ABSTRACT
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 α4ß7 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)] C(max) 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.
Subject(s)
Adjuvants, Immunologic , Immunity, Mucosal/immunology , Tretinoin/immunology , Typhoid-Paratyphoid Vaccines/immunology , Administration, Oral , Adult , Antibodies, Bacterial/immunology , Humans , Immunoglobulin A, Secretory/immunology , Intestinal Mucosa/immunology , Male , Middle Aged , Tretinoin/administration & dosage , Tretinoin/pharmacokinetics , Typhoid-Paratyphoid Vaccines/administration & dosage , Young Adult , ZambiaABSTRACT
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 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).
