Search

OBJECTIVE: To carry out a comparative study of the safety and immunogenicity of Vi polysaccharide vaccine against whole-cell killed (WCK) typhoid vaccine. METHODS: The study was carried out on young adult recruits (aged 18-25 years) of the Malaysian Air Force. A total of 125 subjects received the Vi polyssacharide vaccine and 114 received the WCK vaccine. FINDINGS: The Vi vaccine was significantly less reactogenic than the WCK vaccine with regard to systemic and local reactions. Following administration of the Vi vaccine, seroconversion rates (defined as the percentage of subjects with a 4-fold rise of baseline antibody level) of 75.5% and 67% were observed at 2 weeks and 6 weeks, respectively, after immunization, compared with 25% and 31.3% among recipients of the WCK vaccine. Of the 110 Vi vaccinees with serological data, 21 (19%) had high, seroprotective, pre-immunization levels of anti-Vi antibodies ( > or = 1 mug/ml). The majority of subjects in this group came from a region in Malaysia which is known to have high typhoid endemicity. Interestingly, these antibody levels were boosted considerably following administration of vaccine at a level that was 5- fold higher than in subjects with low pre- immunization levels. In contrast, the seroconversion rates in those receiving the Vi vaccine were higher in subjects with low pre-immunization levels of anti-Vi antibodies (76-84%), compared to those with protective levels of > or = 1 mug/ml prior to immunization (48-57%). CONCLUSIONS: The study reaffirms the safety and efficacy of the Vi polysaccharide vaccine and identifies a hitherto unrecognized advantage in its use, i.e. it is a potent immunogen that boosted considerably the protective antibody levels among a significant number of immunologically sensitized individuals living in typhoid-endemic regions.

Malaria volunteer infection studies (VISs) accelerate new drug and vaccine development. In the induced blood-stage malaria (IBSM) model, volunteers are inoculated with erythrocytes infected with Plasmodium falciparum . Observations of elevated liver enzymes in the IBSM model with new chemical entities (NCEs) promoted an analysis of available data. Data were reviewed from eight IBSM studies of seven different NCEs, plus two studies with the registered antimalarial piperaquine conducted between June 2013 and January 2017 at QIMR Berghofer, Brisbane, Australia. Alanine aminotransferase (ALT) was elevated (> 2.5 times the upper limit of normal [×ULN]) in 20/114 (17.5%) participants. Of these, 8.9% (10/114) had moderate increases (> 2.5-5 × ULN), noted in seven studies of six different NCEs ± piperaquine or piperaquine alone, and 8.9% (10/114) had severe elevations (> 5 × ULN), occurring in six studies of six different NCEs ± piperaquine. Aspartate aminotransferase (AST) was elevated (> 2.5 × ULN) in 11.4% (13/114) of participants, across six of the 10 studies. Bilirubin was > 2 × ULN in one participant. Published data from other VIS models, using sporozoite inoculation by systemic administration or mosquito feeding, also showed moderate/severe liver enzyme elevations. In conclusion, liver enzyme elevations in IBSM studies are most likely multifactorial and could be caused by the model conditions, that is, malaria infection/parasite density and/or effective parasite clearance, or by participant-specific risk factors, acetaminophen administration, or direct hepatotoxicity of the test drug. We make recommendations that may mitigate the risk of liver enzyme elevations in future VISs and propose measures to assist their interpretation, should they occur.

