Oral linezolid compared with benzathine penicillin G for treatment of early syphilis in adults (Trep-AB Study) in Spain: a prospective, open-label, non-inferiority, randomised controlled trial.

BACKGROUND: Management of syphilis, a sexually transmitted infection (STI) with increasing incidence, is challenged by drug shortages, scarcity of randomised trial data, an absence of non-penicillin alternatives for pregnant women with penicillin allergy (other than desensitisation), extended parenteral administration for neurosyphilis and congenital syphilis, and macrolide resistance. Linezolid was shown to be active against Treponema pallidum, the causative agent of syphilis, in vitro and in the rabbit model. We aimed to assess the efficacy of linezolid for treating early syphilis in adults compared with the standard of care benzathine penicillin G (BPG). METHODS: We did a multicentre, open-label, non-inferiority, randomised controlled trial to assess the efficacy of linezolid for treating early syphilis compared with BPG. We recruited participants with serological or molecular confirmation of syphilis (either primary, secondary, or early latent) at one STI unit in a public hospital and two STI community clinics in Catalonia (Spain). Participants were randomly allocated in a 1:1 ratio using a computer-generated block randomisation list with six participants per block, to receive either oral linezolid (600 mg once per day for 5 days) or intramuscular BPG (single dose of 2·4 million international units) and were assessed for signs and symptoms (once per week until week 6 and at week 12, week 24, and week 48) and reagin titres of non-treponemal antibodies (week 12, week 24, and week 48). The primary endpoint was treatment response, assessed using a composite endpoint that included clinical response, serological response, and absence of relapse. Clinical response was assessed at 2 weeks for primary syphilis and at 6 weeks for secondary syphilis following treatment initiation. Serological cure was defined as a four-fold decline in rapid plasma reagin titre or seroreversion at any of the 12-week, 24-week, or 48-week timepoints. The absence of relapse was defined as the presence of different molecular sequence types of T pallidum in recurrent syphilis. Non-inferiority was shown if the lower limit of the two-sided 95% CI for the difference in rates of treatment response was higher than -10%. The primary analysis was done in the per-protocol population. The trial is registered at ClinicalTrials.gov (NCT05069974) and was stopped for futility after interim analysis. FINDINGS: Between Oct 20, 2021, and Sept 15, 2022, 62 patients were assessed for eligibility, and 59 were randomly assigned to linezolid (n=29) or BPG (n=30). In the per-protocol population, after 48 weeks' follow-up, 19 (70%) of 27 participants (95% CI 49·8 to 86·2) in the linezolid group had responded to treatment and 28 (100%) of 28 participants (87·7 to 100·0) in the BPG group (treatment difference -29·6, 95% CI -50·5 to -8·8), which did not meet the non-inferiority criterion. The number of drug-related adverse events (all mild or moderate) was similar in both treatment groups (five [17%] of 29, 95% CI 5·8 to 35·8 in the linezolid group vs five [17%] of 30, 5·6 to 34·7, in the BPG group). No serious adverse events were reported during follow-up. INTERPRETATION: The efficacy of linezolid at a daily dose of 600 mg for 5 days did not meet the non-inferiority criteria compared with BPG and, as a result, this treatment regimen should not be used to treat patients with early syphilis. FUNDING: European Research Council and Fondo de Investigaciones Sanitarias.

Low genetic diversity of Treponema pallidum ssp. pertenue (TPE) isolated from patients' ulcers in Namatanai District of Papua New Guinea: Local human population is infected by three TPE genotypes.

Yaws is an endemic disease caused by Treponema pallidum subsp. pertenue (TPE) that primarily affects children in rural regions of the tropics. The endemic character of yaws infections and the expected exclusive reservoir of TPE in humans opened a new opportunity to start a yaws eradication campaign. We have developed a multi-locus sequence typing (MLST) scheme for TPE isolates combining the previously published (TP0548, TP0488) and new (TP0858) chromosomal loci, and we compared this typing scheme to the two previously published MLST schemes. We applied this scheme to TPE-containing clinical isolates obtained during a mass drug administration study performed in the Namatanai District of Papua New Guinea between June 2018 and December 2019. Of 1081 samples collected, 302 (28.5%) tested positive for TPE DNA, from which 255 (84.4%) were fully typed. The TPE PCR-positivity in swab samples was higher in younger patients, patients with single ulcers, first ulcer episodes, and with ulcer duration less than six months. Non-treponemal serological test positivity correlated better with PCR positivity compared to treponema-specific serological tests. The MLST revealed a low level of genetic diversity among infecting TPE isolates, represented by just three distinct genotypes (JE11, SE22, and TE13). Two previously used typing schemes revealed similar typing resolutions. Two new alleles (one in TP0858 and one in TP0136) were shown to arise by intragenomic recombination/deletion events. Compared to samples genotyped as JE11, the minor genotypes (TE13 and SE22) were more frequently detected in samples from patients with two or more ulcers and patients with higher values of specific TP serological tests. Moreover, the A2058G mutation in the 23S rRNA genes of three JE11 isolates was found, resulting in azithromycin resistance.

