Invasive bacterial infections in Gambians with sickle cell anemia in an era of widespread pneumococcal and hemophilus influenzae type b vaccination.

There is relatively little data on the etiology of bacterial infections in patients with sickle cell anemia (SCA) in West Africa, and no data from countries that have implemented conjugate vaccines against both Streptococcus pneumoniae and Haemophilus influenzae type b (Hib).We conducted a retrospective analysis of SCA patients admitted to the Medical Research Council Unit, The Gambia, during a 5-year period when there was high coverage of Hib and Pneumococcal conjugate vaccination. We evaluated 161 admissions of 126 patients between April 2010 and April 2015.Pathogenic bacteria were identified in blood cultures from 11 of the 131 admissions that had cultures taken (8.4%, 95% CI 4.5-14.1%). The most frequent isolate was Salmonella Typhimurium (6/11; 54.5%), followed by Staphylococcus aureus (2/11; 18.2%) and other enteric Gram-negative pathogens (2/11; 18.2%) and there was 1 case of H influenzae non-type b bacteremia (1/11; 9.1%). There were no episodes of bacteremia caused by S pneumoniae or Hib.The low prevalence of S pneumoniae and Hib and the predominance of nontyphoidal Salmonella as a cause of bacteremia suggest the need to reconsider optimal antimicrobial prophylaxis and the empirical treatment regimens for patients with SCA

Prevalence of Panton-Valentine Leukocidin (PVL) and Antimicrobial Resistance in Community-Acquired Clinical Staphylococcus aureus in an Urban Gambian Hospital : A 11-Year Period Retrospective Pilot Study

This work is supported by MRCG. The source of funding has no role in the design and writing of the manuscript.Peer reviewedPublisher PD

Molecular Epidemiology of Group A Streptococcus Infections in The Gambia.

Molecular epidemiological data on Group A Streptococcus (GAS) infection in Africa is scarce. We characterized the emm-types and emm-clusters of 433 stored clinical GAS isolates from The Gambia collected between 2004 and 2018. To reduce the potential for strain mistyping, we used a newly published primer for emm-typing. There was considerable strain diversity, highlighting the need for vaccine development offering broad strain protection

Efficacy, Safety and Tolerability of Pyronaridine-artesunate in Asymptomatic Malaria-infected Individuals: a Randomized Controlled Trial

BACKGROUND: Pyronaridine-artesunate (PA) is a registered artemisinin-based combination therapy, potentially useful for mass drug administration campaigns. However, further data are needed to evaluate its efficacy, safety and tolerability as full or incomplete treatment in asymptomatic Plasmodium falciparum-infected individuals. METHODS: This phase II, multi-center, open label, randomized clinical trial was conducted in The Gambia and Zambia. Participants with microscopically confirmed asymptomatic P. falciparum infection were randomly assigned (1:1:1) to receive a 3-day, 2-day, or 1-day treatment regimen of PA (180:60 mg), dosed according to bodyweight. The primary efficacy outcome was polymerase chain reaction (PCR)-adjusted adequate parasitological response (APR) at day 28 in the per-protocol population. RESULTS: A total of 303 participants were randomized. Day 28 PCR-adjusted APR was 100% for both the 3-day (98/98) and 2-day regimens (96/96), and 96.8% (89/94) for the 1-day regimen. Efficacy was maintained at 100% until day 63 for the 3-day and 2-day regimens but declined to 94.4% (84/89) with the 1-day regimen. Adverse event frequency was similar between the 3-day (51.5% [52/101]), 2-day (52.5% [52/99]), and 1-day (54.4% [56/103]) regimens; the majority of adverse events were of grade 1 or 2 severity (85% [136/160]). Asymptomatic, transient increases (>3 times the upper limit of normal) in alanine aminotransferase/aspartate aminotransferase were observed for 6/301 (2.0%) participants. CONCLUSIONS: PA had high efficacy and good tolerability in asymptomatic P. falciparum-infected individuals, with similar efficacy for the full 3-day and incomplete 2-day regimens. Although good adherence to the 3-day regimen should be encouraged, these results support the further investigation of PA for mass drug administration campaigns. CLINICAL TRIALS REGISTRATION: NCT03814616

Safety and immunogenicity of an Ad26.ZEBOV booster dose in children previously vaccinated with the two-dose heterologous Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen: an open-label, non-randomised, phase 2 trial.

