Bayesian Estimation of Mixture Models with Prespecified Elements to Compare Drug Resistance in Treatment-Naïve and Experienced Tuberculosis Cases

We propose a Bayesian approach for estimating branching tree mixture models to compare drug-resistance pathways (i.e. patterns of sequential acquisition of resistance to individual antibiotics) that are observed among Mycobacterium tuberculosis isolates collected from treatment-naïve and treatment-experienced patients. Resistant pathogens collected from treatment-naïve patients are strains for which fitness costs of resistance were not sufficient to prevent transmission, whereas those collected from treatment-experienced patients reflect both transmitted and acquired resistance, the latter of which may or may not be associated with lower transmissibility. The comparison of the resistance pathways constructed from these two groups of drug-resistant strains provides insight into which pathways preferentially lead to the development of multiple drug resistant strains that are transmissible. We apply the proposed statistical methods to data from worldwide surveillance of drug-resistant tuberculosis collected by the World Health Organization over 13 years

Nationwide and regional incidence of microbiologically confirmed pulmonary tuberculosis in South Africa, 2004-12 : a time series analysis

BACKGROUND : South Africa has the highest incidence of tuberculosis in the world, largely resulting from a high population prevalence of HIV infection. We investigated the incidence of microbiologically confirmed pulmonary tuberculosis, and new cases of pulmonary tuberculosis registered for treatment, nationally and provincially in South Africa from 2004 to 2012, during which time there were changes in antiretroviral therapy (ART) coverage among individuals with HIV infection. METHODS : We identifi ed cases of microbiologically confi rmed pulmonary tuberculosis from 2004 to 2012 from the National Health Laboratory Service Corporate Data Warehouse. New cases registered for treatment were identifi ed from National Department of Health electronic registries. A time series analysis, using autoregressive models, was undertaken on incidence of microbiologically confi rmed pulmonary disease nationally and provincially; this trend was also examined relative to ART coverage of adults with HIV infection. FINDINGS : During the 9-year period, 3 523 371 cases of microbiologically confirmed pulmonary tuberculosis were recorded nationally. Annual incidence (per 100 000 population) increased from 650 (95% CI 648–652) in 2004 to 848 (845–850) in 2008, declining to 774 (771–776) by 2012 (9% decrease from 2008 to 2012). Incidence varied by age group, sex, and province. There was an inverse association between incidence of microbiologically confirmed disease and ART coverage among HIV-infected individuals nationally and provincially. Trends in incidence of tuberculosis cases registered for treatment mirrored those of microbiologically confirmed cases nationally and provincially; however, incidence of microbiologically confirmed cases was consistently higher than cases registered for treatment nationally and in seven of nine provinces. INTERPRETATION : Since its peak in 2008, the incidence of microbiologically confirmed pulmonary tuberculosis in South Africa had declined by 2012; this decline is associated with an increase in ART coverage. Future integration of registries for microbiologically confirmed cases and new cases registered for treatment would improve the assessment of the burden of pulmonary tuberculosis in South Africa. FUNDING : National Institute for Communicable Diseases: Division of the National Health Laboratory Service, South Africa.SAM has received grants and personal fees from GlaxoSmithKline, Pfizer, and Sanofi Pasteur, and grants from Novartis.http://www.thelancet.com/infectionhb2017Medical Microbiolog

Immunogenicity and seroefficacy of 10-valent and 13-valent pneumococcal conjugate vaccines: a systematic review and network meta-analysis of individual participant data