Mpox in people with past infection or a complete vaccination course: a global case series.

BACKGROUND: Since May, 2022, a large global outbreak of human mpox (formerly known as monkeypox) has predominantly affected men who have sex with men. The strain responsible, Clade IIb, has mutated substantially from precursors originating from the 2017-18 outbreak in Nigeria. Immunity to smallpox, another orthopoxvirus, via previous infection or vaccination provides lifelong immunity. However, since the 2022 mpox outbreak, recent clusters were described in individuals with presumed immunity through recent infection or vaccination. We aim to describe the epidemiological and clinical characteristics of mpox in individuals with past infection or vaccination to improve the understanding of this disease in the setting of previous immunity. METHODS: In this global case series, international collaborators from nine countries provided data on individuals with PCR-confirmed mpox after documented previous infection or vaccination between May 11, 2022, and June 30, 2023. We excluded cases that could not confirm vaccination status or cases with partial immunisation or any doses received before the current multi-national mpox outbreak (cutoff date May 1, 2022). Data were collected via a case report spreadsheet that reported on dates of infection and vaccination, route of immunisation, demographic characteristics, clinical findings, HIV status, concomitant sexually transmitted infections, and markers of disease severity (mpox severity score system). We describe case epidemiology, clinical course, and mpox severity scores; all analyses were descriptive. FINDINGS: We report mpox infections in 37 gay and bisexual men who have sex with men: seven individuals had mpox reinfections, 29 individuals had mpox infections that occurred after two appropriately spaced Modified Vaccinia Ankara-Bavarian Nordic vaccine courses, and one individual had an infection that met the criteria for both reinfection and infection after vaccination. The median age of individuals was 36 years (IQR 30-45; range 21-58). Those with natural immunity after initial infection had a shorter disease course with less mucosal disease upon reinfection than with their initial infection. Infections post-vaccination were characterised by few lesions, little mucosal disease, and minimal analgesia requirements; two people received oral tecovirimat. Overall, there were no deaths, no bacterial superinfections, and all individuals were managed in the ambulatory clinic with one hospital admission for a necrotising neck lesion. INTERPRETATION: The epidemiology of people with mpox reinfection or infection post-vaccination was similar to other published cohorts during the 2022 outbreak-predominantly young, sexually active gay and bisexual men who have sex with men. Clinical features and outcomes of repeat infection and infection after vaccination appear to be less clinically severe than those described in 2022 case literature. Specifically, compared with the 2022 case series, these individuals in the present study had fewer confluent lesions, less mucosal involvement, reduced analgesia requirement, and fewer admissions. Natural immunity and vaccine-induced immunity are not fully protective against mpox infection. However, in this small series both disease duration and severity appear to be reduced. FUNDING: None.

Early administration of tecovirimat shortens the time to mpox clearance in a model of human infection.

Despite use of tecovirimat since the beginning of the 2022 outbreak, few data have been published on its antiviral effect in humans. We here predict tecovirimat efficacy using a unique set of data in nonhuman primates (NHPs) and humans. We analyzed tecovirimat antiviral activity on viral kinetics in NHP to characterize its concentration-effect relationship in vivo. Next, we used a pharmacological model developed in healthy volunteers to project its antiviral efficacy in humans. Finally, a viral dynamic model was applied to characterize mpox kinetics in skin lesions from 54 untreated patients, and we used this modeling framework to predict the impact of tecovirimat on viral clearance in skin lesions. At human-recommended doses, tecovirimat could inhibit viral replication from infected cells by more than 90% after 3 to 5 days of drug administration and achieved over 97% efficacy at drug steady state. With an estimated mpox within-host basic reproduction number, R0, equal to 5.6, tecovirimat could therefore shorten the time to viral clearance if given before viral peak. We predicted that initiating treatment at symptom onset, which on average occurred 2 days before viral peak, could reduce the time to viral clearance by about 6 days. Immediate postexposure prophylaxis could not only reduce time to clearance but also lower peak viral load by more than 1.0 log10 copies/mL and shorten the duration of positive viral culture by about 7 to 10 days. These findings support the early administration of tecovirimat against mpox infection, ideally starting from the infection day as a postexposure prophylaxis.

Prevalence and risk factors associated with Haemophilus ducreyi cutaneous ulcers in Cameroon.