Background: Cambodia is the epicentre of resistance emergence for virtually all antimalarial drugs. Selection and spread of parasites resistant to artemisinin-based combination therapy (ACT) is a major threat for malaria elimination, hence the need to renew the pool of effective treatments., Objectives: To determine whether ACT resistance haplotypes could have an effect on ferroquine in vitro antimalarial activity., Methods: In vitro susceptibility to ferroquine was measured for 80 isolates from Cambodia characterized for their molecular resistance profile to artemisinin, piperaquine and mefloquine., Results: Among the 80 isolates tested, the overall median (IQR) IC50 of ferroquine was 10.9 nM (8.7-18.3). The ferroquine median (IQR) IC50 was 8.9 nM (8.1-11.8) for Pfk13 WT parasites and was 12.9 nM (9.5-20.0) for Pfk13 C580Y parasites with no amplification of Pfpm2 and Pfmdr1 genes. The median (IQR) IC50 of ferroquine for Pfk13 C580Y parasites with amplification of the Pfpm2 gene was 17.2 nM (14.5-20.5) versus 9.1 nM (7.9-10.7) for Pfk13 C580Y parasites with amplification of the Pfmdr1 gene., Conclusions: Ferroquine exerts promising efficacy against ACT-resistant isolates. Whereas Pfpm2 amplification was associated with the highest parasite tolerance to ferroquine, the susceptibility range observed was in accordance with those measured in ACT resistance-free areas. This enables consideration of ferroquine as a relevant therapeutic option against ACT-resistant malaria., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Plasmodium falciparum prevalence (PfPR) is a widely used metric for assessing malaria transmission intensity. This study was carried out concurrently with the RTS,S/AS01 candidate malaria vaccine Phase III trial and estimated PfPR over ≤ 4 standardized cross-sectional surveys., Methods: This epidemiology study (NCT01190202) was conducted in 8 sites from 6 countries (Burkina Faso, Gabon, Ghana, Kenya, Malawi, and Tanzania), between March 2011 and December 2013. Participants were enrolled in a 2:1:1 ratio according to age category: 6 months-4 years, 5-19 years, and ≥ 20 years, respectively, per year and per centre. All sites carried out surveys 1-3 while survey 4 was conducted only in 3 sites. Surveys were usually performed during the peak malaria parasite transmission season, in one home visit, when medical history and malaria risk factors/prevention measures were collected, and a blood sample taken for rapid diagnostic test, microscopy, and haemoglobin measurement. PfPR was estimated by site and age category., Results: Overall, 6401 (survey 1), 6411 (survey 2), 6400 (survey 3), and 2399 (survey 4) individuals were included in the analyses. In the 6 months-4 years age group, the lowest prevalence (assessed using microscopy) was observed in 2 Tanzanian centres (4.6% for Korogwe and 9.95% for Bagamoyo) and Lambaréné, Gabon (6.0%), while the highest PfPR was recorded for Nanoro, Burkina Faso (52.5%). PfPR significantly decreased over the 3 years in Agogo (Ghana), Kombewa (Kenya), Lilongwe (Malawi), and Bagamoyo (Tanzania), and a trend for increased PfPR was observed over the 4 surveys for Kintampo, Ghana. Over the 4 surveys, for all sites, PfPR was predominantly higher in the 5-19 years group than in the other age categories. Occurrence of fever and anaemia was associated with high P. falciparum parasitaemia. Univariate analyses showed a significant association of anti-malarial treatment in 4 surveys (odds ratios [ORs]: 0.52, 0.52, 0.68, 0.41) and bed net use in 2 surveys (ORs: 0.63, 0.68, 1.03, 1.78) with lower risk of malaria infection., Conclusion: Local PfPR differed substantially between sites and age groups. In children 6 months-4 years old, a significant decrease in prevalence over the 3 years was observed in 4 out of the 8 study sites. Trial registration Clinical Trials.gov identifier: NCT01190202:NCT. GSK Study ID numbers: 114001.