Background: Vaccination of infants with pneumococcal conjugate vaccines (PCV) is recommended by the World Health Organization. Evidence is mixed regarding the differences in immunogenicity and efficacy of the different pneumococcal vaccines. Methods: In this systematic-review and network meta-analysis, we searched the Cochrane Library, Embase, Global Health, Medline, clinicaltrials.gov and trialsearch.who.int up to February 17, 2023 with no language restrictions. Studies were eligible if they presented data comparing the immunogenicity of either PCV7, PCV10 or PCV13 in head-to-head randomised trials of young children under 2 years of age, and provided immunogenicity data for at least one time point after the primary vaccination series or the booster dose. Publication bias was assessed via Cochrane's Risk Of Bias due to Missing Evidence tool and comparison-adjusted funnel plots with Egger's test. Individual participant level data were requested from publication authors and/or relevant vaccine manufacturers. Outcomes included the geometric mean ratio (GMR) of serotype-specific IgG and the relative risk (RR) of seroinfection. Seroinfection was defined for each individual as a rise in antibody between the post-primary vaccination series time point and the booster dose, evidence of presumed subclinical infection. Seroefficacy was defined as the RR of seroinfection. We also estimated the relationship between the GMR of IgG one month after priming and the RR of seroinfection by the time of the booster dose. The protocol is registered with PROSPERO, ID CRD42019124580. Findings: 47 studies were eligible from 38 countries across six continents. 28 and 12 studies with data available were included in immunogenicity and seroefficacy analyses, respectively. GMRs comparing PCV13 vs PCV10 favoured PCV13 for serotypes 4, 9V, and 23F at 1 month after primary vaccination series, with 1.14- to 1.54- fold significantly higher IgG responses with PCV13. Risk of seroinfection prior to the time of booster dose was lower for PCV13 for serotype 4, 6B, 9V, 18C and 23F than for PCV10. Significant heterogeneity and inconsistency were present for most serotypes and for both outcomes. Two-fold higher antibody after primary vaccination was associated with a 54% decrease in risk of seroinfection (RR 0.46, 95% CI 0.23–0.96). Interpretation: Serotype-specific differences were found in immunogenicity and seroefficacy between PCV13 and PCV10. Higher antibody response after vaccination was associated with a lower risk of subsequent infection. These findings could be used to compare PCVs and optimise vaccination strategies. Funding: The NIHR Health Technology Assessment Programme

Longitudinal IgA and IgG Response, and ACE2 Binding Blockade, to Full-Length SARS-CoV-2 Spike Protein Variants in a Population of Black PLWH Vaccinated with ChAdOx1 nCoV-19

Vaccines against SARS-CoV-2 have been pivotal in overcoming the COVID-19 pandemic yet understanding the subsequent outcomes and immunological effects remain crucial, especially for at-risk groups e.g., people living with human immunodeficiency virus (HIV) (PLWH). In this study we report the longitudinal IgA and IgG antibody titers, as well as antibody-mediated angiotensin converting enzyme 2 (ACE2) binding blockade, against the SARS-CoV-2 spike (S) proteins after 1 and 2 doses of the ChAdOx1 nCoV-19 vaccine in a population of Black PLWH. Here, we report that PLWH (N = 103) did not produce an anti-S IgA response after infection or vaccination, however, anti-S IgG was detected in response to vaccination and infection, with the highest level detected for infected vaccinated participants. The anti-IgG and ACE2 blockade assays revealed that both vaccination and infection resulted in IgG production, however, only vaccination resulted in a moderate increase in ACE2 binding blockade to the ancestral S protein. Vaccination with a previous infection results in the greatest anti-S IgG and ACE2 blockade for the ancestral S protein. In conclusion, PLWH produce an anti-S IgG response to the ChAdOx1 nCoV-19 vaccine and/or infection, and ChAdOx1 nCoV-19 vaccination with a previous infection produced more neutralizing antibodies than vaccination alone

Effects of conditional cash transfers and pre-test and post-test tuberculosis counselling on patient outcomes and loss to follow-up across the continuum of care in South Africa: a randomised controlled trial.

