Tracking the polyclonal neutralizing antibody response to a dengue virus serotype 1 type-specific epitope across two populations in Asia and the Americas

The four dengue virus serotypes (DENV1-4) cause major public health problems worldwide. Highly neutralizing type-specific human monoclonal antibodies (hmAbs) target conformation-dependent epitopes on the DENV envelope protein, including 1F4, a DENV1 type-specific hmAb. Using a recombinant DENV2 virus displaying the DENV1 1F4 epitope (rDENV2/1), we measured the proportion and kinetics of DENV1 neutralizing antibodies targeting the 1F4 epitope in individuals living in Asia and the Americas where different DENV1 genotypes were circulating. Samples from 20 individuals were analyzed 3 and 18 months post-primary DENV1 infection, alongside samples from 4 individuals collected annually for four years post-primary DENV1 infection, from two studies in Nicaragua. We also analyzed convalescent post-primary DENV1 plasma samples from Sri Lankan individuals. We found that neutralizing antibodies recognizing the 1F4 epitope vary in prevalence across both populations and were detected from 20 days to four years post-infection. Additionally, both populations displayed substantial variability, with a range of high to low proportions of DENV1 type-specific neutralizing antibodies recognizing the 1F4 epitope seen across individuals. Thus, the 1F4 epitope is a major but not exclusive target of type-specific neutralizing antibodies post-primary infection with different DENV1 genotypes in Asia and Latin America, and additional epitopes likely contribute to type-specific neutralization of DENV1

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

Tracking the polyclonal neutralizing antibody response to a dengue virus serotype 1 type-specific epitope across two populations in Asia and the Americas.

The four dengue virus serotypes (DENV1-4) cause major public health problems worldwide. Highly neutralizing type-specific human monoclonal antibodies (hmAbs) target conformation-dependent epitopes on the DENV envelope protein, including 1F4, a DENV1 type-specific hmAb. Using a recombinant DENV2 virus displaying the DENV1 1F4 epitope (rDENV2/1), we measured the proportion and kinetics of DENV1 neutralizing antibodies targeting the 1F4 epitope in individuals living in Asia and the Americas where different DENV1 genotypes were circulating. Samples from 20 individuals were analyzed 3 and 18 months post-primary DENV1 infection, alongside samples from 4 individuals collected annually for four years post-primary DENV1 infection, from two studies in Nicaragua. We also analyzed convalescent post-primary DENV1 plasma samples from Sri Lankan individuals. We found that neutralizing antibodies recognizing the 1F4 epitope vary in prevalence across both populations and were detected from 20 days to four years post-infection. Additionally, both populations displayed substantial variability, with a range of high to low proportions of DENV1 type-specific neutralizing antibodies recognizing the 1F4 epitope seen across individuals. Thus, the 1F4 epitope is a major but not exclusive target of type-specific neutralizing antibodies post-primary infection with different DENV1 genotypes in Asia and Latin America, and additional epitopes likely contribute to type-specific neutralization of DENV1

Odds of progressing to chronic chikungunya-associated arthralgia after an initial presentation with only acute or interim chikungunya-associated arthralgia in Managua, Nicaragua (2014–2018).

Odds of progressing to chronic chikungunya-associated arthralgia after an initial presentation with only acute or interim chikungunya-associated arthralgia in Managua, Nicaragua (2014–2018).</p

Density plot of participants stratified by age range in years in Managua, Nicaragua (2014–2018).

The percent of participants in this study across age are depicted using an age-density plot. Colors correspond to the age-ranges defined within the study (0–4, 5–9, 10–15, and 16+ years old). (TIF)</p

Prevalence of post-acute polyarthralgia by age and body part in Managua, Nicaragua (2014–2018).

Prevalence of post-acute polyarthralgia by age and body part in Managua, Nicaragua (2014–2018).</p

Prevalence of reports of arthralgia in the acute and post-acute phase in Managua, Nicaragua (2014–2018).

Prevalence of reports of arthralgia in the acute and post-acute phase in Managua, Nicaragua (2014–2018).</p

Reported polyarthralgia beyond the acute phase of chikungunya associated-arthralgia by body part and age in year in Managua, Nicaragua (2014–2018).

Cluster dendrogram depicting the relationship between occurrence of polyarthralgia across the different body parts, with the y-axis representing the underlying cluster distance calculated using the Manhattan distance method. The cophenetic distance correlation coefficient is 0.95; the higher the cophenetic distance correlation coefficient is, the more appropriately the dendrogram represents a hierarchical structure present in the original data (A). Age trends of the prevalence of arthralgia among clustered body groups (B) and individual body parts (C), including the 95% confidence intervals, visualized using shading corresponding to each respective color group and depicted using a generalized additive model.</p

Risk factors for acute chikungunya-associated arthralgia in Managua, Nicaragua (2014–2018).

Risk factors for acute chikungunya-associated arthralgia in Managua, Nicaragua (2014–2018).</p

Kaplan-Meier plot showing the proportion of participants reporting arthralgia over time in years in Managua, Nicaragua (2014–2018).

A Kaplan-Meier graph plotting the proportion of participants not reporting arthralgia (y-axis) against days since fever onset (x-axis). Ticks correspond to censoring events. Panels show the distribution of participants beginning 10 days post-fever onset and ending at the last reported data point based on the exclusion criteria (< 625 days post-fever onset), stratified by age range (A) and sex (B). The p-values were calculated using the log-rank test.</p