A phase IIa, randomized, double-blind, safety, immunogenicity and efficacy trial of Plasmodium falciparum vaccine antigens merozoite surface protein 1 and RTS,S formulated with AS02 adjuvant in healthy, malaria-naïve adults.

BACKGROUND: To improve the efficacy of Plasmodium falciparum malaria vaccine RTS,S/AS02, we conducted a study in 2001 in healthy, malaria-naïve adults administered RTS,S/AS02 in combination with FMP1, a recombinant merozoite surface-protein-1, C-terminal 42kD fragment. METHODS: A double-blind Phase I/IIa study randomized N = 60 subjects 1:1:1:1 to one of four groups, N = 15/group, to evaluate safety, immunogenicity, and efficacy of intra-deltoid half-doses of RTS,S/AS02 and FMP1/AS02 administered in the contralateral (RTS,S + FMP1-separate) or same (RTS,S + FMP1-same) sites, or FMP1/AS02 alone (FMP1-alone), or RTS,S/AS02 alone (RTS,S-alone) on a 0-, 1-, 3-month schedule. Subjects receiving three doses of vaccine and non-immunized controls (N = 11) were infected with homologous P. falciparum 3D7 sporozoites by Controlled Human Malaria Infection (CHMI). RESULTS: Subjects in all vaccination groups experienced mostly mild or moderate local and general adverse events that resolved within eight days. Anti-circumsporozoite antibody levels were lower when FMP1 and RTS,S were co-administered at the same site (35.0 µg/mL: 95 % CI 20.3-63), versus separate arms (57.4 µg/mL: 95 % CI 32.3-102) or RTS,S alone (62.0 µg/mL: 95 % CI: 37.8-101.8). RTS,S-specific lymphoproliferative responses and ex vivo ELISpot CSP-specific interferon-gamma (IFN-γ) responses were indistinguishable among groups receiving RTS,S/AS02. There was no difference in antibody to FMP1 among groups receiving FMP1/AS02. After CHMI, groups immunized with a RTS,S-containing regimen had âˆ¼ 30 % sterile protection against parasitemia, and equivalent delays in time-to-parasitemia. The FMP1/AS02 alone group showed no sterile immunity or delay in parasitemia. CONCLUSION: Co-administration of RTS,S and FMP1/AS02 reduced anti-RTS,S antibody, but did not affect tolerability, cellular immunity, or efficacy in a stringent CHMI model. Absence of efficacy or delay of patency in the sporozoite challenge model in the FMP1/AS02 group did not rule out efficacy of FMP1/AS02 in an endemic population. However, a Phase IIb trial of FMP1/AS02 in children in malaria-endemic Kenya did not demonstrate efficacy against natural infection. CLINICALTRIALS: gov identifier: NCT01556945.

Safety and immunogenicity of the RTS,S/AS02A candidate malaria vaccine in children aged 1-4 in Mozambique.

BACKGROUND: The development of a malaria vaccine remains a public health priority for sub-Saharan Africa. RTS,S/AS02A candidate malaria vaccine has been shown to be safe and immunogenic in previous studies in adults and staggered dose-escalation studies in children in The Gambia. However, genetic features and the intensity of malaria transmission may modify the safety and immune response of a vaccine. OBJECTIVE: We carried out a phase I, double-blind randomized controlled trial in 60 children aged 1-4 in Mozambique to evaluate the safety, reactogenicity and immunogenicity of the paediatric vaccine dose (fixed 25 microg RTS,S in 0.25 ml) of RTS,S/AS02A, prior to undertaking a planned larger phase IIb proof-of-concept of efficacy study in the same population. METHOD: Children were randomized to receive either RTS,S/AS02A or Engerix-B vaccine. Monitoring of safety and reactogenicity included detailed clinical and laboratory analyses and assessment of adverse events (AEs). RESULTS: The RTS,S/AS02A was found to be safe and well tolerated. Serious adverse events were balanced between both groups and none was related to vaccination. The frequency of adverse events reported with RTS, S/AS02A was comparable to previous studies in children. Grade 3 AEs were infrequent (one case of pain, one of fever in each group and some swelling greater than 20 mm in diameter), transient and resolved without sequelae. RTS,S/AS02A was highly immunogenic for anti-circumsporozoite protein antibody response and induced a strong anti-hepatitis-B surface antigen response.

Immunogenicity and safety of a combined hepatitis A and B vaccine administered concomitantly with either a measles-mumps-rubella or a diphtheria-tetanus-acellular pertussis-inactivated poliomyelitis vaccine mixed with a Haemophilus influenzae type b conjugate vaccine in infants aged 12-18 months.

