Invasive disease caused by non-typhoidal Salmonella serovars (iNTS) occurs with increased risk in the presence of other comorbidities such as malaria, HIV, malnutrition, anaemia and sickle cell disease. While infection with non-typhoidal (NTS) serovars often results in self-limited enterocolitis in high-income settings, in sub-Saharan Africa (SSA) where these risk-comorbidities are common, an invasive (iNTS) disease phenotype is seen, associated with up to 20 % case-fatality ratio, and antimicrobial resistance is both significant and growing. The need to evaluate the potential public health value of vaccines against iNTS disease is increasingly being recognized, and several candidate vaccines are in early development. A better understanding of the global burden and epidemiology of iNTS disease, as well as the potential public health and socio-economic benefits that iNTS vaccines may offer is fundamental to support and justify the investments in vaccine development. In addition, the pathways for licensure, policy recommendations and eventual vaccine prioritization and use in low- and middle-income countries (LMICs) need to be defined. Here, we report on the proceedings of an expert consultation held on 29 November - 1 December 2021 as part of an overall project to develop a Full Value of Vaccines Assessment (FVVA) for iNTS vaccines and in addition to more recent iNTS vaccine developments. Experts at the consultation reviewed the current evidence on iNTS disease and discussed knowledge gaps to be addressed to accelerate vaccine development, licensure and introduction, as well as LMIC perspectives on potential iNTS vaccine use and demand. The learnings from this consultation are critical inputs to inform remaining work under the iNTS FVVA project.

Background Salmonella enterica serovar Typhi ( Salmonella Typhi) is the cause of typhoid fever. Salmonella Typhi may be transmitted through shedding in the stool, which can continue after recovery from acute illness. Shedding is detected by culturing stool, which is challenging to co-ordinate at scale. We hypothesised that sero-surveillance would direct us to those shedding Salmonella Typhi in stool following a typhoid outbreak. Methods In 2016 a typhoid outbreak affected one in four residents of a Nursing School in Malosa, Malawi. The Department of Health asked for assistance to identify nursing students that might spread the outbreak to other health facilities. We measured IgG antibody titres against Vi capsular polysaccharide (anti-Vi IgG) and IgM / IgG antibodies against H:d flagellin (anti-H:d) three and six months after the outbreak. We selected participants in the highest and lowest deciles for anti-Vi IgG titre (measured at visit one) and obtained stool for Salmonella culture and PCR. All participants reported whether they had experienced fever persisting for three days or more during the outbreak (in keeping with the WHO definitions of ‘suspected typhoid’). We tested for salmonellae in the Nursing School environment. Results We obtained 320 paired serum samples from 407 residents. We cultured stool from 25 residents with high anti-Vi IgG titres and 24 residents with low titres. We did not recover Salmonella Typhi from stool; four stool samples yielded non-typhoidal salmonellae; one sample produced a positive PCR amplification for a Salmonella Typhi target. Median anti-Vi and anti-H:d IgG titres fell among participants who reported persistent fever. There was a smaller fall in anti-H:d IgG titres among participants who did not report persistent fever. Non-typhoidal salmonellae were identified in water sampled at source and from a kitchen tap. Conclusion High titres of anti-Vi IgG did not identify culture-confirmed shedding of Salmonella Typhi. There was a clear serologic signal of recent typhoid exposure in the cohort, represented by waning IgG antibody titres over time. The presence of non-typhoidal salmonellae in drinking water indicates sub-optimal sanitation. Developing methods to detect and treat shedding remains an important priority to complement typhoid conjugate vaccination in efforts to achieve typhoid elimination.

Several population-based studies have recently published data on the incidence of typhoid fever. 1 – 4 These studies redress gaps in our knowledge of disease burden in speci fi c locations and contribute to improved estimates of the global burden of typhoid fever. 5 These data are increasingly important to decision-makers in typhoid-endemic countries as they consider implementing typhoid conjugate vaccine (TCV) programs and apply for GAVI funding. 6 Although typhoid incidence estimates are informative, we should be cautious in generalizing their fi ndings beyond the period during which data were collected. Typhoid incidence is dynamic, with increases following the introduction of new strains with increased antimicrobial resistance, 7,8 and reductions following the introduction of disease control interventions. 9 Long-term incidence data from single-sites is rare, but can provide crucial insights into how various factors in fl uence rates of typhoid fever. 10 This is why the study by Ng ’ eno et al., published in a recent issue of the American Journal of Tropical Medicine and Hygiene , is so relevant. 11 Ng ’ eno et al. provide a decade of typhoid incidence data from the informal Kenyan settlement of Kibera. The authors report crude incidence rates ranging from 144 to 233 per 100,000 person-years of observation (pyo) between 2010 and 2012. This was followed by a decline in typhoid incidence from 2013 to 2017. Cases rebounded in the fi nal two years of surveillance, reaching 130 per 100,000 pyo in 2019. The authors

