Accelerated Immunodeficiency-associated Vaccine-derived Poliovirus Serotype 3 Sequence Evolution Rate in an 11-week-old Boy With X-linked Agammaglobulinemia and Perinatal Human Immunodeficiency Virus Exposure.

Primary B-cell immunodeficiencies are risk factors for the generation of vaccine-derived polioviruses. We report immunodeficiency-associated vaccine-derived poliovirus serotype 3 in an 11-week-old boy with X-linked agammaglobulinemia. Unique characteristics of this case include early age of presentation, high viral evolutionary rate, and the child's perinatal exposure to human immunodeficiency virus.

Impaired Transplacental Transfer of Respiratory Syncytial Virus-neutralizing Antibodies in Human Immunodeficiency Virus-infected Versus -uninfected Pregnant Women.

Human immunodeficiency virus (HIV)-exposed, uninfected infants have higher risks of respiratory syncytial virus-associated hospitalization than HIV-unexposed infants. Despite similar neutralizing antibody titers between HIV-infected and -uninfected women, maternal HIV infection and hypergammaglobulinemia were independently associated with lower titers in newborns. Maternal hypergammaglobulinemia was associated with lower cord-to-maternal antibody ratio.

The presence of prolines in the flanking region of an immunodominant HIV-2 gag epitope influences the quality and quantity of the epitope generated.

Both the recognition of HIV-infected cells and the immunogenicity of candidate CTL vaccines depend on the presentation of a peptide epitope at the cell surface, which in turn depends on intracellular antigen processing. Differential antigen processing maybe responsible for the differences in both the quality and the quantity of epitopes produced, influencing the immunodominance hierarchy of viral epitopes. Previously, we showed that the magnitude of the HIV-2 gag-specific T-cell response is inversely correlated with plasma viral load, particularly when responses are directed against an epitope, 165 DRFYKSLRA173 , within the highly conserved Major Homology Region of gag-p26. We also showed that the presence of three proline residues, at positions 119, 159 and 178 of gag-p26, was significantly correlated with low viral load. Since this proline motif was also associated with stronger gag-specific CTL responses, we investigated the impact of these prolines on proteasomal processing of the protective 165 DRFYKSLRA173 epitope. Our data demonstrate that the 165 DRFYKSLRA173 epitope is most efficiently processed from precursors that contain two flanking proline residues, found naturally in low viral-load patients. Superior antigen processing and enhanced presentation may account for the link between infection with HIV-2 encoding the "PPP-gag" sequence and both strong gag-specific CTL responses as well as lower viral load.

Evaluation of Xpert Carba-R for detecting carbapenemase-producing organisms in South Africa.

This study evaluated the performance of the Xpert Carba-R assay for detecting the five common carbapenemases in carbapenemase-producing organisms in Johannesburg, South Africa between April 2021 and September 2021. The assay demonstrated 98% sensitivity and 97% specificity. It was also able to detect all the carbapenemases in double carbapenemase producers, as well as carbapenemases in non-fermenter organisms. The Xpert Carba-R assay, therefore, allows the rapid (< 1 h) and accurate identification of the common carbapenemases in pure bacterial cultures and rectal swabs. This assay can aid in the timeous institution of appropriate treatment and infection prevention and control measures.

Phylogeographical footprint of colonial history in the global dispersal of human immunodeficiency virus type 2 group A.

Human immunodeficiency virus type 2 (HIV-2) emerged in West Africa and has spread further to countries that share socio-historical ties with this region. However, viral origins and dispersal patterns at a global scale remain poorly understood. Here, we adopt a Bayesian phylogeographic approach to investigate the spatial dynamics of HIV-2 group A (HIV-2A) using a collection of 320 partial pol and 248 partial env sequences sampled throughout 19 countries worldwide. We extend phylogenetic diffusion models that simultaneously draw information from multiple loci to estimate location states throughout distinct phylogenies and explicitly attempt to incorporate human migratory fluxes. Our study highlights that Guinea-Bissau, together with Côte d'Ivoire and Senegal, have acted as the main viral sources in the early stages of the epidemic. We show that convenience sampling can obfuscate the estimation of the spatial root of HIV-2A. We explicitly attempt to circumvent this by incorporating rate priors that reflect the ratio of human flow from and to West Africa. We recover four main routes of HIV-2A dispersal that are laid out along colonial ties: Guinea-Bissau and Cape Verde to Portugal, Côte d'Ivoire and Senegal to France. Within Europe, we find strong support for epidemiological linkage from Portugal to Luxembourg and to the UK. We demonstrate that probabilistic models can uncover global patterns of HIV-2A dispersal providing sampling bias is taken into account and we provide a scenario for the international spread of this virus.