BACKGROUND: Children account for a substantial proportion of cases and deaths during Ebola virus disease outbreaks. We aimed to evaluate the safety and immunogenicity of a booster dose of the Ad26.ZEBOV vaccine in children who had been vaccinated with a two-dose regimen comprising Ad26.ZEBOV as dose one and MVA-BN-Filo as dose two. METHODS: We conducted an open-label, non-randomised, phase 2 trial at one clinic in Kambia Town, Sierra Leone. Healthy children, excluding pregnant or breastfeeding girls, who had received the Ad26.ZEBOV and MVA-BN-Filo vaccine regimen in a previous study, and were aged 1-11 years at the time of their first vaccine dose, received an intramuscular injection of Ad26.ZEBOV (5 × 1010 viral particles) and were followed up for 28 days. Primary outcomes were safety (measured by adverse events) and immunogenicity (measured by Ebola virus glycoprotein-specific IgG binding antibody geometric mean concentration) of the booster vaccine dose. Safety was assessed in all participants who received the booster vaccination; immunogenicity was assessed in all participants who received the booster vaccination, had at least one evaluable sample after the booster, and had no major protocol deviations that could have influenced the immune response. This trial is registered with ClinicalTrials.gov, NCT04711356. FINDINGS: Between July 8 and Aug 18, 2021, 58 children were assessed for eligibility and 50 (27 aged 4-7 years and 23 aged 9-15 years) were enrolled and received an Ad26.ZEBOV booster vaccination, more than 3 years after receiving dose one of the Ad26.ZEBOV and MVA-BN-Filo vaccine regimen. The booster was well tolerated. The most common solicited local adverse event during the 7 days after vaccination was injection site pain, reported in 18 (36%, 95% CI 23-51) of 50 participants. The most common solicited systemic adverse event during the 7 days after vaccination was headache, reported in 11 (22%, 12-36) of 50 participants. Malaria was the most common unsolicited adverse event during the 28 days after vaccination, reported in 25 (50%, 36-64) of 50 participants. No serious adverse events were observed during the study period. 7 days after vaccination, the Ebola virus glycoprotein-specific IgG binding antibody geometric mean concentration was 28 561 ELISA units per mL (95% CI 20 255-40 272), which was 44 times higher than the geometric mean concentration before the booster dose. 21 days after vaccination, the geometric mean concentration reached 64 690 ELISA units per mL (95% CI 48 356-86 541), which was 101 times higher than the geometric mean concentration before the booster dose. INTERPRETATION: A booster dose of Ad26.ZEBOV in children who had received the two-dose Ad26.ZEBOV and MVA-BN-Filo vaccine regimen more than 3 years earlier was well tolerated and induced a rapid and robust increase in binding antibodies against Ebola virus. These findings could inform Ebola vaccination strategies in paediatric populations. FUNDING: Innovative Medicines Initiative 2 Joint Undertaking. TRANSLATION: For the French translation of the abstract see Supplementary Materials section

Asymptomatic Malaria Infection and the Immune Response to the 2-Dose Ad26.ZEBOV, MVA-BN-Filo Ebola Vaccine Regimen in Adults and Children

Background Malaria infection affects the immune response to some vaccines. As Ebola virus (EBOV) outbreaks have occurred mainly in malaria-endemic countries, we have assessed whether asymptomatic malaria affects immune responses to the 2-dose Ad26.ZEBOV, MVA-BN-Filo Ebola vaccine regimen. Methods In this sub-study of the EBOVAC-Salone Ebola vaccine trial in Sierra Leone, malaria microscopy was performed at the time of Ebola vaccination. Participants with symptomatic malaria were treated before vaccination. Ebola vaccine responses were assessed post-dose 1 (day 57) and post-dose 2 (day 78) by the EBOV glycoprotein FANG enzyme-linked immunosorbent assay (ELISA), and responses expressed as geometric mean concentrations (GMCs). Geometric mean ratios (GMRs) of the GMCs in malaria-positive versus malaria-negative participants were derived with 95% confidence intervals (CIs). Results A total of 587 participants were studied, comprising 188 adults (≥18 years) and 399 children (in age groups of 12–17, 4–11, and 1–3 years). Asymptomatic malaria was observed in 47.5% of adults and 51.5% of children on day 1. Post-dose 1, GMCs were lower in 1–3-year-old malaria-positive compared with malaria-negative children (age group–specific GMR, .56; 95% CI, .39–.81) but not in older age groups. Post-dose 2, there was no consistent effect of malaria infection across the different age groups but there was a trend toward a lower response (GMR, .82; 95% CI, .67–1.02). Conclusions The Ad26.ZEBOV, MVA-BN-Filo Ebola vaccine regimen is immunogenic in participants with asymptomatic malaria. Therefore, it is not necessary to screen for asymptomatic malaria infection prior to vaccination with this regimen

