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Highlights • ATRA increased vaccine specific IgA in gut secretions to Vivotif but not Dukoral or Rotarix. • ATRA increased α4β7 and CCR9 gut marker expression in a coordinated manner only when given simultaneously with Vivotif vaccine. • In individuals with coordinated gut marker expression Vivotif specific IgA increase was much stronger., All-trans retinoic acid (ATRA) up-regulates, in laboratory animals, the expression of the gut homing markers α4β7 integrin and CCR9 on lymphocytes, increasing their gut tropism. Here, we show that, in healthy adult volunteers, ATRA induced an increase of these gut homing markers on T cells in vivo in a time dependent manner. The coordinated increase of α4β7 and CCR9 by ATRA was seen in 57% (12/21) of volunteers and only when given together with an oral Vivotif vaccine. When this coordinated response to ATRA and Vivotif vaccine was present, it was strongly correlated with the gut immunoglobulin A (IgA) specific response to vaccine LPS (ρ = 0.82; P = 0.02). Using RNA-Seq analysis of whole blood transcription, patients receiving ATRA and Vivotif in conjunction showed transcriptomic changes in immune-related pathways, particularly including interferon α/β signaling pathway, membrane-ECM interactions and immune hubs. These results suggest that exogenous ATRA can be used to manipulate responses to a subclass of oral vaccines, so far limited to a live attenuated Vivotif vaccine.

Summary There is an urgent need to identify ways of enhancing the mucosal immune response to oral vaccines. Rotavirus vaccine protection is much lower in Africa and Asia than in industrialized countries, and no oral vaccine has efficacy approaching the best systemic vaccines. All-trans retinoic acid (ATRA) up-regulates expression of α4β7 integrin and CCR9 on lymphocytes in laboratory animals, increasing their gut tropism. The aim of this study was to establish the feasibility of using ATRA as an oral adjuvant for oral typhoid vaccination. In order to establish that standard doses of oral ATRA can achieve serum concentrations greater than 10 nmol/l, we measured ATRA, 9-cis and 13-cis retinoic acid in serum of 14 male volunteers before and 3 h after 10 mg ATRA. We then evaluated the effect of 10 mg ATRA given 1 h before, and for 7 days following, oral typhoid vaccine in eight men, and in 24 men given various control interventions. We measured immunoglobulin (Ig)A directed against lipopolysaccharide (LPS)and protein preparations of vaccine antigens in whole gut lavage fluid (WGLF) and both IgA and IgG in serum, 1 day prior to vaccination and on day 14. Median [interquartile range (IQR)] Cmax was 26·2 (11·7–39·5) nmol/l, with no evidence of cumulation over 8 days. No adverse events were observed. Specific IgA responses to LPS (P = 0·02) and protein (P = 0·04) were enhanced in WGLF, but no effect was seen on IgA or IgG in serum. ATRA was well absorbed, well tolerated and may be a promising candidate oral adjuvant.

Epidemics of jaundice, characterized by a high mortality rate in pregnant women, have been recorded for >200 years [1]. The causative virus of this form of non-A, non-B hepatitis was recognized in 1983 to be hepatitis E virus (HEV), a nonenveloped, single-stranded RNA virus that has only 1 serotype but 4 major genotypes [2]. It is one of the leading causes of hepatitis globally, and epidemics can be very large with 29 300 cases recorded in Delhi in 1954–1955 [1]. Throughout the developing world, case fatality rates of up to 73% in pregnancy have been recorded, although the highest figures derived from hospital records probably reflect selection bias toward the most severe cases. Incidence rates in the developing world are hard to estimate, but one study in Bangladesh calculated the rate at 60.3 per 1000 person-years [3]. More recently, the development of chronic hepatitis linked to HEV infection has been described in immunosuppressed patients [4–6]. These studies report a persistence of HEV RNA as well as progression of liver inflammation and fibrosis with HEV-related cirrhosis also being described. Such infections were initially reported in the transplant setting but have now also been observed in hematological patients receiving chemotherapy and in patients infected with human immunodeficiency virus (HIV). As areas of high HIV prevalence overlap widely with regions where HEV is common, the potential for coinfection will be high, which may lead to the emergence of comorbidity. This will be of particular significance in the developing world, which bears the brunt of the HIV pandemic. However, there are few data on HEV epidemiology in African populations and this area remains poorly investigated. Transmission of HEV in the developing world is fecal-oral as with hepatitis A virus, but unlike hepatitis A virus infection, antibody levels wane over time. Whether this reflects imperfect serological tests or a genuine difference in the immune response is uncertain, but there is some evidence that early childhood infection does not protect against reinfection in adulthood [2]. Transmission of HEV through the developing world is via the fecal-oral route linked to contaminated food and water. We have previously reported that tropical enteropathy shows strong evidence of environmental causation, with pronounced seasonal effects and relationships to poor housing and asymptomatic intestinal carriage of pathogens [7]. We now refer to this phenomenon as environmental enteropathy [8], as it is not exclusive to the tropics and there are tropical populations (such as Qatar and Singapore) where it is not found [9]. We set out to investigate the seroepidemiology of HEV infection in both children and adults from a poor township of Lusaka, Zambia. Additional analyses were undertaken to explore associations between HEV and HIV infection and also with environmental enteropathy.

