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Sepsis is a major cause of neonatal mortality and children born in low- and middle-income countries (LMICs) are at greater risk of severe neonatal infections than those in higher-income countries. Despite this disparity, there are limited contemporaneous data linking the clinical features of neonatal sepsis with outcome in LMICs. Here, we aimed to identify factors associated with mortality from neonatal sepsis in Vietnam. We conducted a prospective, observational study to describe the clinical features, laboratory characteristics, and mortality rate of neonatal sepsis at a major children’s hospital in Ho Chi Minh City. All in-patient neonates clinically diagnosed with probable or culture-confirmed sepsis meeting inclusion criteria from January 2017 to June 2018 were enrolled. We performed univariable analysis and logistic regression to identify factors independently associated with mortality. 524 neonates were recruited. Most cases were defined as late-onset neonatal sepsis and were hospital-acquired (91.4% and 73.3%, respectively). The median (IQR) duration of hospital stay was 23 (13–41) days, 344/524 (65.6%) had a positive blood culture (of which 393 non-contaminant organisms were isolated), and 69/524 (13.2%) patients died. Coagulase-negative staphylococci (232/405; 57.3%), Klebsiella spp. (28/405; 6.9%), and Escherichia coli (27/405; 6.7%) were the most isolated organisms. Sclerema (OR = 11.4), leukopenia 4 mmol/L (OR = 3.4), extremely low birth weight (OR = 3.2), and hyperglycaemia >180 mg/dL (OR = 2.6) were all significantly (p

Background\ud \ud Prevention of cardiac surgical site infection has largely focused on reducing infection due to Staphylococcus aureus although other bacteria also play an important role in this complication.\ud \ud \ud \ud Aim\ud \ud We assess the impact of an evolving infection control program on the incidence of sternal wound infection (SWI) and the changing incidence of non-staphylococcal infections.\ud \ud \ud \ud Methods\ud \ud We conducted a retrospective cohort study of all patients who underwent primary sternotomy at a single UK centre between September 2010 and May 2018. Data were collated from two-years prior to the stepwise introduction of a broad-ranging infection control program, including S. aureus decolonisation.\ud \ud \ud \ud Findings\ud \ud 6,903 primary sternotomies were performed of which 2.6% (n=178) were complicated by SWI. Gram-negative bacteria (GNB) and S. aureus were most commonly identified as causative pathogens (45.5% and 30.3% respectively). Following program introduction there was a reduction in the rate of SWI from 3.9 to 1.8 cases/100 patients/month. This was mainly due to a sustained reduction in S. aureus infected cases with no discernible impact on GNB. Multivariable logistic regression analysis identified coronary artery bypass grafting, procedural urgency and procedures performed in the 3rd quarter as independent risk factors for post-operative infection.\ud \ud \ud \ud Conclusion\ud \ud A multifaceted infection control program was successful at reducing the rate of SWI primarily due to a reduction in S. aureus infections. GNB also play an important role in SWI and traditional preventative measures fail to address these. Future intervention and impact assessments should consider Gram negative infection when measuring effectiveness.

The burden of Salmonella Typhi shedding in stool and its contribution to transmission in endemic settings is unknown. During passive surveillance S. Typhi shedding was seen during convalescence in 332 bacteremic typhoid patients although none persisted at one-year follow-up. Anti-Vi-IgG titres were measured in age-stratified cohort of serosurveillance participants. Systematic stool sampling of 303 participants with high anti-Vi-IgG titres identified one asymptomatic carrier shedding. These findings suggest ongoing S. Typhi transmission in this setting is more likely to occur from acute convalescent cases although better approaches are needed to identify true chronic carriers in the community to enable typhoid elimination.

To prepare for potential human infection challenge studies (HICS) involving SARS-CoV-2, we convened a multidisciplinary working group to address ethical questions regarding whether and how much SARS-CoV-2 HICS participants should be paid. Because the goals of paying HICS participants, as well as the relevant ethical concerns, are the same as those arising for other types of clinical research, the same basic framework for ethical payment can apply. This framework divides payment into reimbursement, compensation, and incentives, focusing on fairness and promoting adequate recruitment and retention as counterweights to concerns about undue inducement. Within the basic framework, several factors are especially salient for HICS, and for SARS-CoV-2 HICS in particular, including the nature of participant confinement, anticipated discomfort, risks and uncertainty, participant motivations, and trust. These factors are reflected in a payment worksheet created to help sponsors, researchers, and ethics reviewers systematically develop and assess ethically justifiable payment amounts.

