Sari H. Pakkanen

Antimicrobials Increase Travelers' Risk of Colonization by Extended-Spectrum Betalactamase-Producing Enterobacteriaceae

Colonized travelers contribute to the pandemic spread of resistant intestinal bacteria. This study is the first to show that antimicrobial use during travel predisposes to colonization by intestinal extended-spectrum beta-lactamase-producing Enterobacteriaceae. Travelers refrain from taking unnecessary antibiotics.

Cross-reactive gut-directed immune response against Salmonella enterica serovar Paratyphi A and B in typhoid fever and after oral Ty21a typhoid vaccination.

BACKGROUND There are no vaccines against paratyphoid fever in clinical use. The disease has become more wide-spread and there is a growing problem of antibiotic resistance among the strains. Previous reports suggest that the oral live Salmonella Typhi Ty21a-vaccine confers protection against paratyphoid B fever. Data on efficacy against paratyphoid A fever are somewhat contentious. The present study investigated the immunological basis for such efficacy reports at a single-cell level: plasmablasts (identified as antibody-secreting cells, ASC) were studied for secretion of antibodies cross-reactive with Salmonella Paratyphi in the circulation of patients with enteric fever and of volunteers vaccinated with Ty21a. MATERIALS AND METHODS Thirty volunteers immunized with Ty21a and five patients with enteric fever were investigated for Salmonella Typhi and Salmonella Paratyphi A/B/C-specific circulating plasmablasts. PBMC were sorted by their expression of homing receptors (HR) for the intestine (α4β7), peripheral lymph node (l-selectin) and skin (CLA) and typhoid- and paratyphoid-specific plasmablasts were enumerated with ELISPOT. RESULTS Before vaccination, no cross-reactive ASC were found in the volunteers. In addition to the Salmonella Typhi-specific response, a significant cross-reactive immune response was mounted against Salmonella Paratyphi A and B both in the patients and the vaccinees. The magnitude of the response increased in the order Salmonella Paratyphi A (median 30 ASC/10(6) PBMC)→Salmonella Paratyphi B (median 81)→Salmonella Typhi (median 301) in the vaccinees. Both in patients and in vaccinees, the homing receptor (HR) selection favored homing to the gut, indicating a humoral intestinal immune response. CONCLUSIONS These immunological data provide evidence consistent with previous reports describing certain levels of cross-protective efficacy of Ty21a against paratyphoid fever. Controlled studies are needed to evaluate cross-protective efficacy. In the current situation where paratyphoid fever is emerging and no vaccines are available, any level of cross-protective capacity is valuable.

Expression of Homing Receptors on IgA1 and IgA2 Plasmablasts in Blood Reflects Differential Distribution of IgA1 and IgA2 in Various Body Fluids

ABSTRACT Although secretory IgA is the most abundantly produced Ig isotype, the mechanisms underlying the differential distribution of IgA subclasses in various body fluids remain unclear. To explore these mechanisms, we examined the distribution of IgA subclasses, the influence of the nature and sites of encounters with antigens, and the correlation between IgA subclass distribution and homing potentials of circulating IgA plasmablasts. IgA1 predominated in serum, tears, nasal wash fluid, and saliva; the levels of IgA1 and IgA2 were comparable in vaginal wash fluid; and IgA2 predominated in intestinal lavage fluids. Seventy-one percent of circulating IgA plasmablasts secreted IgA1. The intestinal homing receptor (HR), α4β7, was expressed more frequently on IgA2 than on IgA1 plasmablasts, with no differences in the expression of other HRs. IgA subclass distribution among circulating antigen-specific antibody-secreting cells (ASC) was dependent on the nature of the antigen: following vaccination with Salmonella enterica serovar Typhi, unconjugated pneumococcal polysaccharide, or Haemophilus influenzae polysaccharide-diphtheria toxoid conjugate, the proportions of specific IgA1 ASC were 74%, 47%, 56%, and 80%, respectively. HR expression depended on the route of administration: expression of HRs was different after oral than after parenteral vaccination, while no difference was seen between HR expression of antigen-specific IgA1 and IgA2 ASC induced via the same route. The key factors determining IgA subclass distribution in a given secretion are the nature of the antigens encountered at a particular site and the site-specific homing instructions given to lymphocytes at that site. These two factors are reflected as differences in the homing profiles of the total populations of circulating IgA1 and IgA2 plasmablasts.

A Single Dose of Vero Cell–Derived Japanese Encephalitis (JE) Vaccine (Ixiaro) Effectively Boosts Immunity in Travelers Primed With Mouse Brain–Derived JE Vaccines

The new Japanese encephalitis vaccine (JE-VC, Ixiaro) has replaced mouse brain–derived vaccines (JE-MB) associated with serious safety concerns. A single dose of JE-VC effectively boosted immunity in JE-MB–primed travelers. Current recommendations for booster vaccination should be reevaluated.

Head-to-head comparison of humoral immune responses to Vi capsular polysaccharide and Salmonella Typhi Ty21a typhoid vaccines--a randomized trial.