Background: Malaria remains a major global public health concern, especially in sub-Saharan Africa. The RTS,S/AS01 malaria candidate vaccine was reviewed by the European Medicines Agency and received a positive scientific opinion; WHO subsequently recommended pilot implementation in sub-Saharan African countries. Because malaria and HIV overlap geographically, HIV-infected children should be considered for RTS,S/AS01 vaccination. We therefore aimed to assess the safety of RTS,S/AS01 in HIV-infected children at two sites in western Kenya., Methods: We did a randomised, double-blind, controlled trial at the clinical trial sites of the Kenya Medical Research Institute (KEMRI)-Walter Reed Army Institute of research in Kisumu and the KEMRI/US Centers for Disease Control and Prevention in Siaya. Eligible participants were infants and children aged from 6 weeks to 17 months with WHO stage 1 or 2 HIV disease (documented positive by DNA PCR), whether or not they were receiving antiretroviral therapy (ART). We randomly assigned participants (1:1) to receive three doses of either RTS,S/AS01 or rabies vaccine (both 0·5 mL per dose by intramuscular injection), given once per month at 0, 1, and 2 months. We did the treatment allocation using a web-based central randomisation system stratified by age (6 weeks-4 months, 5-17 months), and by baseline CD4% (<10, 10-14, 15-19, and ≥20). Data were obtained in an observer-blind manner, and the vaccine recipient, their parent or carer, the funder, and investigators responsible for the assessment of endpoints were all masked to treatment allocation (only staff responsible for the preparation and administration of the vaccines were aware of the assignment and these individuals played no other role in the study). We provided ART, even if the participants were not receiving ART before the study, and daily co-trimoxazole for prevention of opportunistic infections. The primary outcome was the occurrence of serious adverse events until 14 months after dose 1 of the vaccine, assessed in the intention-to-treat population. This trial was registered at ClinicalTrials.gov, number NCT01148459., Findings: Between July 30, 2010, and May 24, 2013, we enrolled 200 children to our study and randomly assigned 99 to receive RTS,S/AS01 and 101 to receive rabies vaccine. 177 (89%) of the 200 children enrolled completed 14 months of follow-up. Serious adverse events were noted in 41 (41·4%, 95% CI 31·6-51·8) of 99 RTS,S/AS01 recipients and 37 (36·6%, 27·3-46·8) of 101 rabies-vaccine recipients (relative risk 1·1, 95% CI 0·8-1·6). 20 (20·2%, 95% CI 12·8-29·5) of 99 RTS,S/AS01 recipients and 12 (11·9%, 6·3-19·8) of 101 rabies-vaccine recipients had at least one serious adverse event within 30 days after vaccination, mainly pneumonia, febrile convulsions, and salmonella sepsis. Five (5·1%, 95% CI 1·7-11·4) of 99 RTS,S/AS01 recipients and four (4·0%, 1·1-9·8) of 101 rabies-vaccine recipients died, but no deaths were deemed related to vaccination. Mortality was associated with five cases of pneumonia (1% RTS,S/AS01 recipients vs 3% rabies-vaccine recipients), five cases of gastroenteritis (3% RTS,S/AS01 recipients vs 2% rabies-vaccine recipients), five cases of malnutrition (2% RTS,S/AS01 recipients vs 3% rabies-vaccine recipients), one case of sepsis (1% rabies-vaccine recipients), one case of Haemophilus influenza meningitis (1% rabies-vaccine recipients), and one case of tuberculosis (1% RTS,S/AS01 recipients)., Interpretation: RTS, S/AS01 was well tolerated when given to children with WHO clinical stage 1 or 2 HIV disease along with high antiretroviral and co-trimoxazole use. Children with HIV disease could be included in future RTS,S/AS01 vaccination programmes., Funding: GlaxoSmithKline Biologicals SA and PATH Malaria Vaccine Initiative., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Vaccines interrupting Plasmodium falciparum malaria transmission targeting sexual, sporogonic, or mosquito-stage antigens (SSM-VIMT) are currently under development to reduce malaria transmission. An international group of malaria experts was established to evaluate the feasibility and optimal design of a Phase III cluster randomized trial (CRT) that could support regulatory review and approval of an SSM-VIMT. The consensus design is a CRT with a sentinel population randomly selected from defined inner and buffer zones in each cluster, a cluster size sufficient to assess true vaccine efficacy in the inner zone, and inclusion of ongoing assessment of vaccine impact stratified by distance of residence from the cluster edge. Trials should be conducted first in areas of moderate transmission, where SSM-VIMT impact should be greatest. Sample size estimates suggest that such a trial is feasible, and within the range of previously supported trials of malaria interventions, although substantial issues to implementation exist., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

