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GMMA has been proposed as a potent technology platform for the design of safe, effective and affordable vaccines. As GMMA are vesicles blebbing out of the outer membrane of Gram-negative bacteria, they contain lipopolysaccharides, lipoproteins and peptidoglycans that stimulate immune cells via Toll-like Receptors 4 (TLR4) or TLR2. Being basically nanoparticles, GMMA can be efficiently captured by Follicular Dendritic Cells (FDC) for antigen presentation to cognate B cells. GMMA have shown to be highly immunogenic in preclinical and clinical studies and the engagement of TLR4 and TLR2 or antigen presentation by FDC may have a prominent role in GMMA immunogenicity, which is well worth investigating. By using GMMA derived from Shigella sonnei and Salmonella Typhimurium, we show for the first time that the antigen presentation by FDC to cognate B cells plays a major role in the induction of an effective humoral immune response upon immunization with GMMA by using both models. The engagement of TLR4 is critical to elicit an optimal antibody production, but its effect on antibody functionality is dependent on GMMA type and is dispensable when immunizing with Alum adjuvant, whereas TLR2 does not have any role for GMMA immunogenicity. Our findings represent a substantial advancement of the knowledge on GMMA mode of action and shed a light on novel perspectives for the design of safer and more effective GMMA-based vaccines. ONE SENTENCE SUMMARY: The study demonstrated that the antigen presentation by FDC to cognate B cells plays a major role for GMMA immunogenicity.

Summary Background Typhoid vaccination is a public health priority in developing countries where young children are greatly affected by typhoid fever. Because present vaccines are not recommended for children younger than 2 years, the Novartis Vaccines Institute for Global Health developed a conjugate vaccine (Vi-CRM 197 ) for infant immunisation. We aimed to assess the immunogenicity and safety of Vi-CRM 197 in participants of various ages in endemic countries in south and southeast Asia. Methods We did two randomised, observer-blind, age de-escalation, phase 2 trials at two sites in Pakistan and India (study A), and at one site in the Philippines (study B), between March 2, 2011, and Aug 9, 2012. Adults aged 18–45 years, children aged 24–59 months, older infants aged 9–12 months, and infants aged 6–8 weeks were randomly assigned (1:1) with a computer-generated randomisation list (block size of four) to receive either 5 μg Vi-CRM 197 or 25 μg Vi-polysaccharide vaccine (or 13-valent pneumococcal conjugate vaccine in children younger than 2 years). Both infant populations received Vi-CRM 197 concomitantly with vaccines of the Expanded Programme on Immunization (EPI), according to WHO schedule. With the exception of designated study site personnel responsible for vaccine preparation, study investigators, those assessing outcomes, and data analysts were masked to treatment allocation. We specified no a-priori null hypothesis for the immunogenicity or safety objectives and all analyses were descriptive. Analyses were by modified intention-to-treat. These studies are registered with ClinicalTrials.gov, numbers NCT01229176 and NCT01437267. Findings 320 participants were enrolled and vaccinated in the two trials: 200 in study A (all age groups) and 120 in study B (children and infants only), of whom 317 (99%) were included in the modified intention-to-treat analysis. One dose of Vi-CRM 197 significantly increased concentrations of anti-Vi antibody in adults (from 113 U/mL [95% CI 67–190] to 208 U/mL [117–369]), children (201 U/mL [138–294] to 368 U/mL [234–580]), and older infants (179 U/mL [129–250] to 249 U/mL [130–477]). However, in children and older infants, a second dose of conjugate vaccine had no incremental effect on antibody titres and, at all ages, concentrations of antibodies increased substantially 6 months after vaccination (from 55 U/mL [33–94] to 63 U/mL [35–114] in adults, from 23 U/mL [15–34] to 51 U/mL [34–76] in children, and from 21 U/mL [14–31] to 22 U/mL [14–33] in older infants). Immune response in infants aged 6–8 weeks was lower than that in older participants and, 6 months after third vaccination, antibody concentrations were significantly higher than pre-vaccination concentrations in Filipino (21 U/mL [16–28] vs 2·88 U/mL [1·95–4·25]), but not Pakistani (3·76 U/mL [2·77–5·08] vs 2·77 U/mL [2·1–3·66]), infants. Vi-CRM 197 was safe and well tolerated and did not induce any significant interference with EPI vaccines. No deaths or vaccine-related serious adverse events were reported throughout the studies. Interpretation Vi-CRM 197 is safe and immunogenic in endemic populations of all ages. Given at 9 months of age, concomitantly with measles vaccine, Vi-CRM 197 shows a promise for potential inclusion in EPI schedules of countries endemic for typhoid. An apparent absence of booster response and a reduction in antibody titres 6 months after immunisation should be further investigated, but data show that an immunogenic typhoid vaccine can be safely delivered to infants during EPI visits recommended by WHO. Funding Sclavo Vaccines Association and Regione Toscana.