BACKGROUND: Economic and behavioural factors lead to poor outcomes in patients with tuberculosis. We investigated the effects of a package of interventions consisting of pre-test and post-test tuberculosis counselling with conditional cash transfers on patient outcomes in adults undergoing investigation for pulmonary tuberculosis. METHODS: This pragmatic, open-label, individual randomised controlled trial was done in nine clinics in Johannesburg, South Africa. Participants (aged ≥18 years) undergoing investigation for tuberculosis were randomly assigned (1:1) to the intervention group or control group (standard of care) via permuted block randomisation, stratified by clinic; group assignment was concealed using opaque envelopes. The intervention group received pre-test and post-test tuberculosis counselling, and for participants diagnosed with rifampicin-susceptible tuberculosis, a digital payment (R150; approximately US$10) at treatment initiation and each monthly treatment visit. Payments were contingent on timely attendance: 14 days from initial sputum sample collection and within 7 days on either side of their scheduled monthly appointment. The primary endpoint was successful patient outcome (patients who were cured or completed treatment) or unsuccessful patient outcome (pretreatment loss-to-follow-up, on-treatment loss-to-follow-up, development of rifampicin-resistant tuberculosis while on treatment, treatment failure [ie, smear or culture positive at 5 months or later after commencing treatment], or death). The primary outcome was analysed in the modified intention-to-treat population, defined as all randomly assigned participants with rifampicin-susceptible tuberculosis confirmed before the commencement of tuberculosis treatment. Weighted outcome prevalence, relative risks (RRs), and risk differences were calculated using a multivariable Poisson model with robust standard errors. This trial is registered with the Pan African Clinical Trials Registry (PACTR202410708311054) and is completed. FINDINGS: Between Oct 25, 2018, and Dec 9, 2019, 4110 participants were enrolled and randomly assigned, 2059 to the intervention group and 2051 to the control group. 381 (9·3%) participants had microbiologically confirmed rifampicin-susceptible pulmonary tuberculosis (195 [9·5%] of 2059 in the intervention group vs 186 [9·1%] of 2051 in the control group; median age 37 years [IQR 30 to 45], 257 [67·5%] male, 124 [32·5%] female). At study closure, primary outcome data were available for 128 (65·6%) of 195 participants in the intervention group and 139 (74·7%) of 186 participants in the control group. 105 (82·0%) of 128 participants in the intervention group and 93 (66·9%) of 139 participants in the control group had a successful patient outcome; 23 (18·0%) of 128 participants in the intervention group and 46 (33·1%) of 139 participants in the control group had an unsuccessful patient outcome. The weighted regression analysis showed a substantial reduction in the risk of unsuccessful patient outcomes in the intervention group compared with the control group (weighted prevalence 15·9% vs 28·6%; RR in weighted population 0·52, 95% CI 0·33 to 0·82; risk difference in weighted population -14·1 percentage points, 95% CI -23·3 to -4·8). Pretreatment loss to follow-up was lower in the intervention group than in the control group (unweighted population: five [3·9%] of 128 participants vs 22 [15·8%] of 139 participants; risk difference in weighted population -9·6 percentage points, 95% CI -14·9 to -4·2). INTERPRETATION: The package of interventions consisting of pre-test and post-test tuberculosis counselling with conditional cash transfers significantly reduced the risk of unsuccessful tuberculosis patient outcomes, bringing one of the 90-90-90 targets within reach (ie, achieving 90% tuberculosis treatment success). Furthermore, reduction in pretreatment loss to follow-up is expected to reduce transmission and lower incidence of the disease over time. FUNDING: South African Medical Research Council, UK Medical Research Council, and Newton Fund

T-cell responses induced by ChAdOx1 nCoV-19 (AZD1222) vaccine to wild-type severe acute respiratory syndrome coronavirus 2 among people with and without HIV in South Africa