Background: Gastric cancer is increasingly recognized in Zambia. Although nutritional factors contribute to gastric cancer risk, their effect in Zambia is unknown. Objective: The objective was to investigate the association between intake of dietary antioxidants, urinary 8-iso prostaglandin F2α (8-iso PGF2α) as a marker of oxidative stress, and gastric cancer. Design: This was a case-control study at the University Teaching Hospital in Zambia. Gastric cancer cases were compared with age- and sex-matched controls. Urine 8-iso PGF2α was measured primarily by ELISA, and by gas chromatography–mass spectrometry in a subset, expressed as a ratio to creatinine. Blood was collected for Helicobacter pylori, HIV serology, gastrin-17, and pepsinogen 1 and 2 concentrations. Clinical and dietary data were collected by using questionnaires. Food items were broadly classified into 7 major categories (fruit, vegetables, fish, meat, insects, cereals, and starches). Results: Fifty cases with gastric cancer (mean age: 61 y; n = 31 males) and 90 controls (mean age: 54 y; n = 41 males) were enrolled. Median urinary 8-iso PGF2α excretion was higher in cases (0.014; IQR: 0.008–0.021) than in controls (0.011; IQR: 0.006–0.018; P = 0.039). On univariate analysis, habitual fruit intake was lower in cases than in controls during the dry season (P = 0.02). On multivariate analysis, smoking (OR: 7.22; IQR: 1.38–37.9) and gastric atrophy (OR: 2.43; IQR: 1.12–5.13) were independently associated with cancer, and higher fruit intake was protective (OR: 0.44; IQR: 0.20–0.95). Isoprostane excretion was inversely correlated with total fruit intake (ρ = −0.23; n = 140; P = 0.006). Conclusion: Urinary 8-iso PGF2α excretion was associated with the risk of gastric cancer, as were smoking and gastric atrophy, but increased fruit intake conferred protection. This trial was registered at www.pactr.org as ISRCTN52971746.

Despite the heavy burden of diarrhoeal disease across much of the tropical world, only two diarrhoea-causing pathogens, cholera and rotavirus, are the target of commercially available vaccines. Oral vaccines are generally less immunogenic than the best parenteral vaccines, but the reasons for this are still debated. Over the past decade, several lines of evidence from work in experimental animals have suggested that all- trans retinoic acid (ATRA), a form of vitamin A which is highly transcriptionally active, can alter the homing receptor expression of T lymphocytes. Increased expression of α4β7 integrin and the chemokine receptor CCR9 following exposure to ATRA can be used to redirect T cells to the gut. Early work in human volunteers suggests that oral ATRA administration 1 h prior to dosing with oral typhoid vaccine can augment secretion of specific IgA against vaccine-derived lipopolysaccharide into gut secretions. In this review, we set out the rationale for using ATRA in this way and assess its likely applicability to vaccination programmes for protection of children in low-income countries from the considerable mortality caused by diarrhoeal disease. Comparison of recent work in experimental animals, non-human primates and men suggests that a more detailed understanding of ATRA dosage and kinetics will be important to taking forward translational work into human vaccinology.