New interventions are needed to reduce morbidity and mortality associated with malaria, as well as to accelerate elimination and eventual eradication. Interventions that can break the cycle of parasite transmission, and prevent its reintroduction, will be of particular importance in achieving the eradication goal. In this regard, vaccines that interrupt malaria transmission (VIMT) have been highlighted as an important intervention, including transmission-blocking vaccines that prevent human-to-mosquito transmission by targeting the sexual, sporogonic, or mosquito stages of the parasite (SSM-VIMT). While the significant potential of this vaccine approach has been appreciated for decades, the development and licensure pathways for vaccines that target transmission and the incidence of infection, as opposed to prevention of clinical malaria disease, remain ill-defined. This article describes the progress made in critical areas since 2010, highlights key challenges that remain, and outlines important next steps to maximize the potential for SSM-VIMTs to contribute to the broader malaria elimination and eradication objectives., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The candidate malaria vaccine RTS,S/AS01E has entered phase 3 trials, but data on long-term outcomes are limited., Methods: For 4 years, we followed children who had been randomly assigned, at 5 to 17 months of age, to receive three doses of RTS,S/AS01E vaccine (223 children) or rabies vaccine (224 controls). The end point was clinical malaria (temperature of ≥37.5°C and Plasmodium falciparum parasitemia density of >2500 parasites per cubic millimeter). Each child's exposure to malaria was estimated with the use of the distance-weighted local prevalence of malaria., Results: Over a period of 4 years, 118 of 223 children who received the RTS,S/AS01E vaccine and 138 of 224 of the controls had at least 1 episode of clinical malaria. Vaccine efficacies in the intention-to-treat and per-protocol analyses were 29.9% (95% confidence interval [CI], 10.3 to 45.3; P=0.005) and 32.1% (95% CI, 11.6 to 47.8; P=0.004), respectively, calculated by Cox regression. Multiple episodes were common, with 551 and 618 malarial episodes in the RTS,S/AS01E and control groups, respectively; vaccine efficacies in the intention-to-treat and per-protocol analyses were 16.8% (95% CI, -8.6 to 36.3; P=0.18) and 24.3% (95% CI, 1.9 to 41.6; P=0.04), respectively, calculated by the Andersen-Gill extension of the Cox model. For every 100 vaccinated children, 65 cases of clinical malaria were averted. Vaccine efficacy declined over time (P=0.004) and with increasing exposure to malaria (P=0.001) in the per-protocol analysis. Vaccine efficacy was 43.6% (95% CI, 15.5 to 62.3) in the first year but was -0.4% (95% CI, -32.1 to 45.3) in the fourth year. Among children with a malaria-exposure index that was average or lower than average, the vaccine efficacy was 45.1% (95% CI, 11.3 to 66.0), but among children with a malaria-exposure index that was higher than average it was 15.9% (95% CI, -11.0 to 36.4)., Conclusions: The efficacy of RTS,S/AS01E vaccine over the 4-year period was 16.8%. Efficacy declined over time and with increasing malaria exposure. (Funded by the PATH Malaria Vaccine Initiative and Wellcome Trust; ClinicalTrials.gov number, NCT00872963.).

Background: The candidate malaria vaccine RTS,S/AS01 reduced episodes of both clinical and severe malaria in children 5 to 17 months of age by approximately 50% in an ongoing phase 3 trial. We studied infants 6 to 12 weeks of age recruited for the same trial., Methods: We administered RTS,S/AS01 or a comparator vaccine to 6537 infants who were 6 to 12 weeks of age at the time of the first vaccination in conjunction with Expanded Program on Immunization (EPI) vaccines in a three-dose monthly schedule. Vaccine efficacy against the first or only episode of clinical malaria during the 12 months after vaccination, a coprimary end point, was analyzed with the use of Cox regression. Vaccine efficacy against all malaria episodes, vaccine efficacy against severe malaria, safety, and immunogenicity were also assessed., Results: The incidence of the first or only episode of clinical malaria in the intention-to-treat population during the 14 months after the first dose of vaccine was 0.31 per person-year in the RTS,S/AS01 group and 0.40 per person-year in the control group, for a vaccine efficacy of 30.1% (95% confidence interval [CI], 23.6 to 36.1). Vaccine efficacy in the per-protocol population was 31.3% (97.5% CI, 23.6 to 38.3). Vaccine efficacy against severe malaria was 26.0% (95% CI, -7.4 to 48.6) in the intention-to-treat population and 36.6% (95% CI, 4.6 to 57.7) in the per-protocol population. Serious adverse events occurred with a similar frequency in the two study groups. One month after administration of the third dose of RTS,S/AS01, 99.7% of children were positive for anti-circumsporozoite antibodies, with a geometric mean titer of 209 EU per milliliter (95% CI, 197 to 222)., Conclusions: The RTS,S/AS01 vaccine coadministered with EPI vaccines provided modest protection against both clinical and severe malaria in young infants. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619.).