Two studies were undertaken to investigate the concomitant administration of combined hepatitis A/B vaccine with a diphtheria-tetanus-acellular pertussis-inactivated poliomyelitis vaccine mixed with Haemophilus influenzae vaccine (DTPa-IPV/Hib), or with a measles-mumps-rubella vaccine (MMR), during the second year of life. On completion of the vaccination course, all subjects were seropositive or seroprotected against all antigens except for one subject who was seronegative for anti-PT. Seropositivity and seroprotection rates for all other antibodies were comparable to reference values for each vaccine component, indicating that the immunogenicity of MMR, DTPa-IPV/Hib and combined hepatitis A/B vaccines is not impaired by co-administration. All vaccines were well tolerated.

Cellular immunity induced by the recombinant Plasmodium falciparum malaria vaccine, RTS,S/AS02, in semi-immune adults in The Gambia.

Vaccination of malaria-naive humans with recombinant RTS,S/AS02, which includes the C-terminus of the circumsporozoite protein (CS), has been shown to induce strong T cell responses to both the whole protein antigen and to peptides from CS. Here we show that strong T cell responses were also observed in a semi-immune population in The Gambia, West Africa. In a Phase I study, 20 adult male volunteers, lifelong residents in a malaria-endemic region, were given three doses of RTS,S/AS02 at 0, 1 and 6 months. Responses to RTS,S, hepatitis B surface antigen and peptides from CS were tested using lymphocyte proliferation, interferon (IFN)-gamma production in microcultures, and IFN-gamma ex vivo and cultured ELISPOT, before and after vaccination. Cytotoxic responses were tested only after vaccination and none were detected. Before vaccination, the majority of the volunteers (15/20) had detectable responses in at least one of the tests. After vaccination, responses increased in all assays except cytotoxicity. The increase was most marked for proliferation; all donors responded to RTS,S after the third dose and all except one donor responded to at least one peptide after the second or third dose. There was a lack of close association of peptide responses detected by the different assays, although in microcultures IFN-gamma responses were found only when proliferative responses were high, and responses by cultured ELISPOT and proliferation were found together more frequently after vaccination. We have therefore identified several peptide-specific T cell responses induced by RTS,S/AS02 which provides a mechanism to investigate potentially protective immune responses in the field.

Efficacy of RTS,S/AS02 malaria vaccine against Plasmodium falciparum infection in semi-immune adult men in The Gambia: a randomised trial.

BACKGROUND: RTS,S/AS02 is a pre-erythrocytic malaria vaccine based on the circumsporozoite surface protein of Plasmodium falciparum fused to HBsAg, incorporating a new adjuvant (AS02). We did a randomised trial of the efficacy of RTS,S/AS02 against natural P. falciparum infection in semi-immune adult men in The Gambia. METHODS: 306 men aged 18-45 years were randomly assigned three doses of either RTS,S/AS02 or rabies vaccine (control). Volunteers were given sulfadoxine/pyrimethamine 2 weeks before dose 3, and kept under surveillance throughout the malaria transmission season. Blood smears were collected once a week and whenever a volunteer developed symptoms compatible with malaria. The primary endpoint was time to first infection with P. falciparum. Analysis was per protocol. FINDINGS: 250 men (131 in the RTS,S/AS02 group and 119 in the control group) received three doses of vaccine and were followed up for 15 weeks. RTS,S/AS02 was safe and well tolerated. P. falciparum infections occurred significantly earlier in the control group than the RTS,S/AS02 group (Wilcoxon's test p=0.018). Vaccine efficacy, adjusted for confounders, was 34% (95% CI 8.0-53, p=0.014). Protection seemed to wane: estimated efficacy during the first 9 weeks of follow-up was 71% (46-85), but decreased to 0% (-52 to 34) in the last 6 weeks. Vaccination induced strong antibody responses to circumsporozoite protein and strong T-cell responses. Protection was not limited to the NF54 parasite genotype from which the vaccine was derived. 158 men received a fourth dose the next year and were followed up for 9 weeks; during this time, vaccine efficacy was 47% (4-71, p=0.037). INTERPRETATION: RTS,S/AS02 is safe, immunogenic, and is the first pre-erythrocytic vaccine to show significant protection against natural P. falciparum infection.

Long-term persistence of antibodies induced by vaccination and safety follow-up, with the first combined vaccine against hepatitis A and B in children and adults.