Human challenge trials (HCTs) have been proposed as a means to accelerate SARS-CoV-2 vaccine development. We identify and discuss three potential use cases of HCTs in the current pandemic: evaluating efficacy, converging on correlates of protection, and improving understanding of pathogenesis and the human immune response. We outline the limitations of HCTs and find that HCTs are likely to be most useful for vaccine candidates currently in preclinical stages of development. We conclude that, while currently limited in their application, there are scenarios in which HCTs would be extremely beneficial. Therefore, the option of conducting HCTs to accelerate SARS-CoV-2 vaccine development should be preserved. As HCTs require many months of preparation, we recommend an immediate effort to (1) establish guidelines for HCTs for COVID-19; (2) take the first steps toward HCTs, including preparing challenge virus and making preliminary logistical arrangements; and (3) commit to periodically re-evaluating the utility of HCTs.

Objective\ud \ud There are no vaccines for most of the major invasive Salmonella strains causing severe infection in humans. We evaluated the specificity of adaptive T memory cell responses generated after Salmonella Typhi exposure in humans against other major invasive Salmonella strains sharing capacity for dissemination.\ud \ud \ud \ud Methods\ud \ud T memory cells from eleven volunteers who underwent controlled oral challenge with wt S. Typhi were characterised by flow cytometry for cross‐reactive cellular cytokine/chemokine effector responses or evidence of degranulation upon stimulation with autologous B‐lymphoblastoid cells infected with either S. Typhi, Salmonella Paratyphi A (PA), S. Paratyphi B (PB) or an invasive nontyphoidal Salmonella strain of the S. Typhimurium serovar (iNTSTy).\ud \ud \ud \ud Results\ud \ud Blood T‐cell effector memory (TEM) responses after exposure to S. Typhi in humans evolve late, peaking weeks after infection in most volunteers. Induced multifunctional CD4+ Th1 and CD8+ TEM cells elicited after S. Typhi challenge were cross‐reactive with PA, PB and iNTSTy. The magnitude of multifunctional CD4+ TEM cell responses to S. Typhi correlated with induction of cross‐reactive multifunctional CD8+ TEM cells against PA, PB and iNTSTy. Highly multifunctional subsets and T central memory and T effector memory cells that re‐express CD45 (TEMRA) demonstrated less heterologous T‐cell cross‐reactivity, and multifunctional Th17 elicited after S. Typhi challenge was not cross‐reactive against other invasive Salmonella.\ud \ud \ud \ud Conclusion\ud \ud Gaps in cross‐reactive immune effector functions in human T‐cell memory compartments were highly dependent on invasive Salmonella strain, underscoring the importance of strain‐dependent vaccination in the design of T‐cell‐based vaccines for invasive Salmonella.

Development of an effective vaccine is the clearest path to controlling the coronavirus disease 2019 (COVID-19) pandemic. To accelerate vaccine development, some researchers are pursuing, and thousands of people have expressed interest in participating in, controlled human infection studies (CHIs) with severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) (1, 2). In CHIs, a small number of participants are deliberately exposed to a pathogen to study infection and gather preliminary efficacy data on experimental vaccines or treatments. We have been developing a comprehensive, state-of-the-art ethical framework for CHIs that emphasizes their social value as fundamental to justifying these studies. The ethics of CHIs in general are underexplored (3, 4), and ethical examinations of SARS-CoV-2 CHIs have largely focused on whether the risks are acceptable and participants could give valid informed consent (1). The high social value of such CHIs has generally been assumed. Based on our framework, we agree on the ethical conditions for conducting SARS-CoV-2 CHIs (see the table). We differ on whether the social value of such CHIs is sufficient to justify the risks at present, given uncertainty about both in a rapidly evolving situation; yet we see none of our disagreements as insurmountable. We provide ethical guidance for research sponsors, communities, participants, and the essential independent reviewers considering SARS-CoV-2 CHIs.

