Immunogenicity and reactogenicity of alternative schedules of HPV vaccine in Vietnam: a cluster randomized noninferiority trial.

CONTEXT: Human papillomavirus (HPV) vaccine programs may decrease the morbidity and mortality due to cervical cancer seen among women in low-resource countries. However, the 3-dose schedule over a 6-month period is a potential barrier to vaccine introduction in such settings. OBJECTIVE: To determine the immunogenicity and reactogenicity of different dosing schedules of quadrivalent HPV vaccine in adolescent girls in Vietnam. DESIGN, SETTING, AND PARTICIPANTS: Open-label, cluster randomized, noninferiority study (conducted between October 2007 and January 2010) assessing 4 schedules of an HPV vaccine delivered in 21 schools to 903 adolescent girls (aged 11-13 years at enrollment) living in northwestern Vietnam. INTERVENTION: Intramuscular injection of 3 doses of quadrivalent HPV vaccine delivered on a standard dosing schedule (at 0, 2, and 6 months) and 3 alternative dosing schedules (at 0, 3, and 9 months; at 0, 6, and 12 months; or at 0, 12, and 24 months). MAIN OUTCOME MEASURES: Serum anti-HPV geometric mean titers (GMT) measured 1 month after the third dose of the HPV vaccine was administered; GMT was determined by type-specific competitive immunoassay. Noninferiority of each alternative vaccination dosing schedule was achieved if the lower bound of the multiplicity-adjusted confidence interval (CI) of the type-specific GMT ratio for HPV-16 and HPV-18 was greater than 0.5 (primary outcome). Safety outcomes were immediate reactions, local reactions, fever within 7 days after each dose, and serious adverse events up to 30 days following the last dose. RESULTS: In the intention-to-treat analysis, 809 girls who received at least 1 HPV vaccine dose had valid serum measurements 1 month after the third dose. After the third dose, the GMTs for those in the standard schedule group who received doses at 0, 2, and 6 months were 5808.0 (95% CI, 4961.4-6799.0) for HPV-16 and 1729.9 (95% CI, 1504.0-1989.7) for HPV-18; 5368.5 (95% CI, 4632.4-6221.5) and 1502.3 (95% CI, 1302.1-1733.2), respectively, for those whose received doses at 0, 3, and 9 months; 5716.4 (95% CI, 4876.7-6700.6) and 1581.5 (95% CI, 1363.4-1834.6), respectively, for those who received doses at 0, 6, and 12 months; and 3692.5 (95% CI, 3145.3-4334.9) and 1335.7 (95% CI, 1191.6-1497.3), respectively, for those who received doses at 0, 12, and 24 months. Noninferiority criteria were met for the alternative schedule groups that received doses at 0, 3, and 9 months (HPV-16 GMT ratio: 0.92 [95% CI, 0.71-1.20]; HPV-18 GMT ratio: 0.87 [95% CI, 0.68-1.11]) and at 0, 6, and 12 months (HPV-16 GMT ratio: 0.98 [95% CI, 0.75-1.29]; HPV-18 GMT ratio: 0.91 [95% CI, 0.71-1.17]). Prespecified noninferiority criteria were not met for the alternative schedule group that received doses at 0, 12, and 24 months (HPV-16 GMT ratio: 0.64 [95% CI, 0.48-0.84]; HPV-18 GMT ratio: 0.77 [95% CI, 0.62-0.96]). Pain at the injection site was the most common adverse event. CONCLUSIONS: Among adolescent girls in Vietnam, administration of the HPV vaccine on standard and alternative schedules was immunogenic and well tolerated. The use of 2 alternative dosing schedules (at 0, 3, and 9 months and at 0, 6, and 12 months) compared with a standard schedule (at 0, 2, and 6 months) did not result in inferior antibody concentrations. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00524745.

The Vi conjugate typhoid vaccine is safe, elicits protective levels of IgG anti-Vi, and is compatible with routine infant vaccines.