A 20 year old lady presented to the acute medical unit with new neurological deficits. She described gastrointestinal symptoms in the preceding 24 hours. Her case was discussed with infectious diseases and neurology overnight, both of whom were resident at a hospital on the other side of the city. The infectious diseases team were concerned enough to discuss the case with Public Health England for consideration of botulism antitoxin. When this diagnosis was discounted on the basis of asymmetric neurological deficits, the patient was admitted under the care of the neurologists. Mononeuritis multiplex of unclear aetiology was diagnosed. A subsequent infectious diseases review resulted in a diagnosis of primary EBV infection, the likely trigger of the symptoms. Whilst neurologic deficits resolved, neuropathic pain continues. Learning points include the importance of an early, accurate description of neurologic deficits and the need to consider EBV as an infectious trigger of mononeuritis multiplex. Collaboration between neurology and infectious disease physicians was key in managing this patient and disentangling the broad array of infectious and non-infectious differential diagnoses.

3.5% of the global population.1 In highprevalence areas, new infections occur mainly at birth or in childhood. Most HBV in the UK is among migrant populations from areas with high prevalence, such as SubHealth care is increasingly reliant on immune-modulating drugs that can exacerbate a chronic infection or allow a past, 'cleared' infection to reactivate. Clinicians may not appreciate the high burden of HBV among certain minority migrant groups, who may themselves have misconceptions regarding personal risk and modes of transmission, and who experience barriers to accessing health care.3 The busy GP needs to know who to test for HBV, how to tell if someone has chronic or past HBV infection, and when past

Objective and design: People living with HIV (PLH) suffer disproportionately from the chronic diseases exacerbated by smoking tobacco. We performed a systematic review and meta-analysis to establish the relative prevalence of smoking among PLH. Methods: We included observational studies reporting current smoking rates among PLH and comparators without HIV. We searched Medline, EMBASE, LILACS and SciELO from inception to 31 August 2019. We excluded studies that recruited participants with smoking related illness. We used a random effects model to estimate the odds ratio for current smoking in PLH and people without HIV. We used the Newcastle--Ottawa scale to assess methodological bias. We performed subgroup analysis based on sex and WHO region. We quantified heterogeneity with meta-regression and predictive distributions. PROSPERO registration:CRD42016052608. Results: We identified 6116 studies and included 37. Of 111 258 PLH compared with 10 961 217 HIV-negative participants pooled odds of smoking were 1.64 [(95% confidence interval, 95% CI: 1.45-1.85) (95% prediction interval: 0.66-4.10, I-2 = 98.1%)]. Odds for men and women living with HIV were 1.68 [(95% CI: 1.44-1.95) (95% prediction interval: 0.71-3.98, I-2 = 91.1%)] and 2.16 [(95% CI: 1.77-2.63) (95% prediction interval: 0.92-5.07, I-2 = 81.7%)] respectively. Conclusion: PLH are more likely to be smokers than people without HIV. This finding was true in subgroup analyses of men, women and in four of five WHO regions from which data were available. Meta-regression did not explain heterogeneity, which we attribute to the diversity of PLH populations worldwide. Smoking is a barrier to PLH achieving parity in life expectancy and an important covariate in studies of HIV-associated multimorbidity.

Enteric (typhoid) fever remains a problem in low- and middle-income countries that lack the infrastructure to maintain sanitation and where inadequate diagnostic methods have restricted our ability to identify and control the disease more effectively. As we move into a period of potential disease elimination through the introduction of typhoid conjugate vaccine (TCV), we again need to reconsider the role of typhoid diagnostics in how they can aid in facilitating disease control. Recent technological advances, including serology, transcriptomics, and metabolomics, have provided new insights into how we can detect signatures of invasive Salmonella organisms interacting with the host during infection. Many of these new techniques exhibit potential that could be further explored with the aim of creating a new enteric fever diagnostic to work in conjunction with TCV. We need a sustained effort within the enteric fever field to accelerate, validate, and ultimately introduce 1 (or more) of these methods to facilitate the disease control initiative. The window of opportunity is still open, but we need to recognize the need for communication with other research areas and commercial organizations to assist in the progression of these diagnostic approaches. The elimination of enteric fever is now becoming a real possibility, but new diagnostics need to be part of the equation and factored into future calculations for disease control.