Background: Enteric fever is an acute febrile-illness caused by infection with the human-restricted Salmonella serovars Typhi and Paratyphi. Controlled human infection models (CHIM) of S. Typhi and Paratyphi infection are used to accelerate vaccine development and to better understand host-pathogen interactions. The primary motivations for participants to take part in these studies are unknown. We studied participant motivations, attitudes and the factors influencing CHIM study participation.\ud \ud \ud \ud Methods: Participant surveys were nested in six enteric fever CHIM studies conducted at a single centre in Oxford, UK, between 2011 and 2017. All eligible participants received one invitation to complete an anonymous, self-administered paper or online survey on either day 28 or 60 after challenge. A descriptive analysis was performed on these pooled data. All studies were included, to minimize selection bias.\ud \ud \ud \ud Results: Survey response rates varied from 33.0%-86.1%, yielding 201 participants. In the cohort, 113/198(57.0%) were educated to bachelor’s level, 61.6% were employed, 30.3% were students and 4.6% were unemployed. The most commonly cited motivations for CHIM study participation were a desire to contribute to the progression of medicine (170/201; 84.6%); the prospect of financial reimbursement (166/201; 82.6%) and curiosity about clinical trials (117/201; 57.2%). The majority of respondents (139/197; 70.6%) reported that most people advised them against participation.\ud \ud \ud \ud Conclusion: Motivation to participate in a CHIM study was multi-factorial and heavily influenced by internal drivers beyond monetary reimbursement alone. High educational attainment and employment may be protective factors against financial inducement; however, further research is needed, particularly with CHIM studies expanding to low-income and middle-income countries.

Summary The safe establishment of a protocol for a human challenge model for Salmonella Paratyphi A can be used to expedite the evaluation of novel vaccine candidates and provides insight into the clinical and immune response to paratyphoid infection., Background. To expedite the evaluation of vaccines against paratyphoid fever, we aimed to develop the first human challenge model of Salmonella enterica serovar Paratyphi A infection. Methods. Two groups of 20 participants underwent oral challenge with S. Paratyphi A following sodium bicarbonate pretreatment at 1 of 2 dose levels (group 1: 1–5 × 103 colony-forming units [CFU] and group 2: 0.5–1 × 103 CFU). Participants were monitored in an outpatient setting with daily clinical review and collection of blood and stool cultures. Antibiotic treatment was started when prespecified diagnostic criteria were met (temperature ≥38°C for ≥12 hours and/or bacteremia) or at day 14 postchallenge. Results. The primary study objective was achieved following challenge with 1–5 × 103 CFU (group 1), which resulted in an attack rate of 12 of 20 (60%). Compared with typhoid challenge, paratyphoid was notable for high rates of subclinical bacteremia (at this dose, 11/20 [55%]). Despite limited symptoms, bacteremia persisted for up to 96 hours after antibiotic treatment (median duration of bacteremia, 53 hours [interquartile range, 24–85 hours]). Shedding of S. Paratyphi A in stool typically preceded onset of bacteremia. Conclusions. Challenge with S. Paratyphi A at a dose of 1–5 × 103 CFU was well tolerated and associated with an acceptable safety profile. The frequency and persistence of bacteremia in the absence of clinical symptoms was notable, and markedly different from that seen in previous typhoid challenge studies. We conclude that the paratyphoid challenge model is suitable for the assessment of vaccine efficacy using endpoints that include bacteremia and/or symptomatology. Clinical Trials Registration. NCT02100397.

