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IntroductionEven though hepatitis B is endemic in the Lao PDR, the understanding of the epidemiology of hepatitis B infection is incomplete. This article reviews the available literature about hepatitis B seroprevalence, risk factors and genotypes in the Lao population in order to provide an up- to date summary of the HBV epidemiology in the Lao PDR, identify knowledge gaps and provide public health recommendations.MethodsUsing PubMed/Medline and ScienceDirect, all studies reporting the prevalence of hepatitis B markers or genotype distribution in the Lao PDR published were systematically reviewed.ResultsThe 21 studies included focused on the general population, blood donors, women, children, health care workers and garment factory workers. The studies varied extensively in sample size, target population, methods, study location and time periods. The prevalence of the hepatitis B surface antigen (HBsAg) in blood donors was reported to be 8.7%-9.6% in 2003-2006. In the years 2011-2012, the reported HBsAg prevalence among women (including pregnant women) ranged from 0%-9.5% and among children aged 5-9 years from 1.7%-8.7%, depending on study location and age. The majority of strains characterized in Lao PDR belonged to genotypes B and C.ConclusionStudies displayed considerable heterogeneity in populations, design and laboratory methods. A high HBsAg prevalence was reported in adults including pregnant women. Low infant vaccination coverage and compromised vaccine immunogenicity were found. Only two studies focused on HBV in risk populations, emphasizing the need for further studies to characterize hepatitis B epidemiology in potentially vulnerable groups. Hepatitis B infection continues to represent a substantial public health threat in the Lao PDR and needs to be monitored to inform health authorities and to counteract over-burdening of the health care system. In order to end mother to child transmission, vaccination coverage with the hepatitis B birth dose should be increased.

The epidemiology of typhoid fever in Lao People`s Democratic Republic is poorly defined. Estimating the burden of typhoid fever in endemic countries is complex due to the cost and limitations of population-based surveillance; serological approaches may be a more cost-effective alternative. ELISAs were performed on 937 serum samples (317 children and 620 adults) from across Lao PDR to measure IgG antibody titers against Vi polysaccharide and the experimental protein antigens, CdtB and HlyE. We measured the significance of the differences between antibody titers in adults and children and fitted models to assess the relationship between age and antibody titers. The median IgG titres of both anti-HylE and CdtB were significantly higher in children compared to adults (anti-HylE; 351.7 ELISA Units (EU) vs 198.1 EU, respectively; p, Author summary Typhoid fever is a serious bloodstream infection caused by the bacterium Salmonella Typhi. Estimating the burden of typhoid fever is complex due to the limitations, cost, and scalability of current diagnostic surveillance methods. The detection of specific antibody responses against the organism may be a more sustainable manner of measuring exposure and disease burden in endemic location. We measured antibody (IgG) in 937 serum samples (317 children and 620 adults) from across the Lao People`s Democratic Republic against a polysaccharide (Vi) and two experimental protein antigens, CdtB and HlyE, that may more appropriate markers of disease exposure. We measured the significance of the differences between antibody titers in adults and children and fitted models to assess the relationship between age and antibody titers. The median IgG titres against HylE and CdtB were significantly higher in children than adults. Conversely, the median IgG titres against Vi was significantly higher in adults than children. We identified a significant association between a peak in IgG titres against CdtB and HlyE in children aged under 5 years. These data are indicative of high level of typhoid fever exposure in children under 5 years of age in Lao PDR and we surmise that IgG titres against HylE and CdtB may be a superior measure of typhoid disease burden than IgG titres against Vi. Our approach is scalable and can be further validated to assess the burden of typhoid fever in countries where the disease may be endemic, and evidence is required for the introduction of typhoid vaccines.

Introduction Hepatitis B is endemic in Lao PDR and about 9% of the adult population is chronically infected. In this study, we investigated regional, occupational, age and sex-related differences in hepatitis B epidemiology in Lao blood donors. Methods 5017 voluntary blood donors from 8 different provinces were tested for hepatitis B markers by ELISA. Predictors for the prevalence of hepatitis B surface antigen (HBsAg) and antibodies against the core antigen (anti-HBc) were assessed by bivariate and multivariable analyses. Results In total, 41% of the participants were positive for anti-HBc; the HBsAg prevalence was estimated at 6.9% among all participants (9.2% among first-time donors and 3.9% among repeat donors). Among first-time donors, HBsAg positivity was associated independently with being male (p Conclusion In conclusion, our study confirmed an overall high HBsAg and anti-HBc prevalence in Lao PDR, albeit with considerable regional variation. The identification of a sizeable number of HBsAg positives among repeat donors warrants a thorough investigation of current blood screening, record keeping, donor identification and counselling practises.

