Biomedical subjects

Gunilla Källenius

Publications and source records attributed to Gunilla Källenius.

10 recordsLinked to original sources

PubMed2005

Evaluation of vaccines in the EU TB Vaccine Cluster using a guinea pig aerosol infection model of tuberculosis.

The TB Vaccine Cluster project funded by the EU Fifth Framework programme aims to provide novel vaccines against tuberculosis that are suitable for evaluation in humans. This paper describes the studies of the protective efficacy of vaccines in a guinea pig aerosol-infection model of primary tuberculosis. The objective was to conduct comparative evaluations of vaccines that had previously demonstrated efficacy in other animal models. Groups of 6 guinea pigs were immunized with vaccines provided by the relevant EU Vaccine Cluster partners. Survival over 17 or 26 weeks was used as the principal measure of vaccine efficacy following aerosol challenge with H37Rv. Counts of mycobacteria in lungs and spleens, and histopathological changes in the lungs, were also used to provide evidence of protection. A total of 24 vaccines were evaluated in 4 experiments each of a different design. A heterologous prime-boost strategy of DNA and MVA, each expressing Ag85A and a fusion protein of ESAT-6 and Ag85B in adjuvant, protected the guinea pigs to the same extent as BCG. Genetically modified BCG vaccines and boosted BCG strategies also protected guinea pigs to the same extent as BCG but not statistically significantly better. A relatively high aerosol-challenge dose and evaluation over a protracted time post-challenge allowed superior protection over BCG to be demonstrated by BCG boosted with MVA and fowl pox vectors expressing Ag85A.

Aerosols↗

PubMed2005

Recent developments in tuberculosis vaccines.

PURPOSE OF REVIEW: The aim is to review findings related to the use of Bacille Calmette-Guerin (BCG) vaccine, focusing on its limitations and benefits in controlling tuberculosis (TB). Some new TB vaccines, which have entered or are expected to enter clinical trials, are highlighted. RECENT FINDINGS: BCG is currently the only available vaccine against TB, and is widely administered within the World Health Organization Expanded Programme for Immunization. Several trials have shown that the protective efficacy of BCG varies between different populations. Recently, a 60-year follow-up study of American Indians reported the long-term efficacy of BCG to be 52%. The reasons for the low efficacy of the BCG vaccine may be generic differences in the BCG strains, differences in immunological properties of study populations or exposure to environmental factors such as mycobacteria. The low efficacy of the BCG vaccine has encouraged the search for a new vaccine. Among new vaccine candidates are live attenuated Mycobacterium tuberculosis vaccines, recombinant BCG, DNA vaccines, subunit vaccines and fusion proteins with novel adjuvants and delivery systems. SUMMARY: Today, most of the world's population is vaccinated with BCG. It is generally accepted that BCG protects against childhood TB but this immunity wanes with age, resulting in no or insufficient protection against TB. Using modern techniques, several research groups have developed more than 200 new vaccine candidates. Some of these vaccines are now in clinical trials. The clinical evaluation of these new vaccines should be designed to cover a heterogeneous population with great variation in immune responses.

Adult↗

PubMed2004

Genetic characterization of the Guinea-Bissau family of Mycobacterium tuberculosis complex strains.

In a previous study of Mycobacterium tuberculosis complex isolates from Guinea-Bissau in West Africa, we identified a unique group of strains, designated here as the Guinea-Bissau family of strains, which, although genotypically closely related, phenotypically demonstrated a considerable heterogeneity. We conducted here a detailed genotypic analysis of a subset (n = 35) of these isolates. Based on the data obtained, and by comparison of known corresponding genes in mycobacteria outside the M. tuberculosis complex, we propose that the Guinea-Bissau strains belong to a unique branch of the M. tuberculosis complex tree in between classical M. tuberculosis and classical M. bovis. These observations are discussed in their significance in M. tuberculosis complex classification.

Amidohydrolases↗

PubMed2004

Genetic diversity in clinical isolates of Mycobacterium avium complex from Guinea-Bissau, West Africa.