Background In the context of early vaccine trials aimed at evaluating the safety profile of novel vaccines, abnormal haematological values, such as neutropenia, are often reported. It is therefore important to evaluate how these trials should be planned not to miss potentially important safety signals, but also to understand the implications and the clinical relevance. Methodology We report and discuss the results from five clinical trials (two with a new Shigella vaccine in the early stage of clinical development and three with licensed vaccines) where the absolute neutrophil counts (ANC) were evaluated before and after vaccination. Additionally, we have performed a systematic review of the literature on cases of neutropenia reported during vaccine trials to discuss our results in a more general context. Principal Findings Both in our clinical trials and in the literature review, several cases of neutropenia have been reported, in the first two weeks after vaccination. However, neutropenia was generally transient and had a benign clinical outcome, after vaccination with either multiple novel candidates or well-known licensed vaccines. Additionally, the vaccine recipients with neutropenia frequently had lower baseline ANC than non-neutropenic vaccinees. In many instances neutropenia occurred in subjects of African descent, known to have lower ANC compared to western populations. Conclusions It is important to include ANC and other haematological tests in early vaccine trials to identify potential safety signals. Post-vaccination neutropenia is not uncommon, generally transient and clinically benign, but many vaccine trials do not have a sampling schedule that allows its detection. Given ethnic variability in the level of circulating neutrophils, normal ranges taking into account ethnicity should be used for determination of trial inclusion/exclusion criteria and classification of neutropenia related adverse events. Trial registration ClinicalTrials.gov NCT02017899, NCT02034500, NCT01771367, NCT01765413, NCT02523287

With the emergence of multiple meningococcal serogroups in different geographic areas, broad vaccine protection from infancy is desirable. One hundred and seventy-five infants received either two doses of a meningococcal quadrivalent (A, C, W-135, Y) conjugate vaccine (MenACWY-CRM) at 6 and 12 months, one dose of MenACWY-CRM at 12 months, or MenC at 12 months and MenACWY-CRM at 18 months. Bactericidal antibody titers using human complement were measured before and 1 month after each dose. Injection-site reactions were reported by 22-45% of participants following MenACWY-CRM given at 6 or 12 months. Similar proportions of subjects had injection-site reactions following two doses of MenACWY-CRM (32-41%) or one dose of MenC (26-44%). The incidence of systemic adverse events was comparable between groups. After two doses of MenACWY-CRM, the percentages of participants reporting hSBA titersor=8 were 100% for C, W-135, and Y, and 84% for A. Serogroup C titers were more than 10-fold higher after two doses of MenACWY-CRM than after one dose of MenC or MenACWY-CRM at 12 months. Serogroup C titers were comparable following a single dose of MenACWY-CRM or MenC at 12 months. MenACWY-CRM is well tolerated and immunogenic given at 12 months, or two doses at 6 and 12 months of age.