Epidemics of yaws-like cutaneous ulcers are regularly documented in children in the tropics. They occur mainly in poor and remote communities without access to health facilities. The integration of molecular tools into yaws control efforts has made it possible to describe Haemophilus ducreyi (HD) as a major cause of cutaneous ulcers. The objective of this study was to determine the prevalence of HD as cause of cutaneous ulcers, investigate its presence in asymptomatic individuals and identify associated risk factors. A cross-sectional study was conducted in yaws endemic districts of Cameroon. Participants included people presenting yaws-like ulcers and asymptomatic individuals. Swab samples were collected from each participant and tested for HD and Treponema pallidum (TP) using an established qPCR method. Additionally, demographic, habitat, proximity, and hygiene characteristics were collected using a structured questionnaire. A total of 443 individuals participated in the study, including 271 ulcer cases and 172 asymptomatic contacts. The prevalence of HD in ulcers was 30.3% (Confidence Interval (CI) 95% [24.8-35.7]) and the prevalence of asymptomatic HD carriage was 8.6% (CI95% [4.5-12.9]). TP was also detected in our sample among ulcer cases but in lower proportion (5.2% CI95% [2.5-7.8]) compared to HD. The adjusted logistic regression model showed that women were as much at risk of having HD cutaneous ulcer as men regardless of age. Physical proximity to a confirmed ulcer case was the major factor identified favouring HD transmission. HD ulcers were more likely to be present on Bantu individuals compared to Baka as well as HD colonization. These findings highlight HD as the most common cause of cutaneous ulcers in yaws-endemic communities in Cameroon. The exact implications of detecting HD on intact skin are not yet clear. Further studies are needed to understand the significance of this carriage in the spread dynamics of the disease.

A cross-sectional study to ascertain malaria prevalence among asymptomatic travellers arriving on the Lihir Group of Islands, Papua New Guinea: implications for elimination efforts.

BACKGROUND: The Lihir Islands of Papua New Guinea host a mining operation that has resulted in a mine-impacted zone (MIZ) with reduced malaria transmission and a substantial influx of mine employees, informal cross-country traders, returning locals, and visitors. Prevalence of malaria parasites was assessed in travellers arriving on the Lihir Group of Islands to evaluate the risk of parasite importation. METHODS: In 2018, a cross-sectional study at the airport and main wharf was conducted, targeting asymptomatic travellers who had been away from Lihir for at least 12 days. Microscopy, rapid diagnostic tests (RDTs), and quantitative PCR (qPCR) were used to determine Plasmodium parasite prevalence, employing logistic regression models to identify factors associated with qPCR positivity. RESULTS: 398 travellers arriving by plane and 402 arriving by boat were included. Both cohorts were significantly different. Mean age among travellers arriving by plane was 40.1 years (SD ± 10.1), 93% were male and 96% were employed at the mine. In contrast, among travellers arriving by boat, the mean age was 31.7 years (SD ± 14.0), 68% were male and 36% were employed at the mine. The prevalence of malaria infection among travellers arriving by plane was 1% by RDT and microscopy, and increased to 5% by qPCR. In contrast, those arriving by boat showed a prevalence of 8% by RDT and microscopy, and 17% by qPCR. Risk factors for infection were arriving by boat (OR 4.2; 95%CI 2.45,7.21), arriving from nearby provinces with high malaria incidence (OR 5.02; 95%CI 1.80, 14.01), and having been away from Lihir for 91 days or more (OR 4.15; 95%CI 2.58, 6.66). Being mine worker staying at the mine accommodation was related with less infection risk (OR 0.24; 95% CI 0.14, 0.43); while Lihirian residents returning from a trip, VFRs, or people with trading unrelated to mining had higher risks (p = 0.0066). CONCLUSIONS: Travellers arriving by boat faced increased risk of malaria infection than those arriving by plane. This subpopulation poses an import risk to the MIZ and the rest of Lihir Islands. Screening of high-risk groups at wharfs, and collaboration with nearby Islands, could sustain reduced transmission and facilitate malaria elimination strategies.

Epidemiology and determinants of reemerging bacterial sexually transmitted infections (STIs) and emerging STIs in Europe.

In this scoping review, we offer a comprehensive understanding of the current and recent epidemiology, challenges, and emerging issues related to bacterial sexually transmitted infections (STIs) in the WHO European Region. We endeavour in collating data from both EU/EEA and non- EU/EEA countries, thereby giving a complete picture of the region which highlights the higher notification rates in Northern and Western countries than other regions, likely due to differences in testing, access to testing, and surveillance capacity. We provide an up-to-date review on the current knowledge of determinants and persistent inequities in key populations as well as the use of molecular epidemiology for identifying transmission networks in gonorrhoea and syphilis, and detecting chlamydia mutations that evade molecular diagnosis. Finally, we explore the emerging STIs in the region and the evolving transmission routes of food and waterborne diseases into sexual transmission. Our findings call for harmonized STI surveillance systems, proactive strategies, and policies to address social factors, and staying vigilant for emerging STIs.