Typhoid fever remains a serious problem in developing countries. Current vaccines are licensed for individuals who are 5 years old or older. A conjugate of the capsular polysaccharide (CP) of Salmonella enterica serovar Typhi (Vi) bound to recombinant exoprotein A of Pseudomonas aeruginosa (Vi-rEPA) enhanced Vi immunogenicity and protected 2- to 5-year-olds in Vietnam. In this study, Vi-rEPA was evaluated for use in infants. A total of 301 full-term Vietnamese infants received Expanded Program on Immunization (EPI) vaccines alone or with Vi-rEPA or Haemophilus influenzae type b-tetanus toxoid conjugate (Hib-TT) at 2, 4, and 6 months and Vi-rEPA or Hib-TT alone at 12 months. Infants were visited 6, 24, and 48 h after each injection to monitor adverse reactions. Maternal, cord, and infant sera were assayed for IgG anti-Vi and for IgG antibodies to Hib CP and the diphtheria, tetanus, and pertussis toxins at 7, 12, and 13 months. No vaccine-related serious adverse reactions occurred. In the Vi-rEPA group, the IgG anti-Vi geometric mean (GM) increased from the cord level of 0.66 to 17.4 enzyme-linked immunosorbent assay units (EU) at 7 months, declined to 4.76 EU at 12 months, and increased to 50.1 EU 1 month after the 4th dose (95% of infants had levels of ≥ 3.5 EU, the estimated protective level). Controls had no increase of the IgG anti-Vi GM. Infants with cord anti-Vi levels of <3.5 EU responded with significantly higher IgG anti-Vi levels than those with levels of ≥ 3.5 EU. Anti-diphtheria, -tetanus, and -pertussis toxin levels were similar in all groups. Vi-rEPA was safe, induced protective anti-Vi levels, and was compatible with EPI vaccines, and it can be used in infants. High cord IgG anti-Vi levels partially suppressed infant responses to Vi-rEPA.

Suitable disk antimicrobial susceptibility breakpoints defining Salmonella enterica serovar Typhi isolates with reduced susceptibility to fluoroquinolones.

Infections with Salmonella enterica serovar Typhi isolates that have reduced susceptibility to ofloxacin (MIC ≥ 0.25 µg/ml) or ciprofloxacin (MIC ≥ 0.125 µg/ml) have been associated with a delayed response or clinical failure following treatment with these antimicrobials. These isolates are not detected as resistant using current disk susceptibility breakpoints. We examined 816 isolates of S. Typhi from seven Asian countries. Screening for nalidixic acid resistance (MIC ≥ 16 µg/ml) identified isolates with an ofloxacin MIC of ≥0.25 µg/ml with a sensitivity of 97.3% (253/260) and specificity of 99.3% (552/556). For isolates with a ciprofloxacin MIC of ≥0.125 µg/ml, the sensitivity was 92.9% (248/267) and specificity was 98.4% (540/549). A zone of inhibition of ≤28 mm around a 5-µg ofloxacin disc detected strains with an ofloxacin MIC of ≥0.25 µg/ml with a sensitivity of 94.6% (246/260) and specificity of 94.2% (524/556). A zone of inhibition of ≤30 mm detected isolates with a ciprofloxacin MIC of ≥0.125 µg/ml with a sensitivity of 94.0% (251/267) and specificity of 94.2% (517/549). An ofloxacin MIC of ≥0.25 µg/ml and a ciprofloxacin MIC of ≥0.125 µg/ml detected 74.5% (341/460) of isolates with an identified quinolone resistance-inducing mutation and 81.5% (331/406) of the most common mutant (carrying a serine-to-phenylalanine mutation at codon 83 in the gyrA gene). Screening for nalidixic acid resistance or ciprofloxacin and ofloxacin disk inhibition zone are suitable for detecting S. Typhi isolates with reduced fluoroquinolone susceptibility.

Local environmental predictors of cholera in Bangladesh and Vietnam.