Objectives: Hepatitis B is endemic in Lao PDR with 8–10% of the adult population being chronically infected. We investigated the impact of hepatitis B vaccination on infection in adolescents born shortly before and after the introduction of the vaccine in 2001. Methods: 779 students from Vientiane Capital and Bolikhamxay province were tested for HBV markers by ELISA. Socio-demographic information was collected with a standardized questionnaire. Predictors/risk factors for seroprotection or exposure to hepatitis B infection were assessed by bivariate and multivariable analyses. Results: The prevalence of a serological vaccination profile increased significantly after the introduction of the vaccine (13.2%–21.9%, p < 0.05, in Vientiane; 3.0%–19.7%, p < 0.001, in Bolikhamxay), which translated into at least a 2-times lower prevalence of past infection. In logistic regression, older students in Bolikhamxay were less likely to be vaccinated and more likely to have been infected by HBV in the past. Conclusion: Even though this study documented a sizable and lasting reduction in past hepatitis B infections in adolescents born after the introduction of infant hepatitis B vaccination, the overall levels of protective anti-HBs were low and warrant at least the introduction of a booster for adolescents. Furthermore, we suggest improving the coverage of the hepatitis B birth dose. Keywords: Hepatitis B, Vaccine-preventable diseases, Vaccination coverage, Lao PDR, Epidemiology, Public health

Background The timely administration of vaccines is considered to be important for both individual and herd immunity. In this study, we investigated the timeliness of the diphtheria-tetanus-whole cell pertussis-hepatitis B-Haemophilus influenzae type b (pentavalent) vaccine, scheduled at 6, 10 and 14 weeks of age in the Lao People’s Democratic Republic. We also investigated factors associated with delayed immunization. Methods 1162 children aged 8–28 months who had received the full course of the pentavalent vaccine at different levels of the health care system were enrolled. Vaccination dates documented in hospital records and/or immunisation cards were recorded. Age at vaccination and time intervals between doses were calculated. Predictors for timely completion with the pentavalent vaccine at 24 weeks were assessed by bivariate and multivariable analyses. Results Several discrepancies in dates between vaccination documents were observed. In general, vaccination with the pentavalent vaccine was found to be delayed, especially in health care settings below the provincial hospital level. Compared to the central hospital level, less participants who were vaccinated at the district/health center level received the third dose by 16 (48% at the central hospital level vs. 7.1% at the district and 12.4% at the health center level) and 24 weeks of age (94.4% at the central hospital level vs 64.6% at the district-outreach and 57.4% at the health center level) respectively. In logistic regression analyses, lower education level of the mother as well as vaccination by outreach service, were independently associated with delayed completion of vaccination. Conclusion We observed a general delay of vaccination, especially at lower ranked facilities, which correlated with indicators of poor access to health services. This highlights the need for further improving health equity in rural areas. Age-appropriate vaccination should become a quality indicator for the national immunization programme. In addition, we recommend further training of the health care staff regarding the importance of reliable documentation of dates.

Temporal changes in the GII.4 human norovirus capsid sequences occasionally result in the emergence of genetic variants capable of causing new epidemics. The GII.4 persistence is believed to be associated with the recognition of numerous histo-blood group antigen (HBGA) types and antigenic drift. We found that one of the earliest known GII.4 isolate (1974) and a more recent epidemic GII.4 variant (2012) had varied norovirus-specific monoclonal antibody (MAb) reactivities, yet similar HBGA binding profiles. To better understand the binding interaction of one MAb (10E9) that had varied reactivities with these GII.4 variants, we determined the X-ray crystal structure of the NSW-2012 GII.4 P domain 10E9 Fab complex. We showed that the 10E9 Fab interacted with conserved and variable residues, which could be associated with antigenic drift. Interestingly, the 10E9 Fab binding pocket partially overlapped the HBGA pocket and had direct competition for conserved HBGA binding residues (i.e., Arg345 and Tyr444). Indeed, the 10E9 MAb blocked norovirus VLPs from binding to several sources of HBGAs. Moreover, the 10E9 antibody completely abolished virus replication in the human norovirus intestinal enteroid cell culture system. Our new findings provide first direct evidence that competition for GII.4 HBGA binding residues and steric obstruction could lead to norovirus neutralization. On the other hand, the 10E9 MAb recognized residues flanking the HBGA pocket, which are often substituted as the virus evolves. This mechanism of antigenic drift likely influences herd immunity and impedes the possibility of acquiring broadly reactive HBGA-blocking antibodies. IMPORTANCE The emergence of new epidemic GII.4 variants is thought to be associated with changes in antigenicity and HBGA binding capacity. Here, we show that HBGA binding profiles remain unchanged between 1974 and 2012 GII.4 variants, whereas these variants showed varying levels of reactivities against a panel of GII.4 MAbs. We identified a MAb that bound at the HBGA pocket and blocked norovirus VLPs from binding to HBGAs and neutralized norovirus virions in the cell culture system. Raised against GII.4 2006 strain this MAb was unreactive to GII.4 1987 isolate, but was able to neutralize newer 2012 strain, which has important implications for vaccine design. Altogether, these new findings suggested that the amino acid variations surrounding HBGA pocket lead to temporal changes in antigenicity without affecting the ability of GII.4 variants to bind HBGAs, which are known co-factors for infection.