Prevention strategies for sexually transmitted infections, HIV, and viral hepatitis in Europe.

The current prevention efforts for STIs, HIV and viral hepatitis in the WHO European Region, especially in the Central and Eastern subregions, are hindered by healthcare disparities, data gaps, and limited resources. In this comprehensive narrative review, we aim to highlight both achievements and persisting challenges while also exploring new developments that could significantly impact the prevention of these infections in the near future. While pre-exposure prophylaxis (PrEP) for HIV has been broadly approved and implemented in 38 out of 53 countries in the region, challenges remain, including cost, limited licensing, and incomplete adherence. We explore innovative approaches like on-demand PrEP, long-acting injectable cabotegravir, and intravaginal rings that have shown promising results, alongside the use of six-monthly lenacapavir, the outcomes of which are pending. Additionally, the potential of doxycycline post-exposure prophylaxis has been discussed, revealing efficacy in reducing chlamydia and syphilis risk, but effectiveness against gonorrhoea being contingent on tetracycline resistance rates, and the need of further data to determine potential resistance development in other bacteria and its impact on the gut microbiome. We examine successful vaccination campaigns against HBV and HPV, the ongoing development of vaccines for chlamydia, syphilis, herpesvirus, and gonorrhoea, and challenges in HIV vaccine research, including lines of research with significant potential like sequential immunization, T-cell responses, and mRNA technology. This review underscores the research endeavors that pave the way for a more resilient and robust approach to combating STIs, HIV, and viral hepatitis in the region.

Treatment of bacterial sexually transmitted infections in Europe: gonorrhoea, Mycoplasma genitalium, and syphilis.

This review explores the therapeutic challenges of sexually transmitted infections (STI) in Europe, which include increasing antimicrobial resistance and limited progress in drug discovery. We primarily focus on gonorrhoea, Mycoplasma genitalium, and syphilis infections. For gonorrhoea with escalating resistance rates we explore the possibility of combining ceftriaxone with another antibiotic or using alternative antibiotics to mitigate resistance emergence, and we provide insights on the ongoing evaluation of new antimicrobials, like gepotidacin and zoliflodacin. In the case of M. genitalium, which exhibits high resistance rates to first and second-line treatments, we emphasize the importance of resistance-guided therapy in regions with elevated resistance levels, and highlight the limited alternative options, such as pristinamycin and minocycline. Furthermore, we address the challenges posed by syphilis, where the primary treatment consists of penicillin or doxycycline, with challenges arising in neurosyphilis, allergy, pregnancy, and supply shortages and discuss the ongoing evaluation of alternative antimicrobials (e.g., ceftriaxone, cefixime, linezolid). Our findings identify priority actions and provide concrete solutions for long-term effective management of STIs and antimicrobial resistance mitigation.

Antimicrobial susceptibility of Treponema pallidum subspecies pallidum: an in-vitro study.

BACKGROUND: The increasing incidence of syphilis and the limitations of first-line treatment with penicillin, particularly in neurosyphilis, neonatal syphilis, and pregnancy, highlight the need to expand the therapeutic repertoire for effective management of this disease. We assessed the in-vitro efficacy of 18 antibiotics from several classes on Treponema pallidum subspecies pallidum (T pallidum), the syphilis bacteria. METHODS: Using the in-vitro culture system for T pallidum, we exposed the pathogen to a concentration range of each tested antibiotic. After a 7-day incubation, the treponemal burden was evaluated by quantitative PCR targeting the T pallidum tp0574 gene. The primary outcome was the minimum inhibitory concentration (MIC) at which the quantitative PCR values were not significantly higher than the inoculum wells. We also investigated the susceptibility of macrolide-resistant strains to high concentrations of azithromycin, and the possibility of developing resistance to linezolid, a proposed candidate for syphilis treatment. FINDINGS: Amoxicillin, ceftriaxone, several oral cephalosporins, tedizolid, and dalbavancin exhibited anti-treponemal activity at concentrations achievable in human plasma following regular dosing regimens. The experiments revealed a MIC for amoxicillin at 0·02 mg/L, ceftriaxone at 0·0025 mg/L, cephalexin at 0·25 mg/L, cefetamet and cefixime at 0·0313 mg/L, cefuroxime at 0·0156 mg/L, tedizolid at 0·0625 mg/L, spectinomycin at 0·1 mg/L, and dalbavancin at 0·125 mg/L. The MIC for zoliflodacin and balofloxacin was 2 mg/L. Ertapenem, isoniazid, pyrazinamide, and metronidazole had either a poor or no effect. Azithromycin concentrations up to 2 mg/L (64 times the MIC) were ineffective against strains carrying mutations associated to macrolide resistance. Exposure to subtherapeutic doses of linezolid for 10 weeks did not induce phenotypic or genotypic resistance. INTERPRETATION: Cephalosporins and oxazolidinones are potential candidates for expanding the current therapeutic repertoire for syphilis. Our findings warrant testing efficacy in animal models and, if successful, clinical assessment of efficacy. FUNDING: European Research Council.