Six Salmonella Typhi or Paratyphi human challenge studies were conducted, and daily stool cultures performed. Vi-containing vaccines reduced bacterial shedding, Ty21a or an experimental vaccine did not. Higher Vi immunoglobulin G titers were associated with reduced shedding., Background Shedding of Salmonella Typhi or Paratyphi in the stool or urine leads to contamination of food or water, which is a prerequisite for transmission of enteric fever. Currently, there are limited data on the effect of vaccination or prior exposure on stool shedding. Methods Six Salmonella Typhi or Paratyphi human challenge studies were conducted between 2011 and 2017. Participants were either unvaccinated or vaccinated with 1 of 4 vaccines: Vi-polysaccharide (Vi-PS), Vi-tetanus-toxoid conjugate vaccine (Vi-TT), live oral Ty21a vaccine, or an experimental vaccine (M01ZH09). Daily stool cultures were collected for 14 days after challenge. Results There were 4934 stool samples collected from 430 volunteers. Participants who received Vi-PS or Vi-TT shed less than unvaccinated participants (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.15–0.77; P = .010 and OR, 0.41; 95% CI, 0.19–0.91, P = .029 for Vi-PS and Vi-TT, respectively). Higher anti-Vi immunoglobulin G titers were associated with less shedding of S. Typhi (P < .0001). A nonsignificant reduction in shedding was associated with Ty21a vaccine (OR, 0.57; 95% CI, 0.27–1.20; P = .140). Individuals previously exposed to S. Typhi shed less than previously unexposed individuals (OR, 0.30; 95% CI, 0.1–0.8; P = .016). Shedding of S. Typhi was more common than S. Paratyphi. Conclusions Prior vaccination with Vi vaccines, or natural infection, reduces onward transmission of S. Typhi. Field trials of Vi-TT should be designed to detect indirect protection, reflecting the consequence of reduced stool shedding observed in the human challenge model.

The mechanisms by which oral, live-attenuated vaccines protect against typhoid fever are poorly understood. Here, we analyze transcriptional responses after vaccination with Ty21a or vaccine candidate, M01ZH09. Alterations in response profiles were related to vaccine-induced immune responses and subsequent outcome after wild-type Salmonella Typhi challenge. Despite broad genetic similarity, we detected differences in transcriptional responses to each vaccine. Seven days after M01ZH09 vaccination, marked cell cycle activation was identified and associated with humoral immunogenicity. By contrast, vaccination with Ty21a was associated with NK cell activity and validated in peripheral blood mononuclear cell stimulation assays confirming superior induction of an NK cell response. Moreover, transcriptional signatures of amino acid metabolism in Ty21a recipients were associated with protection against infection, including increased incubation time and decreased severity. Our data provide detailed insight into molecular immune responses to typhoid vaccines, which could aid the rational design of improved oral, live-attenuated vaccines against enteric pathogens.

Typhoid fever is estimated to cause between 11.9–26.9 million infections globally each year with 129,000–216,510 deaths. Access to improved water sources have reduced disease incidence in parts of the world but the use of efficacious vaccines is seen as an important public health tool for countries with a high disease burden.\ud \ud A new generation of Vi typhoid conjugate vaccines (TCVs), licensed for use in young children and expected to provide longer lasting protection than previous vaccines, are now available. The WHO Strategic Advisory Group of Experts on Immunization (SAGE) has convened a working group to review the evidence on TCVs and produce an updated WHO position paper for all typhoid vaccines in 2018 that will inform Gavi, the Vaccine Alliance's future vaccine investment strategies for TCVs.\ud \ud The Typhoid Vaccine Acceleration Consortium (TyVAC) has been formed through a $36.9 million funding program from the Bill & Melinda Gates Foundation to accelerate the introduction of TCVs into Gavi-eligible countries.\ud \ud In October 2016, a meeting was held to initiate planning of TCV effectiveness studies that will provide the data required by policy makers and stakeholders to support decisions on TCV use in countries with a high typhoid burden.\ud \ud Discussion topics included (1) the latest evidence and data gaps in typhoid epidemiology; (2) WHO and Gavi methods and data requirements; (3) data on TCV efficacy; (4) cost effectiveness analysis for TCVs from mathematical models; (5) TCV delivery and effectiveness study design. Specifically, participants were asked to comment on study design in 3 sites for which population-based typhoid surveillance is underway.\ud \ud The conclusion of the meeting was that country-level decision making would best be informed by the respective selected sites in Africa and Asia vaccinating children aged from 9-months to 15-years-old, employing either an individual or cluster randomized design with design influenced by population characteristics, transmission dynamics, and statistical considerations.