A Retrospective Analysis of Culture-Confirmed Enterococci Bloodstream Infections in South Africa, 2016-2020: A Cross-Sectional Study.

(1) Background: The emergence of multidrug resistance enterococci is a major public health concern. This study aimed to determine the prevalence and antimicrobial resistance of enterococci isolated from blood cultures over a five-year period (2016−2020) at public hospitals in South Africa. (2): Methods: A retrospective analysis of clinical enterococci isolated from bloodstream infection samples at the South African public hospitals was conducted. The ESKAPE dataset from January 2016 to December 2020 was obtained from the central data warehouse (CDW) at the National Health Laboratory Service (NHLS). (3): Results: Following de-duplication, a total of 130,352/306,592 organisms isolated from blood cultures were identified as ESKAPE pathogens. In this study, K. pneumoniae (25%; 33,082/130,352), was the most frequently isolated pathogen from blood cultures, followed by S. aureus (23%; 29,922/130,352) and enterococci (16%; 21,339/130,352). Of the enterococci cases, about 43% (9132/21,339) of cases were from the infants aged (<1-year old) and 32% (6745/21,339) from the adult patients. No changes observed in vancomycin, teicoplanin, and linezolid susceptibility; however, E. faecium and E. faecalis blood culture isolates remained highly susceptible (>97%) to these antibiotics. (4): Conclusions: The current study revealed a significant increase of E. faecalis and E. faecium blood culture isolates as compared to the previous national ESKAPE data. Low vancomycin resistance was observed. Continuous monitoring of antimicrobial resistant Enterococcus species is warranted in South Africa.

Acinetobacter baumannii complex, national laboratory-based surveillance in South Africa, 2017 to 2019.

OBJECTIVE: We aimed to provide an analysis of A. baumannii complex (ABC) isolated from blood cultures in South Africa. MATERIALS AND METHODS: ABC surveillance was conducted from 1 April 2017 to 30 September 2019 at 19 hospital sites from blood cultures of any age and sex. Organism identification was performed using the MALDI-TOF MS and antimicrobial susceptibility testing (AST), MicroScan Walkaway System. We confirmed colistin resistance with Sensititre, FRCOL panel, and selected for whole-genome sequencing. RESULTS: During the study period, we identified 4822 cases of ABC, of which 2152 cases were from 19 enhanced surveillance sites were reported during the enhanced surveillance period (1 August 2018 to 30 September 2019). Males accounted for 54% (2611/4822). Of the cases with known age, 41% (1968/4822) were infants (< 1-year-old). Seventy-eight percent (1688/2152) of cases had a known hospital outcome, of which 36% (602/1688) died. HIV status was known for 69% (1168/1688) of cases, and 14% (238/1688) were positive. Eighty-two percent (1389/1688) received antimicrobial treatment in admission. Three percent (35/1389) of cases received single colistin. Four percent (75/2033) were resistant to colistin. At least 75% of the isolates (1530/2033) can be classified as extensively drug-resistant (XDR), with resistance to most antibiotics except for colistin. The majority, 83% (20/24), of the colistin-resistant isolates were of the sequence type (ST) 1. Resistance genes, both plasmid- and chromosomal- mediated were not observed. Although all isolates had, nine efflux pump genes related to antimicrobial resistance. CONCLUSION: Our surveillance data contributed to a better understanding of the natural course of A. baumannii disease, the patient characteristics among infants, and the level of resistance. At least two-thirds of the isolates were extensively drug-resistant, and four percent of isolates were resistant to colistin.

Ibrexafungerp: A First-in-Class Oral Triterpenoid Glucan Synthase Inhibitor.

Ibrexafungerp (formerly SCY-078 or MK-3118) is a first-in-class triterpenoid antifungal or "fungerp" that inhibits biosynthesis of ß-(1,3)-D-glucan in the fungal cell wall, a mechanism of action similar to that of echinocandins. Distinguishing characteristics of ibrexafungerp include oral bioavailability, a favourable safety profile, few drug-drug interactions, good tissue penetration, increased activity at low pH and activity against multi-drug resistant isolates including C. auris and C. glabrata. In vitro data has demonstrated broad and potent activity against Candida and Aspergillus species. Importantly, ibrexafungerp also has potent activity against azole-resistant isolates, including biofilm-forming Candida spp., and echinocandin-resistant isolates. It also has activity against the asci form of Pneumocystis spp., and other pathogenic fungi including some non-Candida yeasts and non-Aspergillus moulds. In vivo data have shown IBX to be effective for treatment of candidiasis and aspergillosis. Ibrexafungerp is effective for the treatment of acute vulvovaginal candidiasis in completed phase 3 clinical trials.