Egocentric sexual network analysis among gay and bisexual men who have sex with men with and without mpox infection.

OBJECTIVES: Recent outbreaks of the mpox (monkeypox) virus have been detected in dense sexual networks of gay and bisexual men who have sex with men (GBMSM). The objective of this study is to describe and compare the epidemiological and behavioural characteristics, as well as the sexual networks, of GBMSM diagnosed with mild mpox in Spain. METHODS: A prospective case-control study was conducted in Spain from July 2022 to February 2023. The study targeted a key population of GBMSM aged 18 years or older. Study participants were categorised into cases, those who were diagnosed with mpox virus infection; and controls, those who were not diagnosed. We examined and compared the sexual network characteristics of the two groups-mpox-positive (mpox-P) and mpox-negative (mpox-N) egos-using χ2, t-test and Wilcoxon test to examine the differences between the two groups in each section. Finally, we conducted univariable and multivariable logistic regressions to determine the factors associated with mpox infection. RESULTS: Among the 105 participants, 35 (33.3%) were mpox-P. Compared with mpox-N, mpox-P respondents more frequently reported syphilis (mpox-P: 31.4%; mpox-N: 12.9%) and HIV (mpox-P: 45.7%; mpox-N: 18.6%), and mpox-P individuals to have had at least one sexual contact with a confirmed mpox case (mpox-P: 62.5%; mpox-N: 8.3%). In the egocentric network analysis, mpox-P respondents had a higher prevalence of group sex with alters (mpox-P: 18.5%; mpox-N: 8.9%) and one-time sexual partners (mpox-P: 46.1%; mpox-N: 31.7%). Multivariable logistic regressions showed that reporting stranger/client ties (adjusted OR (aOR)=10.3, 95% CI 1.39 to 76.6) with alters, being vaccinated for mpox (aOR=0.07, 95% CI 0.02 to 0.24) and tie strength heterogeneity (aOR=0.01, 95% CI 0.00 to 0.42) were associated with mpox infection. CONCLUSIONS: Our findings highlight the role of demographic, epidemiological and sexual network characteristics in the transmission of mpox virus during the outbreak in Spain. These findings have important implications for future prevention efforts.

Rapid Serologic Test for Diagnosis of Yaws in Patients with Suspicious Skin Ulcers.

The Chembio DPP (Dual Path Platform) Syphilis Screen & Confirm kit (https://chembio.com) is a rapid serologic test that can be used to diagnose yaws. We evaluated its capacity to detect patients with ulcers that tested PCR positive for Treponema pallidum subsp. pertenue. DPP detected 84% of ulcers that were positive by PCR.

Population pharmacokinetic model of ivermectin in mass drug administration against lymphatic filariasis.

BACKGROUND: Ivermectin (IVM) is a broad-spectrum anthelmintic drug used to treat diseases caused by filarial worms, such as onchocerciasis and lymphatic filariasis (LF). IVM is part of a triple-drug therapy used by the Mass Drug Administration (MDA) as a preventive strategy to eradicate LF in sub-Saharan Africa. The drug shows high variability in drug exposure in previous pharmacokinetic studies. This study aims to build a population pharmacokinetic (PopPK) model to identify and quantify the possible sources of the variability of IVM exposure after a single-oral dose in LF-infected subjects and healthy individuals. METHODOLOGY / PRINCIPAL FINDINGS: In this analysis, 724 samples were collected from treatment-naïve Wuchereria bancrofti-infected (n = 32) and uninfected (n = 24) adults living in Côte d'Ivoire who had received one dose of IVM as a part of triple-drug therapy. PopPK analysis was conducted using Phoenix NLME 8.3 software. The Monte Carlo simulation based on the final model was performed to simulate drug exposure among different dosing groups (200 µg/kg, 18 mg, and 36 mg). A two-compartment model with zero-order dose input into the absorption compartment with a lag time function followed by first-order absorption and linear elimination best described the IVM's pharmacokinetic (PK) parameters. The final model identifies that the PK parameters of IVM are not affected by LF infection. Sex was a significant covariate on the peripheral volume of distribution (Vp/F, 53% lower in men than in women). IVM drug exposure shows linear pharmacokinetic behavior among the simulated dosing groups with similar drug exposure based on sex. CONCLUSION/SIGNIFICANCE: We have developed a PopPk model to describe and identify possible sources of the variability of IVM exposure. To our knowledge, this is the first PopPK study of IVM in patients with LF. TRIAL REGISTRATION: NCT02845713; NCT03664063.