Background The two typhoid vaccines, the parenteral Vi capsular polysaccharide and the oral live whole-cell Salmonella Typhi Ty21a vaccine, provide similar levels of protection in field trials. Sharing no antigens, they are thought to confer protection by different mechanisms. This is the first head-to-head study to compare the humoral immune responses to these two vaccines. Methods 50 age- and gender-matched volunteers were immunized, 25 with the Vi and 25 with the Ty21a vaccine. Circulating plasmablasts reactive with whole-cell Salmonella Typhi or one of the typhoidal antigenic structures, Vi, O-9,12, and H-d antigens, were identified as antibody-secreting cells (ASC) with ELISPOT. Homing receptor (HR) expressions were determined. These results were compared with ASC in four patients with typhoid fever. Antibodies to S. Typhi lipopolysaccharides were assessed in cultures of ALS (antibodies in lymphocyte supernatants) and in serum with ELISA. Results In 49 out of 50 vaccinees, no typhoid-specific plasmablasts were seen before vaccination. On day 7, response to Vi antigen was mounted in 24/25 volunteers in the Vi, and none in the Ty21a group; response to S. Typhi and O-9,12 was mounted in 49/50 vaccinees; and to H-d in 3/50. The numbers of typhoid-specific plasmablasts (total of ASC to Vi, O-9,12 and H-d antigens) proved equal in the vaccination groups. The HR expressions indicated a mainly systemic homing in the Vi and intestinal in the Ty21a group, the latter resembling that in natural infection. Plasmablasts proved more sensitive than serum and ALS in assessing the immune response. Conclusions The typhoid-specific humoral responses to Vi and Ty21a vaccines are similar in magnitude, but differ in expected localization and antigen-specificity. The unforeseen O antigen-specific response in the Vi group is probably due to lipopolysaccharide contaminating the vaccine preparation. Only the response to Ty21a vaccine was found to imitate that in natural infection. Trial Registration Current Controlled Trials Ltd. c/o BioMed Central ISRCTN68125331

Live oral typhoid vaccine Salmonella Typhi Ty21a - A surrogate vaccine against non-typhoid salmonella?

BACKGROUND Non-typhoid Salmonella (NTS) is a leading cause of food-borne illness with more than 90 million annual cases and an emerging antimicrobial resistance among the strains worldwide. Paradoxically, no vaccines are available against these pathogens. Numerous NTS strains share surface O-antigens with Salmonella enterica serotype Typhi. As intestinal antibodies against O-antigens have proven protective against NTS in animal experiments, it appears conceivable that the oral whole-cell typhoid vaccine, Salmonella Typhi Ty21a (Vivotif(®)), which effectively elicits intestinal antibodies against O-antigens, could exhibit cross-protective efficacy against NTS. We sought immunological evidence in support of cross-protective efficacy of Ty21a against NTS. MATERIALS AND METHODS 35 volunteers receiving Ty21a vaccine and five patients with enteric fever were investigated with ELISPOT for circulating plasmablasts secreting antibodies reactive with Salmonella Typhi and six different NTS serotypes. These plasmablasts were also analysed for homing receptor expressions. RESULTS In all vaccinees and patients, a strong gut-directed cross-reactive plasmablast response was found against serotypes sharing the two O-antigens with Salmonella Typhi (O-9,12) (in vaccinees, mean: 95%CI 268: 228-508 and 363: 234-493 plasmablasts/10(6)PBMC against Salmonella Typhi and Enteritidis). Responses against strains sharing one O-antigen (O-12) were weaker (222: 105-338 against Salmonella Typhimurium), while no significant reactivity was detected against strains without typhoidal O-antigens. CONCLUSIONS Intestinal antibodies against O-antigens protect against NTS in animal experiments. Ty21a was found to elicit intestinal immune responses cross-reactive with NTS strains sharing O-antigens with Ty21a. These include the most common NTS, Salmonella Enteritidis and Typhimurium. The data suggest that Ty21a may have cross-protective efficacy against numerous NTS strains.

High number of diarrhoeal co-infections in travellers to Benin, West Africa

BackgroundTravellers’ diarrhoea (TD) is the most frequent health problem among travellers to the tropics. Using routine techniques, the aetiology mostly remains unresolved, whereas modern molecular methods enable reducing the number of equivocal cases considerably. While many studies address the aetiology of TD in Asian, Central American and North African tourist resorts, only few focus on Western Africa.MethodsStool samples from 45 travellers travelling in Benin, West Africa, were analyzed by a new multiplex qPCR assay for Salmonella, Yersinia, Campylobacter, Vibrio cholerae, Shigella or enteroinvasive (EIEC), enterohaemorrhagic (EHEC), enterotoxigenic (ETEC), enteroaggregative (EAEC), and enteropathogenic Escherichia coli (EPEC).ResultsAll 18 pre-travel samples proved negative for bacterial pathogens. Of the 39/45 (87%) travellers having had TD, EPEC was detected in post-travel samples in 30 (77%) cases, EAEC in 23 (59%), ETEC in 22 (56%), Shigella or EIEC in 7 (18%), EHEC in two (5%), and Salmonella in one (3%). In 31(79%) of the TD cases two or more bacterial pathogens were identified. Two (8%) samples remained negative: both patients had taken antimicrobials for TD.ConclusionsEPEC, EAEC and ETEC were the most common findings. 79% of the cases had a co-infection. As modern diagnostics reveals in most patients a multitude of pathogens, the role of each pathogen should be re-evaluated.