Safety and immunogenicity of the two-dose heterologous Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen in infants: a phase 2, randomised, double-blind, active-controlled trial in Guinea and Sierra Leone.

BACKGROUND: This study assessed the safety and immunogenicity of the Ad26.ZEBOV and MVA-BN-Filo Ebola virus (EBOV) vaccine regimen in infants aged 4-11 months in Guinea and Sierra Leone. METHODS: In this phase 2, randomised, double-blind, active-controlled trial, we randomly assigned healthy infants (1:1 in a sentinel cohort, 5:2 for the remaining infants via an interactive web response system) to receive Ad26.ZEBOV followed by MVA-BN-Filo (Ebola vaccine group) or two doses of meningococcal quadrivalent conjugate vaccine (control group) administered 56 days apart. Infants were recruited at two sites in west Africa: Conakry, Guinea, and Kambia, Sierra Leone. All infants received the meningococcal vaccine 8 months after being randomly assigned. The primary objective was safety. The secondary objective was immunogenicity, measured as EBOV glycoprotein-binding antibody concentration 21 days post-dose 2, using the Filovirus Animal Non-Clinical Group ELISA. This study is registered with ClinicalTrials.gov (NCT03929757) and the Pan African Clinical Trials Registry (PACTR201905827924069). FINDINGS: From Aug 20 to Nov 29, 2019, 142 infants were screened and 108 were randomly assigned (Ebola vaccine n=75; control n=33). The most common solicited local adverse event was injection-site pain (Ebola vaccine 15 [20%] of 75; control four [12%] of 33). The most common solicited systemic adverse events with the Ebola vaccine were irritability (26 [35%] of 75), decreased appetite (18 [24%] of 75), pyrexia (16 [21%] of 75), and decreased activity (15 [20%] of 75). In the control group, ten (30%) of 33 had irritability, seven (21%) of 33 had decreased appetite, three (9%) of 33 had pyrexia, and five (15%) of 33 had decreased activity. The frequency of unsolicited adverse events was 83% (62 of 75 infants) in the Ebola vaccine group and 85% (28 of 33 infants) in the control group. No serious adverse events were vaccine-related. In the Ebola vaccine group, EBOV glycoprotein-binding antibody geometric mean concentrations (GMCs) at 21 days post-dose 2 were 27 700 ELISA units (EU)/mL (95% CI 20 477-37 470) in infants aged 4-8 months and 20 481 EU/mL (15 325-27 372) in infants aged 9-11 months. The responder rate was 100% (74 of 74 responded). In the control group, GMCs for both age groups were less than the lower limit of quantification and the responder rate was 3% (one of 33 responded). INTERPRETATION: Ad26.ZEBOV and MVA-BN-Filo was well tolerated and induced strong humoral responses in infants younger than 1 year. There were no safety concerns related to vaccination. FUNDING: Janssen Vaccines & Prevention and Innovative Medicines Initiative 2 Joint Undertaking. TRANSLATION: For the French translation of the abstract see Supplementary Materials section

Long-term cellular immunity of vaccines for Zaire Ebola Virus Diseases

Recent Ebola outbreaks underscore the importance of continuous prevention and disease control efforts. Authorized vaccines include Merck’s Ervebo (rVSV-ZEBOV) and Johnson & Johnson’s two-dose combination (Ad26.ZEBOV/MVA-BN-Filo). Here, in a five-year follow-up of the PREVAC randomized trial (NCT02876328), we report the results of the immunology ancillary study of the trial. The primary endpoint is to evaluate long-term memory T-cell responses induced by three vaccine regimens: Ad26–MVA, rVSV, and rVSV–booster. Polyfunctional EBOV-specific CD4+ T-cell responses increase after Ad26 priming and are further boosted by MVA, whereas minimal responses are observed in the rVSV groups, declining after one year. In-vitro expansion for eight days show sustained EBOV-specific T-cell responses for up to 60 months post-prime vaccination with both Ad26-MVA and rVSV, with no decline. Cytokine production analysis identify shared biomarkers between the Ad26-MVA and rVSV groups. In secondary endpoint, we observed an elevation of pro-inflammatory cytokines at Day 7 in the rVSV group. Finally, we establish a correlation between EBOV-specific T-cell responses and anti-EBOV IgG responses. Our findings can guide booster vaccination recommendations and help identify populations likely to benefit from revaccination