Environmental factors have been shown to be related to cholera and thus might prove useful for prediction. In Bangladesh and Vietnam, temporal cholera distributions are related to satellite-derived and in-situ environmental time series data in order to examine the relationships between cholera and the local environment. Ordered probit models examine associations in Bangladesh; probit models examine associations at 2 sites in Vietnam. Increases in ocean chlorophyll concentration are related to an increased magnitude of cholera in Bangladesh. Increases in sea surface temperature are most influential in Hue, Vietnam, whereas increases in river height have a significant role in Nha Trang, Vietnam. Cholera appearance and epidemic magnitude are related to the local environment. Local environmental parameters have consistent effects when cholera is regular and more prevalent in endemic settings, but in situations where cholera epidemics are rare there are differential environmental effects.

A study of typhoid fever in five Asian countries: disease burden and implications for controls.

OBJECTIVE: To inform policy-makers about introduction of preventive interventions against typhoid, including vaccination. METHODS: A population-based prospective surveillance design was used. Study sites where typhoid was considered a problem by local authorities were established in China, India, Indonesia, Pakistan and Viet Nam. Standardized clinical, laboratory, and surveillance methods were used to investigate cases of fever of >or= 3 days' duration for a one-year period. A total of 441,435 persons were under surveillance, 159,856 of whom were aged 5-15 years. FINDINGS: A total of 21,874 episodes of fever were detected. Salmonella typhi was isolated from 475 (2%) blood cultures, 57% (273/475) of which were from 5-15 year-olds. The annual typhoid incidence (per 100,000 person years) among this age group varied from 24.2 and 29.3 in sites in Viet Nam and China, respectively, to 180.3 in the site in Indonesia; and to 412.9 and 493.5 in sites in Pakistan and India, respectively. Altogether, 23% (96/413) of isolates were multidrug resistant (chloramphenicol, ampicillin and trimethoprim-sulfamethoxazole). CONCLUSION: The incidence of typhoid varied substantially between sites, being high in India and Pakistan, intermediate in Indonesia, and low in China and Viet Nam. These findings highlight the considerable, but geographically heterogeneous, burden of typhoid fever in endemic areas of Asia, and underscore the importance of evidence on disease burden in making policy decisions about interventions to control this disease.

Temporal trends and climatic factors associated with bacterial enteric diseases in Vietnam, 1991-2001.

OBJECTIVE: In Vietnam, shigellosis/dysentery, typhoid fever, and cholera are important enteric diseases. To better understand their epidemiology, we determined temporal trends, seasonal patterns, and climatic factors associated with high risk periods in eight regions across Vietnam. METHODS: We quantified monthly cases and incidence rates (IR) for each region from national surveillance data (1991-2001). High- and low-disease periods were defined from the highest and lowest IRs (1 SD above and below the mean) and from outbreaks from positive outliers (4 SDs higher in 1 month or 2 SDs higher in > or = 2 consecutive months). We used general linear models to compare precipitation, temperature, and humidity between high- and low-risk periods. RESULTS: Shigellosis/dysentery was widespread and increased 2.5 times during the study period, with the highest average IRs found between June and August (2.1/100,000-26.2/100,000). Typhoid fever was endemic in the Mekong River Delta and emerged in the Northwest in the mid-1990s, with peaks between April and August (0.38-8.6). Cholera was mostly epidemic along the central coast between May and November (0.07-2.7), and then decreased dramatically nationwide from 1997 onward. Significant climate differences were found only between high- and low-disease periods. We were able to define 4 shigellosis/dysentery, 14 typhoid fever, and 8 cholera outbreaks, with minimal geotemporal overlap and no significant climatic associations. CONCLUSIONS: In Vietnam, bacterial enteric diseases have distinct temporal trends and seasonal patterns. Climate plays a role in defining high- and low-disease periods, but it does not appear to be an important factor influencing outbreaks.

Antimicrobial drug resistance of Salmonella enterica serovar typhi in asia and molecular mechanism of reduced susceptibility to the fluoroquinolones.

