viral receptor-binding protein with known MeV receptors. While the SSPE F required the presence of a homotypic attachment protein MeV H in order to fuse, the MIBE F did not. Both F proteins had decreased thermal stability compared to the corresponding wild-type F protein. Finally, recombinant viruses expressing MIBE or SSPE fusion complexes spread in the absence of known MeV receptors, with MIBE F-bearing viruses causing large syncytia in these cells. Our results suggest that alterations to the MeV fusion complex that promote fusion and cell-to-cell spread in the absence of known MeV receptors is a key property for infection of the brain.

 

IMPORTANCE

Measles virus can invade the central nervous system (CNS) and cause severe neurological complications such as MIBE and SSPE. However, mechanisms by which MeV enters the CNS and triggers the disease remain unclear. We analysed viruses from brain tissue of individuals with MIBE or SSPE, infected during the same epidemic, after the onset of neurological disease. Our findings indicate that the emergence of hyper-fusogenic MeV F proteins may be associated with infection of the brain. We also demonstrate that hyper-fusogenic F proteins permit MeV to enter cells and spread without the need to engage nectin-4 or CD150, known receptors for MeV that are not present on neural cells.

Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords: Measles; Subacute Sclerosing Panencephalitis; Measles Inclusion Body Encephalitis; Viral pathogenesis.

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#Outbreak of #MDR #TB in [#ZA] South Africa undetected by #WHO-endorsed commercial #tests: an observational study (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Outbreak of multidrug-resistant tuberculosis in South Africa undetected by WHO-endorsed commercial tests: an observational study

Ndivhuho A Makhado, MSc, Edith Matabane, MSc, Mauro Faccin, PhD, Claire Pinçon, PhD, Agathe Jouet, PhD, Fairouz Boutachkourt, BSc, Léonie Goeminne, BSc, Cyril Gaudin, PhD, Gugu Maphalala, MSc, Patrick Beckert, PhD, Stefan Niemann, PhD, Jean-Charles Delvenne, PhD, Michel Delmée, MD, Lufuno Razwiedani, MD, Maphoshane Nchabeleng, MD, Philip Supply, PhD †, Bouke C de Jong, MD †, Emmanuel André, MD  †

Published: October 17, 2018 / DOI: https://doi.org/10.1016/S1473-3099(18)30496-1

 

Summary

Background

Global roll-out of rapid molecular assays is revolutionising the diagnosis of rifampicin resistance, predictive of multidrug-resistance, in tuberculosis. However, 30% of the multidrug-resistant (MDR) strains in an eSwatini study harboured the Ile491Phe mutation in the rpoB gene, which is associated with poor rifampicin-based treatment outcomes but is missed by commercial molecular assays or scored as susceptible by phenotypic drug-susceptibility testing deployed in South Africa. We evaluated the presence of Ile491Phe among South African tuberculosis isolates reported as isoniazid-monoresistant according to current national testing algorithms.

Methods

We screened records of 37 644 Mycobacterium tuberculosis positive cultures from four South African provinces, diagnosed at the National Health Laboratory Service–Dr George Mukhari Tertiary Laboratory, to identify isolates with rifampicin sensitivity and isoniazid resistance according to Xpert MTB/RIF, GenoType MTBDRplus, and BACTEC MGIT 960. Of 1823 isolates that met these criteria, 277 were randomly selected and screened for Ile491Phe with multiplex allele-specific PCR and Sanger sequencing of rpoB. Ile491Phe-positive strains (as well as 17 Ile491Phe-bearing isolates from the eSwatini study) were then tested by Deeplex-MycTB deep sequencing and whole-genome sequencing to evaluate their patterns of extensive resistance, transmission, and evolution.

Findings

Ile491Phe was identified in 37 (15%) of 249 samples with valid multiplex allele-specific PCR and sequencing results, thus reclassifying them as MDR. All 37 isolates were additionally identified as genotypically resistant to all first-line drugs by Deeplex-MycTB. Six of the South African isolates harboured four distinct mutations potentially associated with decreased bedaquiline sensitivity. Consistent with Deeplex-MycTB genotypic profiles, whole-genome sequencing revealed concurrent silent spread in South Africa of a MDR tuberculosis strain lineage extending from the eSwatini outbreak and at least another independently emerged Ile491Phe-bearing lineage. Whole-genome sequencing further suggested acquisition of mechanisms compensating for the Ile491Phe fitness cost, and of additional bedaquiline resistance following the introduction of this drug in South Africa.

Interpretation

A substantial number of MDR tuberculosis cases harbouring the Ile491Phe mutation in the rpoB gene in South Africa are missed by current diagnostic strategies, resulting in ineffective first-line treatment, continued amplification of drug resistance, and concurrent silent spread in the community.

Funding

VLIR-UOS, National Research Foundation (South Africa), and INNOVIRIS.

Keywords: Antibiotics; Drugs Resistance; Tuberculosis; South Africa.

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