Isolates of Mycobacterium avium complex (MAC) were cultured from sputum samples obtained from patients in Guinea-Bissau, West Africa. Twenty-eight isolates hybridising with MAC probe (AccuProbe) were further characterised by different molecular techniques: hybridisation with species-specific probes (AccuProbe) for M. avium and M. intracellulare, partial sequencing of 16S rRNA gene and PCR detection of the DT1-DT6 sequences and the macrophage-induced gene (mig). Only one of the 28 isolates reacted with the M. avium probe and four with the M. intracellulare probe. Two isolates expressed the DT1 sequence, and three the DT6. The mig was detected in 18 (64%) of the isolates. Sequencing of 16S rRNA had the greatest discriminative power of the typing methods applied, without strong correlation with any other technique. Clinical MAC isolates from Guinea-Bissau demonstrated a wide genetic diversity among the members of M. avium complex that might reflect on biotope variation.

DNA, Bacterial↗

PubMed2004

Comparative proteome analysis of Mycobacterium tuberculosis grown under aerobic and anaerobic conditions.

Data are presented from two-dimensional (2-D) PAGE analysis of Mycobacterium tuberculosis strain Harlingen grown during aerobic and anaerobic culture, according to a modified Wayne dormancy model. M. tuberculosis cultures were grown to the transition point between exponential growth and stationary phase in the presence of oxygen (7 days) and then part of the cultures was shifted to anaerobic conditions for 16 days. Growth declined similarly during aerobic and anaerobic conditions, whereas the ATP consumption rapidly decreased in the anaerobic cultures. 2-D PAGE revealed 50 protein spots that were either unique to, or more abundant during, anaerobic conditions and 16 of these were identified by MALDI-TOF. These proteins were the alpha-crystalline homologue (HspX), elongation factor Tu (Tuf), GroEL2, succinyl-CoA : 3-oxoacid-CoA transferase (ScoB), mycolic acid synthase (CmaA2), thioredoxin (TrxB2), beta-ketoacyl-ACP synthase (KasB), l-alanine dehydrogenase (Ald), Rv2005c, Rv2629, Rv0560c, Rv2185c and Rv3866. Some protein spots were found to be proteolytic fragments, e.g. HspX and GroEL2. These data suggest that M. tuberculosis induces expression of about 1 % of its genes in response to dormancy.

3-Oxoacyl-(Acyl-Carrier-Protein) Synthase↗

PubMed2003

Mycobacterium tuberculosis arabinomannan-protein conjugates protect against tuberculosis.

Lipoarabinomannan (LAM) is a major structural surface component of mycobacteria. Arabinomannan (AM) oligosaccharides derived from LAM of Mycobacterium tuberculosis H37Rv were isolated and covalently conjugated to tetanus toxoid (TT) or to short-term culture filtrate proteins (antigen 85B (Ag85B) or a 75kDa protein) from M. tuberculosis strain Harlingen. The different AM oligosaccharide (AMOs)-protein conjugate vaccine candidates proved to be highly immunogenic, inducing boosterable IgG responses against the AMOs portion of the conjugates in rabbits and guinea-pigs. Proliferation of T-cells from C57BL/6 mice immunized with the conjugates was seen upon in vitro stimulation with PPD. In C57BL/6 mice subcutaneous immunization with the AMOs-antigen 85B conjugate in alum provided significant protection compared to sham (alum only) immunized mice (P < 0.021) as estimated by long term survival against intravenous challenge with 10(5) M. tuberculosis H37Rv. Subcutaneous immunization followed by nasal boost with an AMOs-TT conjugate in Eurocine L3 adjuvant provided high (P < 0.025) protection as determined by long term survival after intranasal challenge with 10(5) virulent M. tuberculosis strain Harlingen. This level of protection was comparable to that obtained with the conventional live attenuated BCG vaccine. In guinea-pigs, immunization with AMOs-Ag85B in Eurocine L3 adjuvant followed by aerogenic challenge with M. tuberculosis H37Rv resulted in increased survival and reduced pathology in lungs and spleens relative to non-immunized animals.

Adjuvants, Immunologic↗

PubMed2002

[Resistant tuberculosis is spreading in Sweden. Molecular epidemiological strain identification by "fingerprinting" can make the infection tracing easier].