BACKGROUND: Complex biomedical research can lead to disquiet in communities with limited exposure to scientific discussions, leading to rumours or to high drop-out rates. We set out to test an intervention designed to address apprehensions commonly encountered in a community where literacy is uncommon, and where complex biomedical research has been conducted for over a decade. We aimed to determine if it could improve the validity of consent. METHODS: Data were collected using focus group discussions, key informant interviews and observations. We designed an intervention that exposed participants to a detailed demonstration of laboratory processes. Each group was interviewed twice in a day, before and after exposure to the intervention in order to assess changes in their views. RESULTS: Factors that motivated people to participate in invasive biomedical research included a desire to stay healthy because of the screening during the recruitment process, regular advice from doctors, free medical services, and trust in the researchers. Inhibiting factors were limited knowledge about samples taken from their bodies during endoscopic procedures, the impact of endoscopy on the function of internal organs, and concerns about the use of biomedical samples. The belief that blood can be used for Satanic practices also created insecurities about drawing of blood samples. Further inhibiting factors included a fear of being labelled as HIV positive if known to consult heath workers repeatedly, and gender inequality. Concerns about the use and storage of blood and tissue samples were overcome by a laboratory exposure intervention. CONCLUSION: Selecting a group of members from target community and engaging them in a laboratory exposure intervention could be a useful tool for enhancing specific aspects of consent for biomedical research. Further work is needed to determine the extent to which improved understanding permeates beyond the immediate group participating in the intervention.

Background . Gastric cancer is a leading cause of cancer deaths worldwide but there are few data from Africa. We recently observed a trend towards diagnosis in younger patients. Objective. To test the hypothesis that HIV might have altered risk factors for acquisition of gastric cancer, in a case-control study in the University Teaching Hospital, Lusaka, Zambia. Methods . Patients (n=52) with confirmed gastric adenocarcinoma and controls (n=94) undergoing endoscopy but with no macroscopic gastric pathology. Established risk factors and HIV status were compared. Results . HIV status did not differ significantly between cases and controls (odds ratio 1.03; 95% CI 0.2 - 4.3; p=1.00) and seroprevalence in cases was similar to that of the Zambian population. Smoking, regular alcohol intake, and gastric atrophy were all associated with cancer in univariate and multivariate analysis. Helicobacter pylori serology was positive in 84% of patients studied and cytotoxin-associated gene A (cagA) serology in 66%; neither serological marker was associated with cancer. Atrophy was common in cases (57%) and controls (30%) and associated with both smoking and alcohol use. Intestinal metaplasia was present in 17% of the controls, but was not associated with atrophy. Conclusions . HIV was not associated with gastric cancer and does not explain the apparent younger age distribution. Atrophy was common and was not essential for the development of intestinal metaplasia, suggesting that gastric carcinogenesis in Africa does not always follow the pathway from atrophy to intestinal metaplasia to gastric carcinoma (the so-called Correa pathway).

AIM: To identify risk factors associated with esophageal cancer in Zambia and association between dietary intake and urinary 8-iso prostaglandin F2α (8-isoPGF2α). METHODS: We conducted a prospective, case control study at the University Teaching Hospital. Subjects included both individuals admitted to the hospital and those presenting for an outpatient upper endoscopy. Esophageal cancer cases were compared to age and sex-matched controls. Cases were defined as patients with biopsy proven esophageal cancer; controls were defined as subjects without endoscopic evidence of esophageal cancer. Clinical and dietary data were collected using a standard questionnaire, developed a priori. Blood was collected for human immunodeficiency virus (HIV) serology. Urine was collected, and 8-isoPGF2α was measured primarily by enzyme-linked immunosorbent assay and expressed as a ratio to creatinine. RESULTS: Forty five controls (mean age 54.2 ± 15.3, 31 male) and 27 cases (mean age 54.6 ± 16.4, 17 males) were studied. Body mass index was lower in cases (median 16.8) than controls (median 23.2), P = 0.01. Histopathologically, 25/27 (93%) were squamous cell carcinoma and 2/27 (7%) adenocarcinoma. More cases smoked cigarettes (OR = 11.24, 95%CI: 1.37-92.4, P = 0.02) but alcohol consumption and HIV seropositivity did not differ significantly (P = 0.14 for both). Fruit, vegetables and fish consumption did not differ significantly between groups (P = 0.11, 0.12, and 0.10, respectively). Mean isoprostane level was significantly higher in cases (0.03 ng/mg creatinine) than controls (0.01 ng/mg creatinine) (OR = 2.35, 95%CI: 1.19-4.65, P = 0.014). CONCLUSION: Smoking and isoprostane levels were significantly associated with esophageal cancer in Zambians, but diet, HIV status, and alcohol consumption were not.