Prevalence of malaria and helminth infections in rural communities in northern Sierra Leone, a baseline study to inform Ebola vaccine study protocols.

INTRODUCTION: Recurrent parasitic infections may influence the immune response to vaccines. In the Partnership for Research on Ebola VACcinations extended follow-UP and clinical research capacity build-UP (PREVAC-UP) study being undertaken in Mambolo, northern Sierra Leone, participants are being followed up to assess the potential impact of exposure to malaria and/or helminth infections on long-term immune response to two Ebola vaccines. To support the development of the assays that will be used in this evaluation, a parasitological survey was conducted in Mambolo between November 2019 and February 2020. METHODS: Healthy individuals aged ≥1 year who were resident in Mambolo Chiefdom were selected using a stratified sampling approach and questionnaires were administered to explore their sociodemographic characteristics. Microscopy was used to detect malaria parasites, intestinal helminths and urinary schistosome infections. Rapid blood tests were used to detect infections with Onchocerca volvulus and Wuchereria bancrofti. We estimated the overall prevalence of these infections and used adjusted logistic regression models to explore risk factors for malaria and hookworm infection. RESULTS: Eight hundred and fifteen (815) residents, 50.9% of whom were female were surveyed. Overall, 309 (39.1%) of 791 persons tested for malaria had a positive blood slide; Plasmodium falciparum was the dominant species. Helminth infection was detected in 122 (15.0%) of 815 stool samples including three mixed infections. The helminth infections comprised 102 (12.5%) cases of hookworm, 11 (1.3%) cases of Trichuris trichiura, 10 (1.2%) cases of Schistosoma mansoni and two (0.2%) cases of Ascaris lumbricoides. Being male (OR = 2.01, 95% CI 1.15-3.50) and residing in a non-riverine community (OR = 4.02, 95%CI 2.32-6.98) were the factors associated with hookworm infection. Onchocerca volvulus and Wuchereria bancrofti infections were found in 3.3% and 0.4% of participants respectively. CONCLUSION: Malaria and hookworm are the most prevalent parasite infections and those most likely to influence long-term immune response to Ebola vaccines among the trial participants

Salmonella infections in The Gambia, 2005-2015

Backround: There are large data gaps in the epidemiology of diseases caused by Salmonella enterica in West Africa. Regional surveillance of Salmonella infections is necessary, especially with the emergence and spread of multidrug-resistant clones. Methods: Data on Salmonella isolated from various clinical specimens from patients from across The Gambia were collected and analyzed retrospectively from 2005 to April 2015. Antibiotic sensitivity testing of Salmonella isolates was performed by disk diffusion method. Serotyping and serogrouping of Salmonella isolates was performed using standard microbiology techniques. Results: Two hundred three Salmonella isolates were isolated from 190 patients: 52% (106/203) from blood and 39% (79/203) from stool specimens. Salmonella was also isolated from urine, aspirates, cerebrospinal fluid, wounds, and abscesses. The prevalence of Salmonella in blood cultures was 0.8% (106/13 905). Of the serotyped salmonellae, 14% (21/152) were Salmonella enterica serovar Typhi, whereas 86% (131/152) were serovars other than Typhi (nontyphoidal Salmonella). Of the 102 typed NTS isolates, 40% (41) were Salmonella enterica serovar Typhimurium, 10% (10) were Salmonella enterica serovar Enteritidis, and 3% (3) were Salmonella enterica serovar Arizonae. Overall, 70% (142/203) of the salmonellae were pansusceptible. Multidrug resistance was found in 4% (9/203) of the isolates, 3 of which were Salmonella Enteritidis. Conclusions: Salmonellae are associated with a wide spectrum of invasive and noninvasive infections across all ages in The Gambia. There is evidence of multidrug resistance in salmonellae that warrants vigilant monitoring and surveillance