It is important to monitor the long-term persistence of antibodies induced by vaccination. Four cohorts were followed for their long-term immunity after vaccination with a combined hepatitis A and B vaccine (Twinrix; SmithKline Beecham Biologicals, Rixsenart, Belgium). Two cohorts of adults (ages 17-60 years), one of 1-6-year-olds, and one of 6-15-year-olds were vaccinated following a 0, 1, and 6-month schedule. Follow-up data until month 72 (adults) and month 60 (children) are available. At month 72, antibody to hepatitis A virus (anti-HAV) seropositivity (S+) was 100% for both adult cohorts (n = 40 and n = 47) and 95% and 89% of the vaccinees were seroprotected against hepatitis B virus (HBV), respectively. The geometric mean titres (GMTs; mIU/ml) for anti-HAV were 977 and 542 and the GMTs for the antibody to hepatitis B surface antigen (anti-HBs) were 322 and 90. For 1-6-year-olds at month 60 (n = 39), anti-HAV S+ was 100% with a GMT of 479 and 97% were protected against HBV with a GMT of 195. At month 60 for the 6-15-year-olds (n = 42), anti-HAV S+ was 100% with a GMT of 990 and 95% were protected against HBV with a GMT of 263. There have been no safety issues during the follow-up. In the past 5 years, a postmarketing surveillance system was available. Using this system, all spontaneous adverse events are collected and archived. Although infrequent, the most commonly reported adverse events after more than 13 million doses were allergic-type reactions followed by fever and injection site reactions. The combined hepatitis A and B vaccine is safe and is well tolerated. Immunity provided by the vaccine remains high in adults and children with comparable results to those obtained with monovalent vaccines.

A prophylactic hepatitis B vaccine with a novel adjuvant system.

Studies with recombinant hepatitis B vaccines show seroprotection rates varying between 91 and 100%. Thus, a limited risk may remain for non-responding populations (e.g. non-responders, haemodialysis patients, elderly) who could benefit from a more immunogenic hepatitis B vaccine. One strategy to enhance the immune response is the use of novel adjuvants. SmithKline Beecham has developed a new adjuvant system containing alum and 3-deacylated monophosphoryl lipid A: SBAS4 (SmithKline Beecham Adjuvant System 4). Pilot studies showed that SBAS4 improved in vivo humoral and in vitro cellular immune responses compared to the response to classical recombinant hepatitis B vaccines and was safe and well-tolerated. Several studies assessed the profile of the HBsAg/SBAS4 vaccine in a healthy population, non-responders or elderly. In general the HBsAg/SBAS4 vaccine was well tolerated. Compared to an established recombinant hepatitis B vaccine, we observed an increased local reactogenicity but few symptoms were reported as severe. The HBsAg/SBAS4 vaccine elicits a strong immune response: subjects are protected faster and the GMTs are usually much higher. HBsAg/SBAS4 thus has the potential to protect those subjects who fail to be protected by well established hepatitis B vaccines.

Efficacy of recombinant circumsporozoite protein vaccine regimens against experimental Plasmodium falciparum malaria.

After initial successful evaluation of the circumsporozoite-based vaccine RTS,S/SBAS2, developed by SmithKline Beecham Biologicals with the Walter Reed Army Institute of Research, protective efficacy of several regimens against Plasmodium falciparum challenge was determined. A controlled phase 1/2a study evaluated 1 or 2 standard doses of RTS,S/SBAS2 in 2 groups whose members received open-label therapy and 3 immunizations in blinded groups who received standard, one-half, or one-fifth doses. RTS,S/SBAS2 was safe and immunogenic in all groups. Of the 41 vaccinees and 23 control subjects who underwent sporozoite challenge, malaria developed in 7 of 10 who received 1 dose, in 7 of 14 who received 2 doses, in 3 of 6 who received 3 standard doses, in 3 of 7 who received 3 one-half doses, in 3 of 4 who received 3 one-fifth doses, and in 22 of 23 control subjects. Overall protective efficacy of RTS,S/SBAS2 was 41% (95% confidence interval, 22%-56%; P=.0006). This and previous studies have shown that 2 or 3 doses of RTS,S/SBAS2 protect against challenge with P. falciparum sporozoites.

Risk and aetiology of diarrhoea at various tourist destinations.

Almost two of three tourists developed traveller's diarrhoea during 2-week stays at high-risk destinations. Large differences in infection rates between hotels were seen. Patients with milder forms of diarrhoea show a similar chronology to those more severely affected. Although enterotoxigenic Escherichia coil was the most frequent cause, viral pathogens were detected more often than in other studies.