Resistance of Mycobacterium tuberculosis to antibiotics is a world wide problem. A study is reported with the aim to analyse the spread of resistant isolates of M tuberculosis complex from patients with tuberculosis in Sweden. The study is based on a sample of 192 M tuberculosis complex isolates from patients with drug resistant tuberculosis during 1994-2000. All isolates resistant to at least one of the drugs streptomycin, isoniazid, ethambutol and rifampicin were included in the study. Restriction fragment length polymorphism (RFLP) was performed, using IS6110 as a probe for hybridisation. Visualised bands were analysed by Gel Compar software. The majority of the isolates were from patients born in high TB prevalence countries. During the years 1996-2000 there was one major cluster generated from 34 isolates. In 1996-1998 there were two isolates per year, in 1999 it increased to 20 isolates, and eight cases in 2000. All strains were resistant to isoniazid. All patients in this cluster were found to be from Africa. In comparing the pattern in the T-base the strains matched with strain BEA-000007341 isolated from a patient in Rwanda. The majority of patients with drug resistant tuberculosis in Sweden are immigrants from countries with high incidence of tuberculosis. Spread of disease to the Swedish born population is uncommon. However, an increasingly prevalent clone of isoniazid resistant tuberculosis was found among African immigrants, mainly living in the Stockholm area.

Adolescent↗

PubMed2002

Evaluation of outpatients with suspected pulmonary tuberculosis in a high HIV prevalence setting in Ethiopia: clinical, diagnostic and epidemiological characteristics.

In a setting with a high prevalence of HIV we studied (i) the prevalence of pulmonary tuberculosis (PTB) and HIV; (ii) clinical and epidemiological characteristics of PTB; and (iii) the usefulness of standard procedures for diagnosing PTB. Of 509 consecutive outpatients evaluated on clinical suspicion of PTB in Addis Ababa, 33.0% were culture-verified as having PTB. PTB patients, non-TB patients and controls were HIV-1-positive in 57.1%, 38.5% and 8.3% of cases, respectively. Predictors for culture-verified PTB were age < 25 y, male gender and the presence of HIV and fever, whereas profound weight loss indicated HIV infection. Diagnosis of PTB based on clinical symptoms, sputum microscopy for acid-fast bacilli and chest radiography was sensitive (86.7%) but unspecific (64.1%). In HIV-positive patients both sensitivity and specificity were significantly lower (p < 0.05). HIV-related pulmonary infections are often misinterpreted as smear-negative PTB. HIV screening is therefore warranted not only in cases of verified TB but also as part of the diagnostic work-up in patients with respiratory symptoms suggestive of PTB. Also, increased awareness of, and improved diagnostic tools for, HIV-related pulmonary infections other than PTB are required, together with algorithms for patients with suspected PTB.

AIDS-Related Opportunistic Infections↗

PubMed2002

Global distribution of Mycobacterium tuberculosis spoligotypes.

We present a short summary of recent observations on the global distribution of the major clades of the Mycobacterium tuberculosis complex, the causative agent of tuberculosis. This global distribution was defined by data-mining of an international spoligotyping database, SpolDB3. This database contains 11708 patterns from as many clinical isolates originating from more than 90 countries. The 11708 spoligotypes were clustered into 813 shared types. A total of 1300 orphan patterns (clinical isolates showing a unique spoligotype) were also detected.

Databases, Factual↗

PubMed1998

Prospective 7-year monitoring of MAC bacteremia in HIV-positive Swedish patients.

OBJECTIVE: To record the cumulative incidence of Mycobacterium avium complex (MAC) bacteremia among HIV-infected patients and to study colonization in relation to symptoms of infection. METHODS: In a prospective study, 61 patients with a CD4 count less-than-or-eq, slant200x106/L were followed by cultures from sputum, feces and blood every 3--6 months and for development of MAC bacteremia and clinical symptoms. The main end-points were MAC bacteremia and death. RESULTS: From the start in November 1989 to January 1997 about 34% had developed MAC bacteremia with a median follow-up of 22 months. At the time of positive blood cultures, all but one patient had symptoms consistent with disseminated MAC infection. Positive cultures from respiratory and gastrointestinal tract were recorded before MAC bacteremia in only four patients. All but one had symptoms at the time of positive blood culture. CONCLUSIONS: The incidence of MAC bacteremia was similar to figures in other studies. The presence of symptoms in close relation to positive blood cultures supports late colonization and late infection in HIV disease. Screening patients with samples from the respiratory and gastrointestinal tracts is not useful

Journal Article↗