Many new interventions are being created to address health problems of the developing world. However, many developing countries have fragile health systems and find it difficult to accommodate change. Consequently, it is essential that new interventions are well aligned with health systems and their users. Establishing target product profiles (TPPs) is a critical, early step towards tailoring interventions to suit both of these constituencies. Specific analyses can help identify and establish relevant TPP criteria such as optimal formulation, presentation and packaging. Clinical trials for a new intervention should be designed to address both TPP-specific questions and anticipated use of the intervention in target countries. Examples are provided from research on malaria vaccines that are also applicable to other new public health interventions.

Background: An ongoing phase 3 study of the efficacy, safety, and immunogenicity of candidate malaria vaccine RTS,S/AS01 is being conducted in seven African countries., Methods: From March 2009 through January 2011, we enrolled 15,460 children in two age categories--6 to 12 weeks of age and 5 to 17 months of age--for vaccination with either RTS,S/AS01 or a non-malaria comparator vaccine. The primary end point of the analysis was vaccine efficacy against clinical malaria during the 12 months after vaccination in the first 6000 children 5 to 17 months of age at enrollment who received all three doses of vaccine according to protocol. After 250 children had an episode of severe malaria, we evaluated vaccine efficacy against severe malaria in both age categories., Results: In the 14 months after the first dose of vaccine, the incidence of first episodes of clinical malaria in the first 6000 children in the older age category was 0.32 episodes per person-year in the RTS,S/AS01 group and 0.55 episodes per person-year in the control group, for an efficacy of 50.4% (95% confidence interval [CI], 45.8 to 54.6) in the intention-to-treat population and 55.8% (97.5% CI, 50.6 to 60.4) in the per-protocol population. Vaccine efficacy against severe malaria was 45.1% (95% CI, 23.8 to 60.5) in the intention-to-treat population and 47.3% (95% CI, 22.4 to 64.2) in the per-protocol population. Vaccine efficacy against severe malaria in the combined age categories was 34.8% (95% CI, 16.2 to 49.2) in the per-protocol population during an average follow-up of 11 months. Serious adverse events occurred with a similar frequency in the two study groups. Among children in the older age category, the rate of generalized convulsive seizures after RTS,S/AS01 vaccination was 1.04 per 1000 doses (95% CI, 0.62 to 1.64)., Conclusions: The RTS,S/AS01 vaccine provided protection against both clinical and severe malaria in African children. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619 .).

The immunogenicity and safety of Okavax trade mark varicella vaccine, when administered concomitantly with Trimovax trade mark measles, mumps, and rubella (MMR) vaccine, were assessed in 300 Filipino children 12-24 months old. Three groups received Okavax only, Trimovax only, or both vaccines concomitantly. In sera obtained six weeks after vaccination, high varicella antibody geometric mean titers (GMTs) (115 and 79.8 mIU/mL, respectively) and seroconversion rates (>or= 91.9%) were similar for Okavax given alone or concomitantly with Trimovax. High MMR GMTs and seroconversion rates (mumps >or= 94.6%, measles and rubella >or= 98.6%) were not affected by concomitant administration of Trimovax with Okavax. Solicited local and systemic reactions recorded by parents were slightly more numerous after concomitant administration, but the majority of all reactions were mild and transient. The good tolerance and high immunogenicity observed supports the concomitant administration of Okavax and Trimovax to children in their second year of life to protect against four life-threatening diseases while simplifying childhood immunization programs.