Sensitivity of the acute flaccid paralysis surveillance system for poliovirus in South Africa, 2016-2019.

Introduction. Global poliovirus eradication is a public health emergency of international concern. The acute flaccid paralysis (AFP) surveillance programme in South Africa has been instrumental in eliminating polioviruses and keeping the country poliovirus free.Gap statement. The sensitivity of surveillance for polioviruses by every African country is of global interest in the effort to ensure global health security from poliovirus re-emergence.Aim. To describe the epidemiology of polioviruses from AFP cases and environmental samples in South Africa and to report the performance of the AFP surveillance system for the years 2016-2019 against targets established by the World Health Organization (WHO).Methods. Stool specimens from AFP or suspected AFP cases were received and tested as per WHO guidelines. Environmental samples were gathered from sites across the Gauteng province using the grab collection method. Concentration was effected by the two-phase polyethylene glycol method approved by the WHO. Suspected polioviruses were isolated in RD and/or L20B cell cultures through identification of typical cytopathic effects. The presence of polioviruses was confirmed by intratypic differentiation PCR. All polioviruses were sequenced using the Sanger method, and their VP1 gene analysed for mutations.Results. Data from 4597 samples (2385 cases) were analysed from the years 2016-2019. Two cases of immunodeficiency-associated vaccine-derived poliovirus (iVDPV) type 3 were detected in 2017 and 2018. A further 24 Sabin type 1 or type 3 polioviruses were detected for the 4 years. The national surveillance programme detected an average of 3.1 cases of AFP/100 000 individuals under 15 years old (2.8/100 000-3.5/100 000). The stool adequacy of the samples received was 53.0 % (47.0-55.0%), well below the WHO target of 80 % adequacy. More than 90 % of results were released from the laboratory within the turnaround time (96.6 %) and non-polio enteroviruses were detected in 11.6 % of all samples. Environmental surveillance detected non-polio enterovirus in 87.5 % of sewage samples and Sabin polioviruses in 12.5 % of samples.Conclusion. The AFP surveillance programme in South Africa is sensitive to detect polioviruses in South Africa and provided no evidence of wild poliovirus or VDPV circulation in the country.

Clearance of Immunodeficiency-associated Vaccine-derived Poliovirus Infection With Pocapavir.

Pocapavir exhibits antiviral activity against both polio and nonpolio enteroviruses. There is limited experience of the use of this investigational drug in young children with enteroviral infection. We describe the successful clearance of prolonged immunodeficiency-associated vaccine-derived type 3 poliovirus infection by pocapavir in an infant with underlying X-linked agammaglobulinemia.

Placental Transfer of Respiratory Syncytial Virus Antibody Among HIV-Exposed, Uninfected Infants.

BACKGROUND: Maternal human immunodeficiency virus (HIV) infection is associated with lower placental transfer of antibodies specific to several childhood pathogens. Our objective for this study was to evaluate the effect of maternal HIV infection on the placental transfer of respiratory syncytial virus (RSV)-neutralizing antibodies. METHODS: We conducted a cross-sectional study of mothers and their newborn infants at a tertiary hospital in Gaborone, Botswana, between March 2015 and December 2015. We measured serum RSV antibody levels by using a microneutralization assay. We used multivariable linear regression to evaluate the effect of maternal HIV infection on maternal RSV antibody levels, placental transfer of RSV antibodies, and newborn RSV antibody levels. RESULTS: Of 316 mothers, 154 (49%) were infected with HIV. The placental transfer ratios for RSV antibodies to HIV-exposed, uninfected (HEU) and HIV-unexposed, uninfected infants were 1.02 and 1.15, respectively. The geometric mean titer (95% confidence interval) of RSV-neutralizing antibodies was 2657 (2251-3136) among HEU newborns and 2911 (2543-3331) among HIV-unexposed, uninfected newborns. In multivariable analyses, maternal HIV infection was associated with lower placental transfer of RSV antibodies (P = .02) and a lower level of RSV antibodies among newborns (P = .002). Among HEU newborns, higher birth weight (P = .004) and an undetectable maternal antenatal viral load (P = .01) were associated with more effective placental transfer of RSV antibodies. CONCLUSIONS: Maternal human immunodeficiency virus (HIV) infection is associated with lower mother-to-fetus transfer of serum RSV-neutralizing antibodies. HEU infants should be prioritized for preventive interventions for RSV. Maternal viral suppression through combination antiretroviral therapy has the potential to improve immunity to RSV among HIV-exposed infants.