Repurposing an integrated national influenza platform for genomic surveillance of SARS-CoV-2 in Ghana: a molecular epidemiological analysis.

BACKGROUND: Genomic surveillance of SARS-CoV-2 is crucial for monitoring the spread of COVID-19 and guiding public health decisions, but the capacity for SARS-CoV-2 testing and sequencing in Africa is low. We integrated SARS-CoV-2 surveillance into an existing influenza surveillance network with the aim of providing insights into SARS-CoV-2 transmission and genomics in Ghana. METHODS: In this molecular epidemiological analysis, which is part of a wider multifaceted prospective observational study, we collected national SARS-CoV-2 test data from 35 sites across 16 regions in Ghana from Sept 1, 2020, to Nov 30, 2021, via the Ghanaian integrated influenza and SARS-CoV-2 surveillance network. SARS-CoV-2-positive samples collected through this integrated national influenza surveillance network and from international travellers arriving in Accra were sequenced with Oxford Nanopore Technology sequencing and the ARTIC tiled amplicon method. The sequence lineages were typed with pangolin and the phylogenetic analysis was conducted with IQ-Tree2 and TreeTime. FINDINGS: During the study period, 5495 samples were submitted for diagnostic testing through the national influenza surveillance network (2121 [46·1%] of 4021 samples with complete demographic data were from female individuals and 2479 [53·9%] of 4021 samples were from male individuals). We also obtained 2289 samples from travellers who arrived in Accra and had a positive lateral flow test, of whom 1626 (71·0%, 95% CI 69·1-72·9) were confirmed to be SARS-CoV-2 positive. Co-circulation of influenza and SARS-CoV-2 in Ghana was detected, with increased cases of influenza in November, 2020, November, 2021, and January and June, 2021. In 4124 samples from individuals with influenza-like illness, SARS-CoV-2 was identified in 583 (14·1%, 95% CI 13·1-15·2) samples and influenza in 356 (8·6%, 7·8-9·5). Conversely, in 476 samples from individuals with of severe acute respiratory illness, SARS-CoV-2 was detected in 58 (12·2%, 9·5-15·5) samples and influenza in 95 (19·9%, 16·5-23·9). We detected four waves of SARS-CoV-2 infections in Ghana; each wave was driven by a different variant: B.1 and B.1.1 were the most prevalent lineages in wave 1, alpha (B.1.1.7) was responsible for wave 2, delta (B.1.617.2) and its sublineages (closely related to delta genomes from India) were responsible for wave 3, and omicron variants were responsible for wave 4. We detected omicron variants among 47 (32%) of 145 samples from travellers during the start of the omicron spread in Ghana (wave 4). INTERPRETATION: This study shows the value of repurposing existing influenza surveillance platforms to monitor SARS-CoV-2. Influenza continued to circulate in Ghana in 2020 and 2021, and remained a major cause of severe acute respiratory illness. We detected importations of SARS-CoV-2 variants into Ghana, including those that did or did not lead to onward community transmission. Investment in strengthening national influenza surveillance platforms in low-income and middle-income countries has potential for ongoing monitoring of SARS-CoV-2 and future pandemics. FUNDING: The EDCTP2 programme supported by the EU.

Syphilis vaccine: challenges, controversies and opportunities.

Syphilis is a sexually or vertically (mother to fetus) transmitted disease caused by the infection of Treponema pallidum subspecie pallidum (TPA). The incidence of syphilis has increased over the past years despite the fact that this bacterium is an obligate human pathogen, the infection route is well known, and the disease can be successfully treated with penicillin. As complementary measures to preventive campaigns and early treatment of infected individuals, development of a syphilis vaccine may be crucial for controlling disease spread and/or severity, particularly in countries where the effectiveness of the aforementioned measures is limited. In the last century, several vaccine prototypes have been tested in preclinical studies, mainly in rabbits. While none of them provided protection against infection, some prototypes prevented bacteria from disseminating to distal organs, attenuated lesion development, and accelerated their healing. In spite of these promising results, there is still some controversy regarding the identification of vaccine candidates and the characteristics of a syphilis-protective immune response. In this review, we describe what is known about TPA immune response, and the main mechanisms used by this pathogen to evade it. Moreover, we emphasize the importance of integrating this knowledge, in conjunction with the characterization of outer membrane proteins (OMPs), to expedite the development of a syphilis vaccine that can protect against TPA infection.