Because of the well-documented increased risk of meningococcal disease among adolescents, vaccination is recommended for this population in many countries, including the United States. This study compared the tolerability and immunogenicity in adolescents of a candidate quadrivalent meningococcal CRM197 glycoconjugate vaccine against serogroups A, C, W-135, and Y (MenACWY-CRM) with that of the licensed unconjugated quadrivalent polysaccharide vaccine (MPSV4).This phase II study was conducted in the United States among 524 adolescents aged 11-17 years in 2 stages, with different randomization schemes. The first 334 participants, enrolled in Stage 1, were randomized (1:1) to receive either MenACWY-CRM(+) (with adjuvant) or MPSV4. The next 190 participants, enrolled in Stage 2, were randomized (4:1) to receive either MenACWY-CRM(-) (without adjuvant) or MPSV4. Safety data were collected using diary cards and active surveillance. Human complement serum bactericidal activity (hSBA) titers were measured 1 and 12 months postvaccination.MenACWY-CRM and MPSV4 vaccines were well tolerated (local reactions, 63%-71% vs. 60%-62%; systemic reactions, 44%-56% vs. 46%-59%, respectively). One month postvaccination, similar hSBA titers were observed with the adjuvanted and nonadjuvanted MenACWY-CRM. The immunogenicity of MenACWY-CRM(-), measured by geometric mean titer, was significantly (P0.05) greater than that of MPSV4 for all 4 vaccine serogroups at 1 month. The percentage of subjects with hSBA titersor =1:4 was also significantly greater (P0.01) for MenACWY-CRM(-) recipients for serogroups A, C, and Y and noninferior for W-135. The proportions of MenACWY-CRM(-) recipients with hSBA titersor =1:4 to the vaccine serogroups at 1 month were 84% to 96% and geometric mean titers were 34 to 100. The percentage of subjects with hSBA titersor =1:4 was significantly (P0.01) greater than MPSV4 for serogroups C, W-135, and Y 12 months postvaccination.MenACWY-CRM was well tolerated and immunogenic, with evidence of persistence of bactericidal antibodies for at least 12 months postvaccination.

For some trials, simple but subtle assumptions can have a profound impact on the size of the trial. A case in point is a vaccine lot consistency (or equivalence) trial. Standard sample size formulas used for designing lot consistency trials rely on only one component of variation, namely, the variation in antibody titers within lots. The other component, the variation in the means of titers between lots, is assumed to be equal to zero. In reality, some amount of variation between lots, however small, will be present even under the best manufacturing practices. Using data from a published lot consistency trial, we demonstrate that when the between-lot variation is only 0.5 per cent of the total variation, the increase in the sample size is nearly 300 per cent when compared with the size assuming that the lots are identical. The increase in the sample size is so pronounced that in order to maintain power one is led to consider a less stringent criterion for demonstration of lot consistency. The appropriate sample size formula that is a function of both components of variation is provided. We also discuss the increase in the sample size due to correlated comparisons arising from three pairs of lots as a function of the between-lot variance.

OBJECTIVE To determine the specificity of the Abbott Murex HIV antigen/antibody combination enzyme immunoassay (EIA) for the diagnosis of HIV infection in Tanzania. METHODS A cross-sectional survey of 7333 Tanzanian adolescents and young adults was carried out. Sera testing positive by the Murex assay were further evaluated using a battery of other EIA which detect either antibody to HIV-1 or p24 antigen, and by PCR using pol primers. RESULTS Of the 674 sera testing positive by the Murex assay, only 53 (7.9%) were confirmed. The specificity of the Murex assay was 91.5%. CONCLUSIONS Serological tests for HIV may perform differently in different populations. New diagnostic tests should not be introduced into populations in which they have not been evaluated.

OBJECTIVE: The impact of a multicomponent intervention programme on the sexual health of adolescents was assessed in rural Tanzania. DESIGN: A community-randomized trial. METHODS: Twenty communities were randomly allocated to receive either a specially designed programme of interventions (intervention group) or standard activities (comparison group). The intervention had four components: community activities; teacher-led, peer-assisted sexual health education in years 5-7 of primary school; training and supervision of health workers to provide 'youth-friendly' sexual health services; and peer condom social marketing. Impacts on HIV incidence, herpes simplex virus 2 (HSV2) and other sexual health outcomes were evaluated over approximately 3 years in 9645 adolescents recruited in late 1998 before entering years 5, 6 or 7 of primary school. RESULTS: The intervention had a significant impact on knowledge and reported attitudes, reported sexually transmitted infection symptoms, and several behavioural outcomes. Only five HIV seroconversions occurred in boys, whereas in girls the adjusted rate ratio (intervention versus comparison) was 0.75 [95% confidence interval (CI) 0.34, 1.66]. Overall HSV2 prevalences at follow-up were 11.9% in male and 21.1% in female participants, with adjusted prevalence ratios of 0.92 (CI 0.69, 1.22) and 1.05 (CI 0.83, 1.32), respectively. There was no consistent beneficial or adverse impact on other biological outcomes. The beneficial impact on knowledge and reported attitudes was confirmed by results of a school examination in a separate group of students in mid-2002. CONCLUSION: The intervention substantially improved knowledge, reported attitudes and some reported sexual behaviours, especially in boys, but had no consistent impact on biological outcomes within the 3-year trial period.