Objective(s): This study aimed to investigate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T-cell responses 14 days after single-dose ChAdOx1 nCoV-19 (AZD1222) vaccination in black Africans with and without HIV in South Africa, as well as determine the effect of AZD1222 vaccination on cell-mediated immune responses in people with HIV (PWH) with prior SARS-CoV-2 infection. Methods: A total of 70 HIV-uninfected people and 104 PWH were prospectively enrolled in the multicentre, randomized, double-blinded, placebo-controlled, phase Ib/IIa trial (COV005). Peripheral blood mononuclear cells (PBMCs) were collected from trial participants 14 days after receipt of first dose of study treatment (placebo or AZD1222 vaccine). T-cell responses against the full-length spike (FLS) glycoprotein of wild-type SARS-CoV-2 and mutated S-protein regions found in the Alpha, Beta and Delta variants were assessed using an ex-vivo ELISpot assay. Results: Among AZD1222 recipients without preceding SARS-CoV-2 infection, T-cell responses to FLS of wild-type SARS-CoV-2 were similarly common in PWH and HIV-uninfected people (30/33, 90.9% vs. 16/21, 76.2%; P = 0.138); and magnitude of response was similar among responders (78 vs. 56 SFCs/106 PBMCs; P = 0.255). Among PWH, AZD1222 vaccinees with prior SARS-CoV-2 infection, displayed a heightened T-cell response magnitude compared with those without prior infection (186 vs. 78 SFCs/106 PBMCs; P = 0.001); and similar response rate (14/14, 100% vs. 30/33, 90.9%; P = 0.244). Conclusion: Our results indicate comparable T-cell responses following AZD1222 vaccination in HIV-uninfected people and PWH on stable antiretroviral therapy. Our results additionally show that hybrid immunity acquired through SARS-CoV-2 infection and AZD1222 vaccination, induce a heightened T-cell response

ChAdOx1 nCoV-19 (AZD1222) vaccine-induced Fc receptor binding tracks with differential susceptibility to COVID-19

Despite the success of COVID-19 vaccines, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern have emerged that can cause breakthrough infections. Although protection against severe disease has been largely preserved, the immunological mediators of protection in humans remain undefined. We performed a substudy on the ChAdOx1 nCoV-19 (AZD1222) vaccinees enrolled in a South African clinical trial. At peak immunogenicity, before infection, no differences were observed in immunoglobulin (Ig)G1-binding antibody titers; however, the vaccine induced different Fc-receptor-binding antibodies across groups. Vaccinees who resisted COVID-19 exclusively mounted FcγR3B-binding antibodies. In contrast, enhanced IgA and IgG3, linked to enriched FcγR2B binding, was observed in individuals who experienced breakthrough. Antibodies unable to bind to FcγR3B led to immune complex clearance and resulted in inflammatory cascades. Differential antibody binding to FcγR3B was linked to Fc-glycosylation differences in SARS-CoV-2-specific antibodies. These data potentially point to specific FcγR3B-mediated antibody functional profiles as critical markers of immunity against COVID-19

Sero-epidemiology of measles Immunoglobulin G antibodies among newborn from South East Asia and sub-Saharan Africa: an observational, multicentre study.

ObjectivesTo investigate the transplacental acquisition of measles immunoglobulin (Ig)G in newborns at delivery in Bangladesh, Bhutan, India, Ethiopia, Mozambique, Kenya, Nigeria, Mali, and South Africa.MethodsArchived cord serum, from a multicenter study on Group B Streptococcus, were tested for measles IgG using a commercial enzyme link immunosorbent assay (ELISA). We tested 323 randomly selected samples from each of the sites. Models using various measles antibody decay rates in infancy were explored.ResultsOverall, 2,907 cord serum samples were analyzed. At birth, 49.9% of newborns were measles IgG seronegative. Measles seronegativity ranged from 21.7% in Nigeria to 73.4% in Bhutan. The adjusted odds of seronegativity in infants of mothers born after measles vaccination implementation was 1.78 times that for infants born to unvaccinated mothers (adjusted odds ratio 1.78; 95% confidence interval 1.43-2.21; P &lt;0.001). Modeling measles-IgG kinetics predicted that 70.8%, 88.3%, and 100% of infants would be seronegative by 2, 4, and 6 months, respectively, without further exposure.ConclusionsOur findings suggest low transplacental acquisition of measles IgG in newborns, which is likely to yield susceptibility to measles infection at a very young age. The currently recommended measles vaccine schedules in low- and middle-income countries (LMICs), with the first dose recommended from 9 months of age and onward, warrant reconsideration, including the need for earlier dosing schedules.</p