A single dose, combined vaccine against typhoid fever and hepatitis A: consistency, immunogenicity and reactogenicity.

BACKGROUND: Vaccines against hepatitis A and typhoid fever are well established and have an excellent safety and immunogenicity profile. Yet these diseases, which share the same geographic distribution, remain an important cause of morbidity in travelers to endemic countries. Combined vaccination provides dual protection and improves compliance and coverage for travelers. METHODS: This multicenter study evaluated the consistency of three lots of combined hepatitis A and typhoid fever vaccine. A total of 462 healthy subjects, aged 15-50 years, were enrolled and randomly allocated to 3 groups. The single dose of vaccine contains 25 microg typhoid Vi polysaccharide and at least 1,440 ELISA units of inactivated hepatitis A in a 1 mL dose. RESULTS: Bioequivalence of all production lots was shown in terms of safety and immunogenicity. Pain at injection site was the most frequent reported local symptom, and headache was the most frequent reported general symptom. As early as 14 days after immunization >95% of the subjects were positive for anti-Vi antibodies and >86% were positive for anti-HAV antibodies. The GMTs and seropositivity rates were maintained during the 6 month follow-up. CONCLUSION: The first combined vaccine against typhoid fever and hepatitis A was safe and elicited a very good immune response, with the majority of subjects seropositive at 1 month for both antigens. This combined vaccine offered more convenience and rapid seroconversion to travelers.

Epidemiology, etiology, and impact of traveler's diarrhea in Jamaica.

CONTEXT: Traveler's diarrhea (TD) can incapacitate travelers. Characteristics of TD could be helpful in identifying individuals who might benefit from a vaccine against TD. OBJECTIVE: To determine epidemiology, etiology, and impact of TD in Jamaica. Design Two-armed, cross-sectional survey conducted between March 1996 and May 1997. SETTING: Sangster International Airport and 10 hotels in Montego Bay area, Jamaica. SUBJECTS: To investigate epidemiology and impact, 30369 short-term visitors completed a questionnaire just before boarding their homebound aircrafts. To investigate etiology, 322 patients (hotel guests) with TD provided stool samples. MAIN OUTCOME MEASURES: Attack and incidence rates of reported diarrhea and of classically defined TD (> or =3 unformed stool samples in 24 hours and > or =1 accompanying symptom), incapacity, risk factors, and etiology. RESULTS: The attack rate for diarrhea was 23.6% overall, with 11.7% having classically defined TD. For a mean duration of stay of 4 to 7 days, the incidence rate was 20.9% (all TD) and 10.0% (classic TD). Among airport respondents, the incapacity lasted a mean of 11.6 hours. Less than 3% of all travelers avoided potentially high-risk food and beverages. The most frequently detected pathogens were enterotoxigenic Escherichia coli, Rotavirus, and Salmonella species. CONCLUSIONS: A realistic plan for reducing TD is needed. Preventive measures such as the improvement of hygienic conditions at the destination, and/or the development of vaccines against the most frequent pathogens associated with TD may contribute toward achieving this goal.

A phase I safety and immunogenicity trial with the candidate malaria vaccine RTS,S/SBAS2 in semi-immune adults in The Gambia.

RTS,S is a novel pre-erythrocytic malaria vaccine based on the circumsporozoite surface protein (CSP) of Plasmodium falciparum linked to hepatitis B surface antigen (HBs) and combined with a novel adjuvant system (SBAS2). We have conducted a Phase I trial with three doses of this vaccine given at 0, 1, and 6 months to 20 semi-immune, adult, male volunteers in The Gambia to assess its safety and immunogenicity. Eighteen of the 20 volunteers completed the study. There were no clinically significant local or systemic adverse events following each vaccination. Hematologic and biochemical indices before and two weeks after each vaccination showed no evidence of toxicity. Antibody titers to both CSP and HBs showed a significant increase after vaccination; these were the largest after the third dose. We conclude that the RTS,S/SBAS2 vaccine induces no significant toxicity in this semi-immune population and produces significant increases in antibody titers to CSP.

Infectious considerations in the world traveler.

Travel-associated dermatoses are among the six most frequent medical problems encountered by international travelers. Skin disorders caused by parasites previously confined to the tropics are seen with increasing frequency by physicians in nonendemic areas. Cutaneous manifestations may provide important clues to the underlying infection. This article describes the epidemiology, assessment, and management of important parasitoses with cutaneous involvement.

Tuberculosis among foreign-born persons in New York City, 1992-1994: implications for tuberculosis control.