This study describes the pattern and extent of drug resistance in 1,774 strains of Salmonella enterica serovar Typhi isolated across Asia between 1993 and 2005 and characterizes the molecular mechanisms underlying the reduced susceptibilities to fluoroquinolones of these strains. For 1,393 serovar Typhi strains collected in southern Vietnam, the proportion of multidrug resistance has remained high since 1993 (50% in 2004) and there was a dramatic increase in nalidixic acid resistance between 1993 (4%) and 2005 (97%). In a cross-sectional sample of 381 serovar Typhi strains from 8 Asian countries, Bangladesh, China, India, Indonesia, Laos, Nepal, Pakistan, and central Vietnam, collected in 2002 to 2004, various rates of multidrug resistance (16 to 37%) and nalidixic acid resistance (5 to 51%) were found. The eight Asian countries involved in this study are home to approximately 80% of the world's typhoid fever cases. These results document the scale of drug resistance across Asia. The Ser83-->Phe substitution in GyrA was the predominant alteration in serovar Typhi strains from Vietnam (117/127 isolates; 92.1%). No mutations in gyrB, parC, or parE were detected in 55 of these strains. In vitro time-kill experiments showed a reduction in the efficacy of ofloxacin against strains harboring a single-amino-acid substitution at codon 83 or 87 of GyrA; this effect was more marked against a strain with a double substitution. The 8-methoxy fluoroquinolone gatifloxacin showed rapid killing of serovar Typhi harboring both the single- and double-amino-acid substitutions.

Geographical distribution and risk factors associated with enteric diseases in Vietnam.

In Vietnam, shigellosis, typhoid fever, and cholera are important enteric diseases. To determine their magnitude and geographical distribution, and explore associated risk factors, we examined national surveillance data from 1991 to 2001 and potential ecological determinants. Average annual incidence rates were calculated and mapped for each province. Bivariate and multiple regression analyses were used to explore associations with selected environmental and human risk factors. Overall, shigellosis rates per 100,000 population (median, 41; mean, 70) were higher and more widespread than rates for typhoid fever (median, 7; mean, 23) and cholera (median, 0.3; mean, 2.7). Shigellosis was highest in the Central Highlands and was significantly associated with rainfall and urban poverty; typhoid fever prevailed in the Mekong River Delta and was most associated with vapor pressure and river/stream drinking water; and cholera predominated along the Central Coastal regions and correlated positively with rainfall and public well drinking water. The distinct geographical patterns of each disease appear to be driven by a combination of different ecological factors.

Trial participation and vaccine desirability for Vi polysaccharide typhoid fever vaccine in Hue City, Viet Nam.

OBJECTIVES: To identify demand for Vi typhoid fever vaccine for school-age children; obstacles and enabling factors for vaccine delivery; and socio-behavioural factors associated with trial participation and possible predictors of future vaccine acceptance, in Hue City, Viet Nam. METHODS: Pre- and post-trial surveys of randomly selected households with children aged 6-17 years. Simple multinomial logistic analyses for ratios of relative risks (RRR) and significance on trial participation by demographics and variables related to typhoid fever, vaccination, and pre-trial experiences with information and consents. Multiple logistic regressions to assess differences in participation based on child's characteristics. RESULTS: As many as 62.6% of households let all school age children participate, 10.2% let some participate, and 26.8% let none of their children participate in the trial. Factors associated with all children participating included past use of healthcare facilities (RRR, 0.45; 95% CI, 0.24-0.83), knowledge of vaccines (RRR, 0.17; 95% CI, 0.03-0.86), and perceived causes of typhoid fever (RRR, 0.90; 95% CI, 0.81-0.99). Factors associated with some children participating included utilization of healthcare facilities (RRR, 0.08; 95% CI, 0.01-0.66) and perceived severity of typhoid fever (RRR, 0.64; 95% CI 0.46-0.88). Participation was associated with satisfaction regarding pre-vaccination information and consent procedures. Children and adolescents were active decision-makers. Only 14 of 461 (2.2%) respondents would not use the Vi vaccine in the future for their child(ren). CONCLUSIONS: Inter-related factors contribute to participation in a clinical vaccine trial, which may differ from desire to participate in a public health campaign. Educational campaigns need to be targeted to children and adolescents, and consideration for assent procedures for minors. Obtaining informed consent may affect trial participation within a social and political system unaccustomed to these procedures.