Prevalence of hepatitis B virus infection among pregnant women and cord blood hepatitis B surface antigen positive newborns in sub-Saharan Africa and South Asia

Background: Newborns infected with Hepatitis B Virus (HBV) are at risk of chronic liver disease and hepatocellular carcinoma. Objectives: This study investigated the prevalence of HBV infection among pregnant women and cord blood Hepatitis B surface antigen (HBsAg) positivity of their newborns in Bangladesh, Bhutan, India, Ethiopia, Mozambique, Kenya, Nigeria, Mali, and South Africa. Study design: Randomly selected paired maternal and cord blood samples (n = 101 each site) taken at delivery were tested for HBsAg and Hepatitis B extractable antigen (HBeAg) in the women using a chemiluminescent microparticle immunoassay. Similarly, cord blood sample of newborn was assessed for HBsAg reactivity. HBV DNA was quantified using the Xpert® HBV viral load assay, followed by genotyping. Results: The overall prevalence of maternal HBsAg positivity was 5.5 % (95 %CI: 0.4 %–7.1 %; n = 50/909). HBsAg positivity was higher in African countries (7.3 %; 95 %CI: 5.4 %–9.6 %; n = 44/606) compared to South Asian countries (2.0 %; 95 %CI: 0.8 %–4.3 %; n = 6/303; p = 0.002). Relative to South Africa, there were higher odds of HBsAg sero-positivity in women from Mozambique ((aOR): 7.7, 95 %CI: 1.6 %–37.8 %) and Mali (aOR: 5.7; 95 %CI: 1.1 %–29.7 %). The rate of HBsAg positivity in cord blood of babies born to HBsAg positive women was 28.0 % (95 %CI: 17.1 %–42.3 %; n = 14/50), including 31.8 % (95 %CI: 19.5–47.4 %; n = 14/44) in African countries. No cord blood HBsAg positivity was observed in South Asia. Genotypic analysis revealed HBV genotypes A (41.7 %) and E (58.3 %) were pre-dominant. Conclusion: The high rate of cord blood positivity (28.0 %) for HBsAg underscores the urgency of enhancing HBV prevention strategies to meet the World Health Organization's target of a 90 % reduction in new HBV infections by 2030.</p

Efficacy of primary series AZD1222 (ChAdOx1 nCoV-19) vaccination against SARS-CoV-2 variants of concern: Final analysis of a randomized, placebo-controlled, phase 1b/2 study in South African adults (COV005)

COVID-19 vaccine efficacy (VE) has been observed to vary against antigenically distinct SARS-CoV-2 variants of concern (VoC). Here we report the final analysis of VE and safety from COV005: a phase 1b/2, multicenter, double-blind, randomized, placebo-controlled study of primary series AZD1222 (ChAdOx1 nCoV-19) vaccination in South African adults aged 18-65 years. South Africa's first, second, and third waves of SARS-CoV-2 infections were respectively driven by the ancestral SARS-CoV-2 virus (wild type, WT), and SARS-CoV-2 Beta and Delta VoCs. VE against asymptomatic and symptomatic infection was 90.6% for WT, 6.7% for Beta and 77.1% for Delta. No cases of severe COVID-19 were documented ahead of unblinding. Safety was consistent with the interim analysis, with no new safety concerns identified. Notably, South Africa's Delta wave occurred ≥ 9 months after primary series vaccination, suggesting that primary series AZD1222 vaccination offers a good durability of protection, potentially due to an anamnestic response. Clinical trial identifier: CT.gov NCT04444674