Presence of a multidrug-resistance mutation in an HIV-2 variant infecting a treatment-naive individual in Caio, Guinea Bissau.

We report the possible transmission of drug-resistant human immunodeficiency virus type 2. A 66-year-old woman from rural Guinea Bissau who had no obvious antiretroviral exposure was found to harbor a variant with the multidrug-resistance mutation Q151M. Finding this mutation among a drug-naive population presents an important public health issue that needs to be addressed for treatment to be effective.

Virological response to highly active antiretroviral therapy in patients infected with human immunodeficiency virus type 2 (HIV-2) and in patients dually infected with HIV-1 and HIV-2 in the Gambia and emergence of drug-resistant variants.

Drug design, antiretroviral therapy (ART), and drug resistance studies have focused almost exclusively on human immunodeficiency virus type 1 (HIV-1), resulting in limited information for patients infected with HIV-2 and for those dually infected with HIV-1 and HIV-2. In this study, 20 patients, 12 infected with HIV-2 and 8 dually infected with HIV-1 and HIV-2, all treated with zidovudine (ZDV), lamivudine (3TC), and lopinavir-ritonavir (LPV/r), were followed up longitudinally for about 3 years. For 19/20 patients, viral loads were reduced to undetectable levels; the patient whose viral load remained detectable reported adverse effects associated with LPV/r that had caused him to stop taking all the drugs. HIV-2 strains containing mutations in both the protease and the reverse transcriptase gene that may confer drug resistance were observed in two patients with viral rebound, as early as 130 days (4.3 months) after the initiation of therapy. We conclude that the combination of ZDV, 3TC, and LPV/r is able to provide efficient and durable suppression of HIV-1 and HIV-2 for as long as 3 years in HIV-2-infected and dually infected patients. However, the emergence of HIV-1 and HIV-2 strains containing drug-resistant mutations can compromise the efficacy of this highly active ART.

Pneumococcal conjugate vaccine in HIV-infected and HIV-exposed, uninfected children.

INTRODUCTION: Incidence of invasive pneumococcal disease (IPD) among HIV-infected children is 20-40 fold greater compared to HIV-uninfected children, including among HIV-infected children on antiretroviral therapy (ART). Also, HIV-exposed, uninfected children have 2.7-fold greater risk of IPD compared to HIV-unexposed children. Areas covered: We reviewed studies identified on Pubmed database with the terms 'PCV' and 'HIV'; studies involving adults only were excluded. Expert commentary: While ART and pneumococcal conjugate vaccines (PCV) have reduced IPD morbidity and mortality in HIV-infected children, ART-naïve and immunosuppressed children have inferior immunogenicity to most PCV serotypes; highlighting the need for concomitant use of ART with PCV. Furthermore, studies to determine optimal PCV dosing schedules, timing and number of doses, are urgently required to ensure sustained vaccine efficacy in HIV-infected children.

Maternal HIV infection associated with reduced transplacental transfer of measles antibodies and increased susceptibility to disease.

BACKGROUND: Transplacental transfer of measles antibodies from mother to fetus is important in protecting against measles during early infancy. Changes in population immunity against measles in adults, including waning of immunity among HIV-infected pregnant women, could affect passive immunity acquired in utero by newborns. OBJECTIVES: To evaluate the effect of maternal HIV infection on transplacental transfer of measles antibody in mother-newborn dyads in a setting of high maternal HIV prevalence. STUDY DESIGN: Serum at birth was obtained from 303 mother-newborn dyads, including 196 HIV-infected and 107 HIV-uninfected women, and tested for measles IgG antibodies by ELISA. Seronegativity was defined as antibody levels <150mIU/ml and seroprotective titers as ≥330mIU/ml. RESULTS: HIV-infected and -uninfected women had similar measles antibody titers, however, cord-blood titers were lower among HIV-exposed (788.06mIU/ml) compared to HIV- unexposed newborns (1306.6mIU/ml; p≤0.001), due to lower transplacental antibody transfer ratio in HIV-exposed (0.63) than in HIV-unexposed newborns (0.97; p≤0.001). Maternal age <25years of age was associated with lower antibody titers and lower percentage with seroprotective titer, as well as less likelihood of their newborns having seroprotective titers (70.2% vs. 86.5%; p=0.001). CONCLUSIONS: Lower levels of measles antibody in HIV-exposed newborns and in younger women <25years old, increases the susceptibility of their newborns to developing measles. This suggest a need to re-evaluate measles immunization of women of child bearing age and the timing of measles vaccination among infants in settings with a high prevalence of maternal HIV-infection.