Subcutaneous anti-COVID-19 hyperimmune immunoglobulin for prevention of disease in asymptomatic individuals with SARS-CoV-2 infection: a double-blind, placebo-controlled, randomised clinical trial.

Background: Anti-COVID-19 hyperimmune immunoglobulin (hIG) can provide standardized and controlled antibody content. Data from controlled clinical trials using hIG for the prevention or treatment of COVID-19 outpatients have not been reported. We assessed the safety and efficacy of subcutaneous anti-COVID-19 hyperimmune immunoglobulin 20% (C19-IG20%) compared to placebo in preventing development of symptomatic COVID-19 in asymptomatic individuals with SARS-CoV-2 infection. Methods: We did a multicentre, randomized, double-blind, placebo-controlled trial, in asymptomatic unvaccinated adults (≥18 years of age) with confirmed SARS-CoV-2 infection within 5 days between April 28 and December 27, 2021. Participants were randomly assigned (1:1:1) to receive a blinded subcutaneous infusion of 10 mL with 1 g or 2 g of C19-IG20%, or an equivalent volume of saline as placebo. The primary endpoint was the proportion of participants who remained asymptomatic through day 14 after infusion. Secondary endpoints included the proportion of individuals who required oxygen supplementation, any medically attended visit, hospitalisation, or ICU, and viral load reduction and viral clearance in nasopharyngeal swabs. Safety was assessed as the proportion of patients with adverse events. The trial was terminated early due to a lack of potential benefit in the target population in a planned interim analysis conducted in December 2021. ClinicalTrials.gov registry: NCT04847141. Findings: 461 individuals (mean age 39.6 years [SD 12.8]) were randomized and received the intervention within a mean of 3.1 (SD 1.27) days from a positive SARS-CoV-2 test. In the prespecified modified intention-to-treat analysis that included only participants who received a subcutaneous infusion, the primary outcome occurred in 59.9% (91/152) of participants receiving 1 g C19-IG20%, 64.7% (99/153) receiving 2 g, and 63.5% (99/156) receiving placebo (difference in proportions 1 g C19-IG20% vs. placebo, -3.6%; 95% CI -14.6% to 7.3%, p = 0.53; 2 g C19-IG20% vs placebo, 1.1%; -9.6% to 11.9%, p = 0.85). None of the secondary clinical efficacy endpoints or virological endpoints were significantly different between study groups. Adverse event rate was similar between groups, and no severe or life-threatening adverse events related to investigational product infusion were reported. Interpretation: Our findings suggested that administration of subcutaneous human hyperimmune immunoglobulin C19-IG20% to asymptomatic individuals with SARS-CoV-2 infection was safe but did not prevent development of symptomatic COVID-19. Funding: Grifols.

Comparison of Reverse Transcription (RT)-Quantitative PCR and RT-Droplet Digital PCR for Detection of Genomic and Subgenomic SARS-CoV-2 RNA.

Most individuals acutely infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibit mild symptoms. However, 10 to 20% of those infected develop long-term symptoms, referred to as post-coronavirus disease 2019 (COVID-19) condition (PCC). One hypothesis is that PCC might be exacerbated by viral persistence in tissue sanctuaries. Therefore, the accurate detection and quantification of SARS-CoV-2 are not only necessary for viral load monitoring but also crucial for detecting long-term viral persistence and determining whether viral replication is occurring in tissue reservoirs. In this study, the sensitivity and robustness of reverse transcription (RT)-droplet digital PCR (ddPCR) and RT-quantitative PCR (qPCR) techniques have been compared for the detection and quantification of SARS-CoV-2 genomic and subgenomic RNAs from oropharyngeal swabs taken from confirmed SARS-CoV-2-positive, SARS-CoV-2-exposed, and nonexposed individuals as well as from samples from mice infected with SARS-CoV-2. Our data demonstrated that both techniques presented equivalent results in the mid- and high-viral-load ranges. Additionally, RT-ddPCR was more sensitive than RT-qPCR in the low-viral-load range, allowing the accurate detection of positive results in individuals exposed to the virus. Overall, these data suggest that RT-ddPCR might be an alternative to RT-qPCR for detecting low viral loads in samples and for assessing viral persistence in samples from individuals with PCC. IMPORTANCE We developed one-step reverse transcription (RT)-droplet digital PCR (ddPCR) protocols to detect SARS-CoV-2 RNA and compared them to the gold-standard RT-quantitative PCR (RT-qPCR) method. RT-ddPCR was more sensitive than RT-qPCR in the low-viral-load range, while both techniques were equivalent in the mid- and high-viral-load ranges. Overall, these results suggest that RT-ddPCR might be a viable alternative to RT-qPCR when it comes to detecting low viral loads in samples, which is a highly relevant issue for determining viral persistence in as-yet-unknown tissue reservoirs in individuals suffering from post-COVID conditions or long COVID.