Geographic analysis of vaccine uptake in a cluster-randomized controlled trial in Hue, Vietnam.

This paper identifies spatial patterns and predictors of vaccine uptake in a cluster-randomized controlled trial in Hue, Vietnam. Data for this study result from the integration of demographic surveillance, vaccine record, and geographic data of the study area. A multi-level cross-classified (non-hierarchical) model was used for analyzing the non-nested nature of individual's ecological data. Vaccine uptake was unevenly distributed in space and there was spatial variability among predictors of vaccine uptake. Vaccine uptake was higher among students with younger, male, or not literate family heads. Students from households with higher per-capita income were less likely to participate in the trial. Residency south of the river or further from a hospital/polyclinic was associated with higher vaccine uptake. Younger students were more likely to be vaccinated than older students in high- or low-risk areas, but not in the entire study area. The findings are important for the management of vaccine campaigns during a trial and for interpretation of disease patterns during vaccine-efficacy evaluation.

Safety and immunogenicity of a reformulated Vietnamese bivalent killed, whole-cell, oral cholera vaccine in adults.

Vietnam currently produces an orally administered, bivalent (O1 and O139) killed whole-cell vaccine and is the only country in the world with endemic cholera to use an oral cholera vaccine in public health practice. In order to allow international use, the vaccine had to be reformulated to meet World Health Organization (WHO) requirements. We performed a randomized, placebo controlled, safety and immunogenicity studies of this reformulated vaccine among Vietnamese adults. One hundred and forty-four subjects received the two-dose regimen and 143 had two blood samples obtained for analysis. We found that this reformulated oral killed whole-cell cholera vaccine was safe, well tolerated and highly immunogenic.

The feasibility of a school-based VI polysaccharide vaccine mass immunization campaign in Hue City, central Vietnam: streamlining a typhoid fever preventive strategy.

We report the coverage, safety, and logistics of a school-based typhoid fever immunization campaign that took place in Hue City, central Vietnam; a typhoid fever endemic area. A cluster-randomized evaluation-blinded controlled trial was designed where 68 schools (cluster) were randomly allocated the single dose Vi polysaccharide vaccine (Typherix) or the active control hepatitis A vaccine (Havrix). A safety surveillance system was implemented. A total of 32,267 children were immunized with a coverage of 57.5%. Strong predictors for vaccination were attending primary schools, peri-urban location of the school, and low family income. Human resources were mainly schoolteachers and the campaign was completed in about 1 month. Most adverse events reported were mild. Safe injection and safe sharp-waste disposal practices were followed. A typhoid fever school-based immunization campaign was safe and logistically possible. Coverage was moderate and can be interpreted as the minimum that could have been achievable because individual written informed consent procedures were sought for the first time in Hue City and the trial nature of the campaign. The lessons learned, together with cost-effectiveness results to be obtained by the end of follow-up period, will hopefully accelerate the introduction of Vi typhoid fever vaccine in Vietnam.

A multicentre study of Shigella diarrhoea in six Asian countries: disease burden, clinical manifestations, and microbiology.