Immunogenicity of 13-valent pneumococcal conjugate vaccine among children with underlying medical conditions.

BACKGROUND: Streptococcus pneumoniae is a leading cause of vaccine-preventable disease in children under 5years. Immunocompromised children and those with underlying diseases are at increased risk of severe complications from vaccine-preventable infections. We studied the humoral immune response to the 13-valent pneumococcal conjugate vaccine (PCV13) in children with HIV-infection, kidney or lung disease and compared this to the response in healthy control children. METHODS: Children aged 12-71months with underlying conditions including HIV-infection and those with kidney and lung diseases (at-risk children), and a healthy control group were vaccinated with PCV13. The at-risk children received two doses of PCV13 and the controls received one dose. Serotype-specific antibodies for all PCV13 serotypes were measured by a luminex-based enzyme immunoassay at baseline and post-vaccination. RESULTS: After the first PCV13 dose, the fold-increase in serotype-specific antibody geometric mean concentrations (GMCs) from baseline and the percentage of participants with ≥4-fold-increase in antibody concentrations was similar between the control and at-risk children. GMCs were, however, lower for three of the 13 serotypes in HIV-infected children, higher for serotype 6B in children with kidney disease and higher for serotypes 6B and 14 in children with lung disease. After second vaccine dose HIV-infected children had an increase in GMCs from post-first dose for nine serotypes but the percentage of participants with ≥4-fold-increase from baseline was similar post-second dose compared to post-first dose except for serotypes 6A and 19F. In children with kidney or lung diseases the immune responses after second vaccine dose were similar to post-first dose. Attenuated responses were observed for serotypes 3 and 19A in all study-groups, which was especially pronounced in the at-risk groups. CONCLUSION: All study-groups mounted an immune response to PCV13, with the at-risk groups having responses that were mostly similar to the control children.

HLA Correlates of Long-Term Survival in Vertically Infected HIV-1-Positive Adolescents in Harare, Zimbabwe.

African infants with vertically acquired HIV infection progress rapidly, with only 50% surviving beyond 2 years in the absence of treatment. Despite this high initial mortality, recent reports describe a substantial burden of older children living with untreated vertically acquired HIV infection in Southern Africa. The immunological and genetic factors associated with long-term survival following vertical infection are poorly understood. We performed medium-to-high resolution HLA typing on DNA samples obtained from a cohort of presumed vertically HIV-1-infected children and age-matched uninfected controls in Harare, Zimbabwe. Overall, 93 HLA class I alleles were detected in the study population with a significant enrichment of HLA-C*08:02 and -C*08:04 in the HIV-1-infected long-term survivor group. Conversely, HLA-A*02:01, A*34:02, and -B*58:02 were overrepresented in the uninfected control group. Our data indicate that HLA alleles may have differential effects against HIV acquisition and disease progression in vertical HIV-1 infection.

Antiretroviral Therapy for HIV-2 Infection: Recommendations for Management in Low-Resource Settings.

HIV-2 contributes approximately a third to the prevalence of HIV in West Africa and is present in significant amounts in several low-income countries outside of West Africa with historical ties to Portugal. It complicates HIV diagnosis, requiring more expensive and technically demanding testing algorithms. Natural polymorphisms and patterns in the development of resistance to antiretrovirals are reviewed, along with their implications for antiretroviral therapy. Nonnucleoside reverse transcriptase inhibitors, crucial in standard first-line regimens for HIV-1 in many low-income settings, have no effect on HIV-2. Nucleoside analogues alone are not sufficiently potent enough to achieve durable virologic control. Some protease inhibitors, in particular those without ritonavir boosting, are not sufficiently effective against HIV-2. Following review of the available evidence and taking the structure and challenges of antiretroviral care in West Africa into consideration, the authors make recommendations and highlight the needs of special populations.