Objective: To assess the validity of sexual behaviour data collected from African adolescents using five methods. Methods: 9280 Tanzanian adolescents participated in a biological marker and face to face questionnaire survey and 6079 in an assisted self-completion questionnaire survey; 74 participated in in-depth interviews and 56 person weeks of participant observation were conducted. Results: 38% of males and 59% of females reporting sexual activity did so in only one of the two 1998 questionnaires. Only 58% of males and 29% of females with biological markers consistently reported sexual activity in both questionnaires. Nine of 11 (82%) in-depth interview respondents who had had biological markers provided an invalid series of responses about sex in the survey and in-depth interview series. Only one of six female in-depth interview respondents with an STI reported sex in any of the four surveys, but five reported it in the in-depth interviews. Conclusion: In this low prevalence population, biological markers on their own revealed that a few adolescents had had sex, but in combination with in-depth interviews they may be useful in identifying risk factors for STIs. Self-reported sexual behaviour data were fraught with inconsistencies. In-depth interviews seem to be more effective than assisted self-completion questionnaires and face to face questionnaires in promoting honest responses among females with STIs. Participant observation was the most useful method for understanding the nature, complexity, and extent of sexual behaviour.

Background/aims: The prevalence of significant refractive errors and other eye diseases was measured in 2511 secondary school students aged 11–27 years in Mwanza City, Tanzania. Risk factors for myopia were explored. Methods: A questionnaire assessed the students’ socioeconomic background and exposure to near work followed by visual acuity assessment and a full eye examination. Non-cycloplegic objective and subjective refraction was done on all participants with visual acuity of worse than 6/12 in either eye without an obvious cause. Results: 154 (6.1%) students had significant refractive errors. Myopia was the leading refractive error (5.6%). Amblyopia (0.4%), strabismus (0.2%), and other treatable eye disorders were uncommon. Only 30.3% of students with significant refractive errors wore spectacles before the survey. Age, sex, ethnicity, father’s educational status, and a family history of siblings with spectacles were significant independent risk factors for myopia. Conclusion: The prevalence of uncorrected significant refractive errors is high enough to justify a regular school eye screening programme in secondary schools in Tanzania. Risk factors for myopia are similar to those reported in European, North-American, and Asian populations.

The surrogate of protection against invasive meningococcal disease is the presence of serum bactericidal activity (SBA) at a titer ≥4 in an assay using human serum as the complement source (hSBA). However, for various practical and logistical reasons, many meningococcal vaccines in use today were licensed based on a modified SBA assay that used baby rabbit serum as the complement source (rSBA). To assess the strength of correlation between the two assay systems for serogroups A, C, W-135 and Y, we analyzed a subset of samples from adolescent subjects enrolled in a Phase II study of Novartis' MenACWY-CRM conjugate vaccine vs. an ACWY polysaccharide vaccine; samples were analyzed in parallel using hSBA and rSBA. We compared geometric mean titers (GMTs), calculated Pearson correlation coefficients between paired hSBA and rSBA results, and calculated sensitivity/specificity and likelihood ratios for an rSBA ≥8 or ≥128 for classifying hSBA ≥4, taking hSBA as the 'gold standard'. Correlations between hSBA and rSBA ranged from 0.46 to 0.78 for serogroup C, but were weaker for serogroups A, W-135 and Y (range -0.15 to 0.57). In post vaccination samples, nearly all subjects had rSBA titers ≥8, though up to 15% remained seronegative by hSBA. In post vaccination settings, rSBA titers at ≥8 or ≥128 was highly sensitive for an hSBA titer ≥4, but non-specific. In conclusion, results generated by rSBA did not accurately classify serostatus according to hSBA for serogroups A, W-135 and Y.

The persistence of human bactericidal activity (hSBA) responses in adolescents was assessed 22 months after vaccination with one dose of Menveo® (MenACWY-CRM; Novartis) or Menactra® (MCV4) (sanofi pasteur). The proportion of subjects with hSBA titers ≥8 was significantly higher among recipients of MenACWY-CRM than MCV4 for serogroups A, W-135 and Y.