OBJECTIVE: To study the pattern of transmission of tuberculosis (TB) among foreign-born persons living in New York City. DESIGN: A retrospective multicenter study comparing 158 foreign-born patients to 231 US-born patients diagnosed with TB between 1992 and 1994. The patients were stratified according to their Mycobacterium tuberculosis isolate DNA fingerprint patterns. RESULTS: Nineteen (16%) of 122 isolates from foreign-born TB patients and 75 (42%) of 180 isolates from US-born TB patients had DNA fingerprint patterns (cluster patterns) indicative of recent exogenous transmission (P < 0.001). All cluster pattern strains from foreign-born cases were identical to those found among US-born patients. The likelihood of infection with a cluster pattern strain among foreign-born persons increased with duration of residence in the US, and was significantly associated with being homeless (P < 0.05), or having multidrug-resistant TB (P = 0.00072). CONCLUSION: Although most (84%) cases of TB among foreign-born persons in New York City appear to result from reactivation of infections they acquired abroad, the ones who acquire new infections become infected with strains that are already circulating among the US-born TB patients in New York City, and they have risk factors similar to those faced by US-born tuberculosis patients.

Risk factors associated with vancomycin-resistant Enterococcus faecium infection or colonization in 145 matched case patients and control patients.

Risk factors and mortality associated with vancomycin-resistant Enterococcus faecium (VREF) infection or colonization were examined at a tertiary care hospital by comparing 145 patients who had VREF isolates (cases) to 145 patients with vancomycin-susceptible Enterococcus faecium (VSEF) isolates (controls). The number of deaths per 100 person-days of hospitalization after diagnosis did not differ significantly between VREF patients (1.2) and VSEF patients (0.8). Multivariate analyses found that the duration of hospitalization ( > or = 7 days), intrahospital transfer between floors, use of antimicrobials (i.e., vancomycin and third-generation cephalosporins), and duration of vancomycin use ( > or = 7 days) was independently associated with VREF infection or colonization. This study, which has a large sample size, confirms some earlier observations regarding risks for VREF infection or colonization and identifies factors that may be potentially exploited to develop interventional strategies for the control of this emerging nosocomial problem.

Differentiation of pathogenic Escherichia coli strains in Brazilian children by PCR.

A PCR technique to differentiate pathogenic enteric Escherichia coli strains in a field setting was evaluated. Among 76 children with acute diarrhea, this technique identified 12 children (16%) with enterotoxigenic E. coli, 6 (8%) with enteropathogenic E. coli, and 1 (1%) with enteroinvasive E. coli infection. Compared with the conventional assays, the PCR method proved to be simpler, more rapid, and inexpensive and therefore suitable for application in a developing-country field setting.

Identification of enteropathogenic Escherichia coli by PCR-based detection of the bundle-forming pilus gene.

A rapid and simple method of detecting enteropathogenic Escherichia coli (EPEC) was developed. The procedure is based on amplifying by the PCR method a 326-bp region of the bundle-forming pilus gene of EPEC. The oligonucleotide DNA primers used in this procedure did not amplify DNA of any other bacterial enteropathogens tested. The procedure was 100% specific for EPEC strains that exhibit a characteristic pattern of attachment (localized adherence) to HeLa cells.

The gastroenterologist's approach to dysphagia.

In the gastroenterological diagnostic armamentarium, dysphagia is considered as an important symptom for diseases of the esophagus. Concerning the history of illness, symptoms such as retrosternal pain and heartburn are often associated with gastroesophageal reflux disease. Morphological changes of the mucosa can be diagnosed by flexible endoscopy and radiographic examinations. Investigation with 24-h pH monitoring, manometry, and pharmacological tests is necessary for the diagnosis of functional disorders. Additionally, dysphagia can be associated with multiple internal diseases, including muscular diseases such as dermatomyositis, progressive systemic sclerosis, as well as lupus erythematosus. Difficulties in swallowing associated with hypo- and hyperthyroidism can also be interpreted as muscular lesions. Metabolic disorders such as alcoholism, and diabetes mellitus can be the cause of dysphagia. Increasing importance in the differential diagnosis of dysphagia is attached to infections of the upper GI tract. Especially in immunocompromised patients, infections of Candida albicans, mycobacterias, herpes, varicella zoster, and cytomegaloviruses can produce dysphagia and odynophagia. The differential diagnosis of the "angina-like chest pain" has to differentiate between cardiac disease and a noncardiac genesis. Therefore, besides the cardiac diagnostic investigation, endoscopy, radiography, and manometry are often indicated.