BACKGROUND: The burden of shigellosis is greatest in resource-poor countries. Although this diarrheal disease has been thought to cause considerable morbidity and mortality in excess of 1,000,000 deaths globally per year, little recent data are available to guide intervention strategies in Asia. We conducted a prospective, population-based study in six Asian countries to gain a better understanding of the current disease burden, clinical manifestations, and microbiology of shigellosis in Asia. METHODS AND FINDINGS: Over 600,000 persons of all ages residing in Bangladesh, China, Pakistan, Indonesia, Vietnam, and Thailand were included in the surveillance. Shigella was isolated from 2,927 (5%) of 56,958 diarrhoea episodes detected between 2000 and 2004. The overall incidence of treated shigellosis was 2.1 episodes per 1,000 residents per year in all ages and 13.2/1,000/y in children under 60 months old. Shigellosis incidence increased after age 40 years. S. flexneri was the most frequently isolated Shigella species (1,976/2,927 [68%]) in all sites except in Thailand, where S. sonnei was most frequently detected (124/146 [85%]). S. flexneri serotypes were highly heterogeneous in their distribution from site to site, and even from year to year. PCR detected ipaH, the gene encoding invasion plasmid antigen H in 33% of a sample of culture-negative stool specimens. The majority of S. flexneri isolates in each site were resistant to amoxicillin and cotrimoxazole. Ciprofloxacin-resistant S. flexneri isolates were identified in China (18/305 [6%]), Pakistan (8/242 [3%]), and Vietnam (5/282 [2%]). CONCLUSIONS: Shigella appears to be more ubiquitous in Asian impoverished populations than previously thought, and antibiotic-resistant strains of different species and serotypes have emerged. Focusing on prevention of shigellosis could exert an immediate benefit first by substantially reducing the overall diarrhoea burden in the region and second by preventing the spread of panresistant Shigella strains. The heterogeneous distribution of Shigella species and serotypes suggest that multivalent or cross-protective Shigella vaccines will be needed to prevent shigellosis in Asia.

Long-term effectiveness against cholera of oral killed whole-cell vaccine produced in Vietnam.

We assessed the long-term protection afforded by a killed whole-cell oral cholera vaccine produced in Vietnam. A mass immunization of children and adults with the killed whole-cell oral cholera vaccine was undertaken in half of the communes of Hue, Vietnam, in 1998; the remaining communes were immunized in 2000. No cholera was observed in Hue until 2003, when an outbreak of El Tor cholera made it possible to conduct a case-control study. The overall vaccine effectiveness 3-5 years after vaccination was 50% (9-63%). This low-cost, easily administered vaccine should be considered as a tool for the control of cholera.

The burden of rotavirus diarrhea in Khanh Hoa Province, Vietnam: baseline assessment for a rotavirus vaccine trial.

BACKGROUND: In Vietnam, rotavirus is seen as a priority disease because studies have demonstrated that >50% of children hospitalized for treatment of diarrhea have rotavirus as the pathogen. To anticipate the availability of new vaccines, we have examined our field area in Nha Trang, Khanh Hoa Province, Vietnam, as a potential site to conduct a field trial of a future rotavirus vaccine. METHODS: Data from a population census, incidence rates of diarrhea from a previous cholera vaccine trial and hospitalization rates from computerized records collected from the 2 main hospitals in the province were reviewed to estimate the burden of rotavirus-related diarrhea that might be expected during a field trial of a rotavirus vaccine. RESULTS: For a birth cohort of approximately 5000 children, we would expect approximately 2500 clinic visits and 650-850 hospitalizations for treatment of diarrhea, of which approximately 375-425 would be attributable to rotavirus. For the Vietnamese birth cohort of 1,639,000 children, these numbers translate into approximately 820,000 clinic visits, 122,000-140,000 hospitalizations and 2900-5400 deaths annually attributable to rotavirus-related diarrhea. CONCLUSIONS: Vietnam is an early adaptor of new vaccines, has high national coverage rates (>85%) for childhood immunization and receives international donor support for the introduction of new vaccines. We found the epidemiologic features of rotavirus in rural Vietnam to be more similar to those of rotavirus in a developed country than to those of rotavirus in India or Bangladesh.

A multi-country cluster randomized controlled effectiveness evaluation to accelerate the introduction of Vi polysaccharide typhoid vaccine in developing countries in Asia: rationale and design.