Background: Typhoid fever causes more than 21 million cases of disease and 200,000 deaths yearly worldwide, with more than 90% of the disease burden being reported from Asia. Epidemiological data show high disease incidence in young children and suggest that immunization programs should target children below two years of age: this is not possible with available vaccines. The Novartis Vaccines Institute for Global Health developed a conjugate vaccine (Vi-CRM197) for infant vaccination concomitantly with EPI vaccines, either starting at 6 weeks with DTP or at 9 months with measles vaccine. We report the results from a Phase 1 and a Phase 2 dose ranging trial with Vi-CRM197 in European adults. Methodology: Following randomized blinded comparison of single vaccination with either Vi-CRM197 or licensed polysaccharide vaccines (both containing 25•0 µg of Vi antigen), a randomised observer blinded dose ranging trial was performed in the same center to compare three concentrations of Vi-CRM197 (1•25 µg, 5•0 µg and 12•5 µg of Vi antigen) with the polysaccharide vaccine. These studies are registered with ClinicalTrials.gov, number NCT01123941 and NCT01193907. Principal Findings: All vaccines were well tolerated. Compared to the polysaccharide vaccine, Vi-CRM197 induced a higher incidence of mild to moderate short lasting local pain. All Vi-CRM197 formulations induced higher Vi antibody levels compared to licensed control, with clear dose response relationship. Conclusions: Vi-CRM197 did not elicit safety concerns, was highly immunogenic and is therefore suitable for further clinical testing in endemic populations of South Asia.

This study evaluated the safety, tolerability, and immunogenicity of an investigational quadrivalent meningococcal conjugate vaccine, MenACWY-CRM, when administered concomitantly with a combined tetanus, reduced diphtheria, and acellular pertussis (Tdap) vaccine, in subjects aged 11 to 25 years. Subjects received either MenACWY-CRM and Tdap, MenACWY-CRM and saline placebo, or Tdap and saline placebo. No significant increase in reactogenicity and no clinically significant vaccine-related adverse events (AEs) occurred when MenACWY-CRM and Tdap were administered concomitantly. Similar immunogenic responses to diphtheria, tetanus, and meningococcal (serogroups A, C, W-135, and Y) antigens were observed, regardless of concomitant vaccine administration. Antipertussis antibody responses were comparable between vaccine groups for filamentous hemagglutinin and were slightly lower, although not clinically significantly, for pertussis toxoid and pertactin when the two vaccines were administered concomitantly. These results indicate that the investigational MenACWY-CRM vaccine is well tolerated and immunogenic and that it can be coadministered with Tdap to adolescents and young adults.

This Phase III study evaluates an investigational quadrivalent meningococcal CRM(197) conjugate vaccine, MenACWY-CRM (Novartis Vaccines), when administered concomitantly or sequentially with two other recommended adolescent vaccines; combined tetanus, reduced diphtheria and acellular pertussis (Tdap), and human papillomavirus (HPV) vaccine. In this single-centre study, 1620 subjects 11-18 years of age, were randomized to three groups (1:1:1) to receive MenACWY-CRM concomitantly or sequentially with Tdap and HPV. Meningococcal serogroup-specific serum bactericidal assay using human complement (hSBA), and antibodies to Tdap antigens and HPV virus-like particles were determined before and 1 month after study vaccinations. Proportions of subjects with hSBA titres > or =1:8 for all four meningococcal serogroups (A, C, W-135, Y) were non-inferior for both concomitant and sequential administration. Immune responses to Tdap and HPV antigens were comparable when these vaccines were given alone or concomitantly with MenACWY-CRM. All vaccines were well tolerated; concomitant or sequential administration did not increase reactogenicity. MenACWY-CRM was well tolerated and immunogenic in subjects 11-18 years of age, with comparable immune responses to the four serogroups when given alone or concomitantly with Tdap or HPV antigens. This is the first demonstration that these currently recommended adolescent vaccines could be administered concomitantly without causing increased reactogenicity.