Current diagnostic tests for typhoid fever, the disease caused by Salmonella Typhi, are poor. We aimed to identify serodiagnostic signatures of typhoid fever by assessing microarray signals to 4,445 S. Typhi antigens in sera from 41 participants challenged with oral S. Typhi. We found broad, heterogeneous antibody responses with increasing IgM/IgA signals at diagnosis. In down-selected 250-antigen arrays we validated responses in a second challenge cohort (n = 30), and selected diagnostic signatures using machine learning and multivariable modeling. In four models containing responses to antigens including flagellin, OmpA, HlyE, sipC, and LPS, multi-antigen signatures discriminated typhoid (n = 100) from other febrile bacteremia (n = 52) in Nepal. These models contained combinatorial IgM, IgA, and IgG responses to 5 antigens (ROC AUC, 0.67 and 0.71) or 3 antigens (0.87), although IgA responses to LPS also performed well (0.88). Using a novel systematic approach we have identified and validated optimal serological diagnostic signatures of typhoid fever.

Introduction Invasive infections caused by Salmonella enterica serovar Typhi and Paratyphi A are estimated to account for 12–27 million febrile illness episodes worldwide annually. Determining the true burden of typhoidal Salmonellae infections is hindered by lack of population-based studies and adequate laboratory diagnostics.\ud \ud The Strategic Typhoid alliance across Africa and Asia study takes a systematic approach to measuring the age-stratified burden of clinical and subclinical disease caused by typhoidal Salmonellae infections at three high-incidence urban sites in Africa and Asia. We aim to explore the natural history of Salmonella transmission in endemic settings, addressing key uncertainties relating to the epidemiology of enteric fever identified through mathematical models, and enabling optimisation of vaccine strategies.\ud \ud Methods/design Using census-defined denominator populations of ≥100 000 individuals at sites in Malawi, Bangladesh and Nepal, the primary outcome is to characterise the burden of enteric fever in these populations over a 24-month period. During passive surveillance, clinical and household data, and laboratory samples will be collected from febrile individuals. In parallel, healthcare utilisation and water, sanitation and hygiene surveys will be performed to characterise healthcare-seeking behaviour and assess potential routes of transmission. The rates of both undiagnosed and subclinical exposure to typhoidal Salmonellae (seroincidence), identification of chronic carriage and population seroprevalence of typhoid infection will be assessed through age-stratified serosurveys performed at each site. Secondary attack rates will be estimated among household contacts of acute enteric fever cases and possible chronic carriers.\ud \ud Ethics and dissemination This protocol has been ethically approved by the Oxford Tropical Research Ethics Committee, the icddr,b Institutional Review Board, the Malawian National Health Sciences Research Committee and College of Medicine Research Ethics Committee and Nepal Health Research Council. The study is being conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Informed consent was obtained before study enrolment. Results will be submitted to international peer-reviewed journals and presented at international conferences.\ud \ud Trial registration number ISRCTN 12131979.\ud \ud Ethics references Oxford (Oxford Tropical Research Ethics Committee 39-15).\ud \ud Bangladesh (icddr,b Institutional Review Board PR-15119).\ud \ud Malawi (National Health Sciences Research Committee 15/5/1599).\ud \ud Nepal (Nepal Health Research Council 306/2015).

In human challenge trials, volunteers are deliberately infected with a pathogen to accelerate vaccine development and answer key scientific questions. In the U.S., preparations for challenge trials with the novel coronavirus are complete, and in the U.K., challenge trials have recently begun. However, ethical concerns have been raised about the potential for invalid consent or exploitation. These concerns largely reflect worries that challenge trial volunteers may be unusually risk-seeking or too economically vulnerable to refuse the payments these trials provide, rather than being motivated primarily by altruistic goals. We conducted the first large-scale survey of intended human challenge trial volunteers and found that SARS-CoV-2 challenge trial volunteers exhibit high levels of altruistic motivations without any special indication of poor risk perception or economic vulnerability. Findings indicate that challenge trials with the novel coronavirus can attract volunteers with background conditions, attitudes, and motivations that should allay key ethical concerns.