This trial was conducted to assess the immunogenicity and safety of the varicella vaccine, Okavax, when administered concomitantly with the measles, mumps and rubella vaccine, MMR-II, to children aged 12-24 months. A total of 299 children were randomized into three groups, those receiving Okavax only, MMR-II only, or both vaccines concomitantly. Antibody titers were determined by ELISA in blood samples taken immediately before, and 6 weeks after, vaccination. Parents recorded local and systemic reactions. Okavax elicited similar varicella seroconversion rates (> or = 93.9%) and high GMTs when given alone or with MMR-II (99.6 and 95.7 mIU/ml, respectively). The seroconversion rates (measles and rubella 100%, mumps > or = 75.0%) and high GMTs elicited by MMR-II were not affected by concomitant administration of Okavax. The incidence of adverse events was similar whether MMR-II and Okavax were administered concomitantly or separately, and the majority of local reactions were mild and transient, with fever the most frequent systemic event in all groups. In conclusion, these results show that the immune response and the reactogenicity profile of Okavax and MMR-II were similar when given together or alone. Concomitant administration of these vaccines can therefore be recommended for children in their second year of life.

Objective: To estimate frequency of acute bacterial meningitis (ABM) in early childhood in hospital admissions, to describe clinical and diagnostic features, and to analyze mortality, complications and long term sequelae., Design: Prospective study., Setting: Pediatric wards and Rehabilitation Center of KEM Hospital, Pune., Method: Study subjects between the ages of 1 months to 5 years with ABM were recruited. Clinical details were recorded. CSF was analysed by routine biochemical methods, antigen detection tests (Latex agglutination LAT) and microbiological studies on special media. Management was as per standard protocols. Survivors were followed up long term with neurodevelopmental studies and rehabilitation programmes., Results: In a study period of 2 years, 54 children (1.5% of all admissions) satisfied the criteria of ABM in early childhood; 78% were below one year and 52% were under the age of six months. Chief presentation was high fever, refusal of feeds, altered sensorium and seizures. Meningeal signs were present in only 26%. CSF C-reactive protein was positive in 41%, gram stain was positive in 67% LAT in 78% and cultures grew causative organisms in 50% of the cases. The final etiological diagnosis (as per LAT and/or cultures) were Streptococcus pneumoniae 39% Hemophilus influenzae type b 26% and others in 35% The others included one case of Neisseria meningitidis and 10 who were LAT negative and culture sterile. 39% patients developed acute neurological complications during the hospital course. 31% children with ABM died in hospital or at home soon after discharge. Six were lost to follow up. Of the 31 children, available for long term follow up (1-3 years), 14 (45%) had no sequelae. The remaining had significant neurodevelopmental handicaps ranging from isolated hearing loss to severe mental retardation with multiple disabilities., Conclusion: ABM in early childhood has a considerable mortality, morbidity and serious long term sequelae. Neurodevelopmental follow up and therapy should begin early. Etiological diagnosis can be enhanced by LAT and good culture media. H. influenzae b and S. pneumoniae account for more than 60% of ABM in early childhood.