BACKGROUND: The highest rate of invasive meningococcal disease is among children under 2 years of age. There is currently no licensed quadrivalent (serogroups A, C, W-135, and Y) meningococcal glycoconjugate vaccine approved for infants. We evaluated the immunogenicity and reactogenicity of a novel quadrivalent nonadjuvanted meningococcal glycoconjugate vaccine (MenACWY-CRM) in healthy infants. METHODS: One hundred eighty infants (90 in Canada and 90 in the United Kingdom) received 2 doses of MenACWY-CRM at 2 and 4 months of age administered concomitantly with routine infant vaccines. At 12 months of age, the Canadian infants received either MenACWY-CRM or a reduced dose of a licensed meningococcal polysaccharide vaccine. In the United Kingdom, all infants received a further dose of MenACWY-CRM. The serological marker of protection was a titer of > or =1:4 using a serum bactericidal assay with human complement (hSBA). RESULTS: Two doses of MenACWY-CRM induced hSBA titers > or =1:4 in 57% (95% confidence interval [CI]: 45-67) and 50% (95% CI: 38-62) of infants against serogroup A in Canada and the United Kingdom, respectively, 93% (95% CI: 85-97) and 86% (95% CI: 46-93) against serogroup C, 95% (95% CI: 87-99) and 82% (95% CI: 71-90) against serogroup W-135, and 91% (95% CI: 82-96) and 74% (95% CI: 63-83) against serogroup Y. After a booster dose of MenACWY-CRM at 12 months, at least 94% of participants achieved hSBA titers > or =1:4 against each of the serogroups C, W-135, and Y and more than 79% against serogroup A. The vaccine was well tolerated. CONCLUSIONS: The nonadjuvanted MenACWY-CRM is immunogenic and well tolerated in infancy and could provide broad protection against meningococcal disease in this vulnerable age group.

Context Immunization with a meningococcal tetravalent (serogroup ACWY) glycoconjugate vaccine is recommended for all US adolescents. However, the currently licensed vaccine is poorly immunogenic in infancy, when the highest rates of disease are observed. Objective To determine the immunogenicity of a novel tetravalent CRM197-conjugated meningococcal vaccine (MenACWY) in infants. Design, Setting, and ParticipantsRandomized, open-label, controlled study of 225 UK and 196 Canadian 2-month-olds from August 2004 to September 2006.Intervention UK infants received a primary course of MenACWY (at 2, 3, and 4 months or 2 and 4 months) or Neisseria meningitidis serogroup C monovalent meningococcal glycoconjugate vaccine (MenC) (at 2 and 4 months). All received MenACWY at 12 months. Canadian infants received MenACWY at 2, 4, and 6 months or 2 and 4 months; at 12 months they received MenACWY, a plain tetravalent polysaccharide vaccine, or no vaccine. Main Outcome MeasurePercentage of infants with a human complement serum bactericidal activity (hSBA) titer ≥1:4 after a primary course of MenACWY and after a 12-month booster. Safety and reactogenicity of MenACWY were also assessed.Results According to the prespecified per-protocol analysis, the percentages (95% CIs) of MenACWY 2-, 3-, and 4-month recipients with hSBA titers ≥1:4 after primary immunization were serogroup A, 93% (84%-98%); C, 96% (89%-99%); W-135, 97% (90%-100%); and Y, 94% (86%-98%). With a post hoc intention-to-treat analysis with imputed values for missing data, these values were unchanged for serogroups C and Y; for serogroup A, values were 92% (84%-97%), and for W-135, 97% (91%-99%). For the per-protocol analysis of MenACWY 2-, 4-, and 6-month recipients, the percentages (95% CIs) of responders were A, 81% (71%-89%); C, 98% (92%-100%); W-135, 99% (93%-100%); and Y, 98% (92%-100%). With the imputed value analysis, these values were A, 83% (74%-89%); C, 98% (93%-99%); W-135, 99% (94%-100%); and Y, 98% (92%-99%). At least 84% of MenACWY 2- and 4-month recipients achieved hSBA titers ≥1:4 for serogroups C, W-135, and Y after primary immunization, as did at least 60% for serogroup A (per-protocol and imputation analysis). At least 95% of primary and booster MenACWY recipients achieved hSBA titers ≥1:4 for serogroups C, W-135, and Y at 13 months, as did at least 84% for serogroup A (per-protocol and imputation analysis). During the primary immunization course, postimmunization pain on leg movement was observed in 2% of UK MenACWY 2- and 4-month recipients and 4% of MenC 2- and 4-month recipients; a temperature of 38°C or greater was observed in 4% and 2% in these groups, respectively. ConclusionMenACWY is well tolerated and immunogenic in infancy.Trial Registration clinicaltrials.gov Identifier: NCT00262002