Immunosuppression Adversely Affects TST but Not IGRAs in Patients with Psoriasis or Inflammatory Musculoskeletal Diseases

The performance of the interferon gamma release assays (IGRAs) and tuberculin skin test (TST) was reviewed retrospectively in patients with psoriasis, inflammatory musculoskeletal diseases, or miscellaneous inflammatory conditions. The study was carried out over a 22-month period using 109 records of patients with psoriasis (n = 21), musculoskeletal disease (n = 74), or other inflammatory conditions (n = 14). Forty-four (48%) of 109 patients were on immunosuppressive therapy and 38/109 (35%) on systemic glucocorticoid therapy. The agreement between the IGRAs was substantial (κ = 0.71) whilst that between the IGRAs and TST was low (κ = 0.32). Logistic regression models revealed that IGRAs associated with risk factors for latent tuberculosis infection better than TST. TST was influenced by age, BCG vaccination, sex, and glucocorticoid therapy. We found that IGRAs performed equally well with low level of indeterminate results (1-2%). IGRAs were superior to TST because the latter was influenced by BCG-vaccination status and immunosuppressive therapy.

T-helper Cell-Mediated Proliferation and Cytokine Responses against Recombinant Merkel Cell Polyomavirus-Like Particles

The newly discovered Merkel Cell Polyomavirus (MCPyV) resides in approximately 80% of Merkel cell carcinomas (MCC). Causal role of MCPyV for this rare and aggressive skin cancer is suggested by monoclonal integration and truncation of large T (LT) viral antigen in MCC cells. The mutated MCPyV has recently been found in highly purified leukemic cells from patients with chronic lymphocytic leukemia (CLL), suggesting a pathogenic role also in CLL. About 50–80% of adults display MCPyV-specific antibodies. The humoral immunity does not protect against the development of MCC, as neutralizing MCPyV antibodies occur in higher levels among MCC patients than healthy controls. Impaired T-cell immunity has been linked with aggressive MCC behavior. Therefore, cellular immunity appears to be important in MCPyV infection surveillance. In order to elucidate the role of MCPyV-specific Th-cell immunity, peripheral blood mononuclear cells (PBMC) of healthy adults were stimulated with MCPyV VP1 virus-like particles (VLPs), using human bocavirus (HBoV) VLPs and Candida albicans antigen as positive controls. Proliferation, IFN-γ, IL-13 and IL-10 responses were examined in 15 MCPyV-seropositive and 15 seronegative volunteers. With the MCPyV antigen, significantly stronger Th-cell responses were found in MCPyV-seropositive than MCPyV-seronegative subjects, whereas with the control antigens, the responses were statistically similar. The most readily detectable cytokine was IFN-γ. The MCPyV antigen tended to induce stronger IFN-γ responses than HBoV VLP antigen. Taken together, MCPyV-specific Th-cells elicit vigorous IFN-γ responses. IFN-γ being a cytokine with major antiviral and tumor suppressing functions, Th-cells are suggested to be important mediators of MCPyV-specific immune surveillance.

Cross-reactive immune response induced by the Vi capsular polysaccharide typhoid vaccine against Salmonella Paratyphi strains.

There are no vaccines in clinical use against paratyphoid fever, caused by Salmonella Paratyphi A and B or, rarely, C. Oral Salmonella Typhi Ty21a typhoid vaccine elicits a significant cross‐reactive immune response against S. Paratyphi A and B, and some reports suggest cross‐protective efficacy against the disease. These findings are ascribed to the O‐12 antigen shared between the strains. The Vi capsular polysaccharide vaccine has been shown to elicit antibodies reactive with O‐9,12. Twenty‐five volunteers immunized with the parenteral Vi vaccine (Typherix®) were explored for plasmablasts cross‐reactive with paratyphoid strains; the responses were compared to those in 25 age‐ and gender‐matched volunteers immunized with Ty21a (Vivotif®). Before vaccination, 48/50 vaccinees had no plasmablasts reactive with the antigens. Seven days after vaccination, 15/25 and 22/25 Vi‐ and Ty21a‐vaccinated volunteers had circulating plasmablasts producing antibodies cross‐reactive with S. Paratyphi A, 18/25 and 23/25 with S. Paratyphi B and 16/25 and 9/25 with Paratyphi C, respectively. Compared to the Ty21a group, the Vi group showed significantly lower responses to S. Paratyphi A and B and higher to S. Paratyphi C. To conclude, the Vi vaccine elicited a cross‐reactive plasmablast response to S. Paratyphi C (Vi antigen in common) and less marked responses to S. Paratyphi A and B than the Ty21a preparation. S. Paratyphi A and B both being Vi‐negative, the result can be explained by trace amounts of bacterial cell wall O‐12 antigen in the Vi preparation, despite purification. The clinical significance of this finding remains to be determined.