Phase-III vaccine efficacy trials typically employ individually randomized designs intended to ensure that measurements of vaccine protective efficacy reflect only direct vaccine effects. As a result, decisions about introducing newly licensed vaccines into public health programmes often fail to consider the substantially greater protection that may occur when a vaccine is deployed in public health programmes, due to the combination of direct plus indirect vaccine protective effects. Vaccine total protection can be better evaluated with cluster randomized trials. Such a design was considered to generate policy relevant data to accelerate the rationale introduction of the licensed typhoid fever Vi polysaccharide (PS) vaccine in Asia by the Diseases of the Most Impoverished (DOMI) typhoid fever programme. The DOMI's programme multi-country study is one of the largest cluster randomized vaccine trials ever mounted in Asia, which includes approximately 200,000 individuals. Its main objective is to determine the effectiveness of a licensed Vi PS vaccine. The rationale and design of this study are discussed. Preliminary results are presented that determined the final planning of the trial before immunization. Important methodological and practical issues regarding vaccine cluster randomized designs are illustrated.

Neighborhood size and local geographic variation of health and social determinants.

BACKGROUND: Spatial filtering using a geographic information system (GIS) is often used to smooth health and ecological data. Smoothing disease data can help us understand local (neighborhood) geographic variation and ecological risk of diseases. Analyses that use small neighborhood sizes yield individualistic patterns and large sizes reveal the global structure of data where local variation is obscured. Therefore, choosing an optimal neighborhood size is important for understanding ecological associations with diseases. This paper uses Hartley's test of homogeneity of variance (Fmax) as a methodological solution for selecting optimal neighborhood sizes. The data from a study area in Vietnam are used to test the suitability of this method. RESULTS: The Hartley's Fmax test was applied to spatial variables for two enteric diseases and two socioeconomic determinants. Various neighbourhood sizes were tested by using a two step process to implement the Fmaxtest. First the variance of each neighborhood was compared to the highest neighborhood variance (upper, Fmax1) and then they were compared with the lowest neighborhood variance (lower, Fmax2). A significant value of Fmax1 indicates that the neighborhood does not reveal the global structure of data, and in contrast, a significant value in Fmax2 implies that the neighborhood data are not individualistic. The neighborhoods that are between the lower and the upper limits are the optimal neighbourhood sizes. CONCLUSION: The results of tests provide different neighbourhood sizes for different variables suggesting that optimal neighbourhood size is data dependent. In ecology, it is well known that observation scales may influence ecological inference. Therefore, selecting optimal neigborhood size is essential for understanding disease ecologies. The optimal neighbourhood selection method that is tested in this paper can be useful in health and ecological studies.

Effect of dosage on immunogenicity of a Vi conjugate vaccine injected twice into 2- to 5-year-old Vietnamese children.

In a double-blind, randomized, and placebo-controlled previous trial, the efficacy of Vi-rEPA for typhoid fever in 2- to 5-year-olds was 89.0% for 46 months. Vi-rEPA contained 25 microg of Vi and induced a greater-than-eightfold rise in immunoglobulin G (IgG) anti-Vi in all of the vaccinees tested. In this investigation, we conducted a dosage-immunogenicity study of 5, 12.5, and 25 microg of Vi-rEPA in this age group. Two doses of Vi-rEPA were injected 6 weeks apart. Blood samples were taken before and at 10 weeks (4 weeks after the second injection) and 1 year later. All postimmunization geometric mean (GM) levels were higher than the preimmune levels (P < 0.0001). At 10 weeks, the GM IgG anti-Vi level elicited by 25 microg (102 EU/ml) was higher than those elicited by 12.5 microg (74.7 EU/ml) and 5 microg (43 EU/ml) (P < 0.004): all of the children had > or = 3.52 EU/ml (estimated minimum protective level). One year later, the levels declined about sevenfold (13.3 and 11.3 versus 6.43 EU/ml, P < 0.0001) but remained significantly higher than the preimmune levels (P < 0.0001), and >96% of the children had a greater-than-eightfold rise. This study also confirmed the safety and consistent immunogenicity of the four lots of Vi-rEPA used in this and previous trials.