To determine the specificity of the Abbott Murex HIV antigen/antibody combination enzyme immunoassay (EIA) for the diagnosis of HIV infection in Tanzania.A cross-sectional survey of 7333 Tanzanian adolescents and young adults was carried out. Sera testing positive by the Murex assay were further evaluated using a battery of other EIA which detect either antibody to HIV-1 or p24 antigen, and by PCR using pol primers.Of the 674 sera testing positive by the Murex assay, only 53 (7.9%) were confirmed. The specificity of the Murex assay was 91.5%.Serological tests for HIV may perform differently in different populations. New diagnostic tests should not be introduced into populations in which they have not been evaluated.

Trachoma causes blindness; the prevention strategy includes mass antibiotic treatment. In a community in Northern Tanzania offered mass treatment with azithromycin for the control of trachoma, we used focus group discussions, individual interviews, questionnaires and direct observation to quantify, explore and contextualize reasons for acceptance or refusal of the drug. In the village studied, 76% of the population eligible to receive azithromycin were treated. Uptake was significantly higher among women (79% treated) than men (72%). Factors affecting acceptability included: local prevention norms (such as the belief that injections, rather than oral medicine, should be used for prevention); perceptions of drugs in general and azithromycin in particular; perceptions of the distribution team's expertise; witnessing adverse effects in others; and the timing, quality and quantity of information about azithromycin and its availability. Familiarity with trachoma as a blinding disease was significantly associated with uptake. Individuals who refused treatment seemed to be less altruistic than other respondents. Neither socio-economic status nor use of traditional healers was related to uptake. Pre-distribution community assessment and community education, advance notice of the distribution, standardized distribution guidelines and improved distributor training are recommended to maximize acceptance of azithromycin in future campaigns.

OBJECTIVES To develop and test a sexual behaviour survey method for semi-literate populations, combining the privacy of a self-completion questionnaire (SCQ) with the clarity of a face-to-face questionnaire (FFQ). METHODS In 1998, 6079 Tanzanian primary school students (mean age 15.1 years) were surveyed using an innovative assisted self-completion questionnaire (ASCQ). The format of the questionnaire was simple, all responses were closed, and conceptually complex questions such as those involving ranking or multiple answers were avoided. The ASCQ was administered to groups of 20 by a research assistant who read questions and answers aloud in two languages so pupils could tick or write responses independently. A total of 4958 of respondents from the 1998 ASCQ Cohort also participated in a 1998 FFQ interview and, in 2000, 4424 again completed an ASCQ. RESULTS In the 1998 ASCQ survey, 55.0% of males and 21.1% of females reported they had had vaginal intercourse, of whom 71.5% and 66.0%, respectively reported their first sexual relationship lasted for a week or less, and 49.5% and 59.6%, respectively reported they had had sex in the last 4 weeks. After adjustment for age, reported sex was associated with alcohol use in both males (OR = 1.57) and females (OR = 1.69), earning money for males (OR = 1.32) and not living with a mother for females (OR = 0.77). The vast majority of respondents did not appear to have difficulty completing the ASCQ, but 7.4% of 1998 respondents and 2.9% of 2000 respondents selected all first or all last answers in a section for which this was inconsistent. This bias was associated with female, less educated and more geographically remote respondents. Of those respondents who reported sex in the 1998 ASCQ survey, 32.1% reported fewer total partners in the 2000 ASCQ survey, 25.2% reported having had sex fewer times than originally reported, and 61.9% of those who reported having used a condom in 1998 reported never having used one in 2000. While the proportions reporting sex were very similar in the 1998 ASCQ and FFQ surveys, 37.9% of males and 59.2% of females reporting sex only did so on one of the two questionnaires. Higher proportions of respondents reported sensitive information in the ASCQ than the FFQ, although in some cases this may have related to answer order bias. CONCLUSION The results suggest that an ASCQ may be useful in assessing sexual behaviour in African adolescents, particularly for older, male and/or educated respondents. However, triangulation with data from other surveys raises questions about the validity of self-reported sexual behaviour in general.