Objectives: It is commonly held that Haemophilus influenzae pneumonia among children in Asia is mostly caused by serotypes other than b (Hib). If so, Hib conjugate vaccines would play little role in the prevention of pneumonia. In two prospective series of children hospitalized for pneumonia in China, the causative agents were searched for with a wide panel of microbiologic assays., Methods: In the university hospitals of Beijing and Hefei, 156 consecutive children 3 months of age and older with symptoms and signs of pneumonia were studied. Blood culture, chest radiograph, nasopharyngeal aspirate for viral antigen detection and paired sera for 20 microbiologic assays were taken. Severity was graded, and the course of illness was monitored uniformly., Results: In Beijing only likely contaminants grew from blood cultures, and in Hefei pathogens were identified in two cases. In combined series evidence for bacterial, mixed and viral etiology was obtained in 30, 7 and 21% of cases, respectively. The dominant bacteria were pneumococcus, Hib, Mycoplasma pneumoniae and Chlamydia pneumoniae, responsible for 13, 10, 8 and 8% of cases, respectively. Most patients were treated with extended spectrum antimicrobials such as piperacillin, cefotaxime or ceftriaxone, alone or in combination. One child died., Conclusions: As in most other series from other countries, the leading agent causing childhood pneumonia was pneumococcus but, in line with our previous experience from Beijing, the second most common agent detected was Hib. This observation suggests great potential for pneumococcal and Hib vaccinations in China. Because no evidence supported the need for routine use of extended spectrum antimicrobials, narrower spectrum agents would be safer for patients, would be cheaper for the community and would offer a way to address increasing resistance problems.

Background: Little is known of the etiology of childhood acute lower respiratory infections in China, where the use of antimicrobials is indiscriminate. Trials to change such a policy require etiologic data, especially on the bacteria most relevant to these common diseases., Methods: One hundred consecutive infants and children from 3 months to 14 years of age with symptoms and signs compatible with acute lower respiratory infections were studied prospectively in the largest pediatric hospital in Beijing from February to May, 1997. Blood culture, thorax radiography and paired sera for 20 microbiologic assays were taken, and the course of illness was monitored uniformly. Disease severity was graded., Results: In 24 cases there was evidence only of bacterial etiology, and in 5 solely viral agents were found; 3 children probably had a mixed bacterial-viral infection. Surprisingly no pneumococcal infection was detected, Mycoplasma pneumoniae (n = 21), Haemophilus influenzae type b (n = 8) and Chlamydia pneumoniae (n = 7) being the dominant bacteria. All children recovered., Conclusions: Routine use of antimicrobials for these patients seems unjustified. Serologic evidence for the H. influenzae type b etiology is encouraging in terms of vaccination, but confirmatory studies are needed.

Over the 33-day duration of the 1999 Haj in Saudi Arabia, we collected daily health status reports for 2070 Pakistani pilgrims over 13 years of age, 54% of whom had elected to receive influenza vaccine immediately before departing for the Haj. We calculated vaccine preventable outcome incidence as the difference in attack rates between vaccinated and unvaccinated persons. The incidences of vaccine preventable influenza-like illness (sore throat in combination with cough or fever of at least 38 degrees C), fever, and any symptom of upper respiratory infection were 22, 17, and 24 per 100 pilgrims per Haj. For every 100 persons who attended the Haj, 17 had a course of antibiotics and 23 had a course of nonprescription cold medication that was preventable with influenza vaccine use. Influenza leads to significant morbidity and medication use among Haj pilgrims. Vaccine against influenza should be considered for pilgrims before entry into Saudi Arabia.

Markers for acute hepatitis A, B, C and E virus infections were examined in the sera of 72 patients suffering from acute hepatitis in Senegal and Tunisia. Hepatitis B was responsible for 36% and hepatitis C for 21% of the cases. Acute hepatitis A was not diagnosed. HEV infection was not observed in Senegal and represents only 4% of the acute hepatitis cases in Tunisia.

The polymerase chain reaction was used to search for hepatitis B virus (HBV)-DNA sequences in the sera of HBsAg-negative Senegalese patients suffering from liver cirrhosis or liver cancer. Amplified HBV-DNA sequences were detected by hybridization with a digoxigenin-labelled HBV-DNA probe. HBV-DNA was detected in 17% of HBsAg negative Senegalese subjects from the general population and in 44% and 58% of the patients suffering from cirrhosis or primary hepatocellular carcinoma (PHCC) respectively. In the control group, amplified HBV-DNA was detected in 25% of the subjects without HBsAg and anti-HBs antibodies, and in 6% of subjects positive for anti-HBs antibodies. This study confirmed the hypothesis that there is an etiologic link between HBV and PHCC in HBsAg-negative patients.