Temporal changes in the GII.4 human norovirus capsid sequences occasionally result in the emergence of genetic variants capable of causing new epidemics. The persistence of GII.4 is believed to be associated with the recognition of numerous histo-blood group antigen (HBGA) types and antigenic drift. We found that one of the earliest known GII.4 isolates (in 1974) and a more recent epidemic GII.4 variant (in 2012) had varied norovirus-specific monoclonal antibody (MAb) reactivities but similar HBGA binding profiles. To better understand the binding interaction of one MAb (10E9) that had varied reactivity with these GII.4 variants, we determined the X-ray crystal structure of the NSW-2012 GII.4 P domain 10E9 Fab complex. We showed that the 10E9 Fab interacted with conserved and variable residues, which could be associated with antigenic drift. Interestingly, the 10E9 Fab binding pocket partially overlapped the HBGA pocket and had direct competition for conserved HBGA binding residues (i.e., Arg345 and Tyr444). Indeed, the 10E9 MAb blocked norovirus virus-like particles (VLPs) from binding to several sources of HBGAs. Moreover, the 10E9 antibody completely abolished virus replication in the human norovirus intestinal enteroid cell culture system. Our new findings provide the first direct evidence that competition for GII.4 HBGA binding residues and steric obstruction could lead to norovirus neutralization. On the other hand, the 10E9 MAb recognized residues flanking the HBGA pocket, which are often substituted as the virus evolves. This mechanism of antigenic drift likely influences herd immunity and impedes the possibility of acquiring broadly reactive HBGA-blocking antibodies. IMPORTANCE The emergence of new epidemic GII.4 norovirus variants is thought to be associated with changes in antigenicity and HBGA binding capacity. Here, we show that HBGA binding profiles remain unchanged between the 1974 and 2012 GII.4 variants, whereas these variants showed various levels of reactivity against a panel of GII.4 MAbs. We identified a MAb that bound at the HBGA pocket, blocked norovirus VLPs from binding to HBGAs, and neutralized norovirus virions in the cell culture system. Raised against a GII.4 2006 strain, this MAb was unreactive to a GII.4 1974 isolate but was able to neutralize the newer 2012 strain, which has important implications for vaccine design. Altogether, these new findings suggest that the amino acid variations surrounding the HBGA pocket lead to temporal changes in antigenicity without affecting the ability of GII.4 variants to bind HBGAs, which are known cofactors for infection.

Background The Lao People’s Democratic Republic continues to sustain a considerable burden of vaccine-preventable diseases because of incomplete vaccine coverage and weak vaccine responses. We have assessed seroconversion after routine vaccination with the pentavalent vaccine to capture weaknesses of vaccine management at the different levels of the healthcare system. Methods A total of 1151 children (aged 8–28 months) with 3 documented doses of the pentavalent vaccine delivered at central hospitals in Vientiane and the provincial hospital, 3 district hospitals, and 10 health centers in Bolikhamxay province were enrolled. Sociodemographic information was collected with a standardized questionnaire. Serum samples were analyzed for antibodies against vaccine components, and bivariate and multivariable analyses were performed to identify risk factors for low vaccine responses. Results Seroprotection rates at the provincial, district, and health center level were as high as in central hospitals, but seroprotection rates in areas covered by remote health centers were significantly lower. Protective levels also rapidly decreased with age at sampling. Seroprotection rates in Bolikhamxay against the different components reached 70%–77% and were up to 20% higher than in previous studies in the same region; 18.8% more children received the hepatitis B vaccine birth dose and the hepatitis B virus infection rate was 4 times lower. Conclusions Vaccine immunogenicity has dramatically improved in a central province, likely due to training and investment in the cold chain. Nevertheless, there remains a need to focus on the “last mile” in remote areas were most children are vaccinated through outreach activities., Seroprotection rates after vaccination with the pentavalent vaccine were assessed at different levels of the healthcare system in Laos. While seroprotection did not necessarily decline at lower levels of the healthcare system, they were particularly suboptimal in remote areas.