Objectives: To measure the prevalence of HIV and other STIs in communities neighbouring new large scale gold mines in northern Tanzania in order to inform the design of a targeted HIV/STI intervention programme. Methods: Cross sectional surveys were conducted in adults aged 16–54 years from different sectors of communities neighbouring two newly opened, large scale gold mines near Lake Victoria. Mine workers, men, women, and female food and recreational facility workers (FRFW) from the community were randomly selected for interview and HIV and STI testing. Results: 207 male Tanzanian mine workers, 206 FRFW, 202 other male and 205 female community members were enrolled. Overall, 42% of FRFW were HIV positive, compared to 6% of male mine workers, and 16% and 18% of other community men and women respectively. HIV prevalence in FRFW was significantly associated with alcohol consumption (adjusted odds ratio (aOR) = 2.5, 95% confidence interval (CI) 1.1 to 5.5), past or present syphilis (TPPA+) (aOR = 2.7, 95% CI 1.4 to 5.1) and single status (aOR = 3.8, 95% CI 1.2 to 11.9). Among FRFW, 24% had active syphilis (RPR+, TPPA+), 9% Chlamydia trachomatis, and 4% Neisseria gonorrhoeae. Overall, 50% of FRFW and 50% of community men never used condoms during sex, and 55% mineworkers, 61% male, and 20% female community members reported receiving/giving payment for sex during the previous year. Conclusions: There is a high prevalence of HIV and other STIs in communities around new goldmines in Tanzania, especially in FRFW. HIV and STI prevalence in the mining workforce is still relatively low, but high risk sexual behaviour is reported by all adult subgroups surveyed in this study. Programmes focusing on HIV/STI prevention, with targeted interventions for high risk women such as FRFW, will be extremely important in such high transmission communities where there is substantial recent in-migration of men and women seeking work. Such programmes have recently been initiated by a private/public/NGO partnership.

Objective: The present study was carried out to evaluate the safety and immunogenicity of the Haemophilus influenzae type b-CRM 1 9 7 (Hib-CRM 1 9 7 ) conjugate vaccine in relation to the change of adjuvant from aluminum hydroxide to aluminum phosphate (AlPO 4 ). Methods: The present study was a clinical phase II, observer-blind, randomized, multicenter, controlled study. Subjects were healthy infants aged 6-12 weeks, eligible for expanded program of immunization (EPI) routine vaccination and admitted to Hacettepe University Department of Social Pediatrics and Giilveren Health Center, Ankara. A total of 520 healthy infants were randomized in a 2:2:1 ratio to receive at either Chiron Hib/AlPO 4 vaccine or VaxemHib (aluminum hydroxide adjuvant) vaccine or HibTiter (no adjuvant). Vaccines were administered simultaneously with routine diphtheria, tetanus and pertussis (DTaP) and oral polio vaccine (OPV) vaccines at 2, 4 and 6 months of age. Blood samples for anti-plain polysaccharide (PRP) antibody measurement were collected before the first vaccination and 1 month after the last vaccination. After each vaccination parents filled out a diary for 7 days. Results: Out of 520 subjects enrolled, 514 received three doses and were included for safety analysis. Local and systemic reactions occurred with low and similar frequencies in all groups. Only erythema was more common in Chiron Hib/AlPO 4 vaccine (19, 10, 11% in Chiron Hib/AlPO 4 , VaxemHib and HibTiter, respectively, P < 0.05). Nine serious adverse events were reported in seven cases of which none were related to vaccines. A total of 504 subjects were included in the immunogenicity analysis. The three vaccines were highly immunogenic and equivalent in terms of percentage of acquisition of long-term protective levels. The anti-PRP geometric mean titers were 9.9, 8.3 and 5.14 pg/mL, respectively (P < 0.05). Conclusions: The use of aluminum compounds adjuvants in Hib-CRM 1 9 7 conjugate vaccines does not impact the safety profile, while it does increase the magnitude of anti-PRP antibody titers.

535 Immunogenicity Profile of Menveo ® in Adolescents and Adults Enrolled in Phase III Clinical Trials

532 Safety Profile of Menveo ® in Adolescents and Adults Enrolled in Phase Iii Clinical Trials