Mpox in people with advanced HIV infection: a global case series.

BACKGROUND: People living with HIV have accounted for 38-50% of those affected in the 2022 multicountry mpox outbreak. Most reported cases were in people who had high CD4 cell counts and similar outcomes to those without HIV. Emerging data suggest worse clinical outcomes and higher mortality in people with more advanced HIV. We describe the clinical characteristics and outcomes of mpox in a cohort of people with HIV and low CD4 cell counts (CD4 <350 cells per mm3). METHODS: A network of clinicians from 19 countries provided data of confirmed mpox cases between May 11, 2022, and Jan 18, 2023, in people with HIV infection. Contributing centres completed deidentified structured case report sheets to include variables of interest relevant to people living with HIV and to capture more severe outcomes. We restricted this series to include only adults older than 18 years living with HIV and with a CD4 cell count of less than 350 cells per mm3 or, in settings where a CD4 count was not always routinely available, an HIV infection clinically classified as US Centers for Disease Control and Prevention stage C. We describe their clinical presentation, complications, and causes of death. Analyses were descriptive. FINDINGS: We included data of 382 cases: 367 cisgender men, four cisgender women, and ten transgender women. The median age of individuals included was 35 (IQR 30-43) years. At mpox diagnosis, 349 (91%) individuals were known to be living with HIV; 228 (65%) of 349 adherent to antiretroviral therapy (ART); 32 (8%) of 382 had a concurrent opportunistic illness. The median CD4 cell count was 211 (IQR 117-291) cells per mm3, with 85 (22%) individuals with CD4 cell counts of less than 100 cells per mm3 and 94 (25%) with 100-200 cells per mm3. Overall, 193 (51%) of 382 had undetectable viral load. Severe complications were more common in people with a CD4 cell count of less than 100 cells per mm3 than in those with more than 300 cells per mm3, including necrotising skin lesions (54% vs 7%), lung involvement (29% vs 0%) occasionally with nodules, and secondary infections and sepsis (44% vs 9%). Overall, 107 (28%) of 382 were hospitalised, of whom 27 (25%) died. All deaths occurred in people with CD4 counts of less than 200 cells per mm3. Among people with CD4 counts of less than 200 cells per mm3, more deaths occurred in those with high HIV viral load. An immune reconstitution inflammatory syndrome to mpox was suspected in 21 (25%) of 85 people initiated or re-initiated on ART, of whom 12 (57%) of 21 died. 62 (16%) of 382 received tecovirimat and seven (2%) received cidofovir or brincidofovir. Three individuals had laboratory confirmation of tecovirimat resistance. INTERPRETATION: A severe necrotising form of mpox in the context of advanced immunosuppression appears to behave like an AIDS-defining condition, with a high prevalence of fulminant dermatological and systemic manifestations and death. FUNDING: None.

Coronavirus Disease 2019 Convalescent Plasma Outpatient Therapy to Prevent Outpatient Hospitalization: A Meta-Analysis of Individual Participant Data From 5 Randomized Trials.

BACKGROUND: Outpatient monoclonal antibodies are no longer effective and antiviral treatments for coronavirus disease 2019 (COVID-19) disease remain largely unavailable in many countries worldwide. Although treatment with COVID-19 convalescent plasma (CCP) is promising, clinical trials among outpatients have shown mixed results. METHODS: We conducted an individual participant data meta-analysis from outpatient trials to assess the overall risk reduction for all-cause hospitalizations by day 28 in transfused participants. Relevant trials were identified by searching Medline, Embase, medRxiv, World Health Organization COVID-19 Research Database, Cochrane Library, and Web of Science from January 2020 to September 2022. RESULTS: Five included studies from 4 countries enrolled and transfused 2620 adult patients. Comorbidities were present in 1795 (69%). The virus neutralizing antibody dilutional titer levels ranged from 8 to 14 580 in diverse assays. One hundred sixty of 1315 (12.2%) control patients were hospitalized, versus 111 of 1305 (8.5%) CCP-treated patients, yielding a 3.7% (95% confidence interval [CI], 1.3%-6.0%; P = .001) absolute risk reduction and 30.1% relative risk reduction for all-cause hospitalization. The hospitalization reduction was greatest in those with both early transfusion and high titer with a 7.6% absolute risk reduction (95% CI, 4.0%-11.1%; P = .0001) accompanied by at 51.4% relative risk reduction. No significant reduction in hospitalization was seen with treatment >5 days after symptom onset or in those receiving CCP with antibody titers below the median titer. CONCLUSIONS: Among outpatients with COVID-19, treatment with CCP reduced the rate of all-cause hospitalization and may be most effective when given within 5 days of symptom onset and when antibody titer is higher.