- Volume 61, Issue 7, 2012

This discussion is intended to be an overview of current advances in the development of fungal cell wall vaccines with an emphasis on Candida; it is not a comprehensive historical review of all fungal cell wall vaccines. Selected, more recent, innovative strategies for developing fungal vaccines will be highlighted. Both scientific and logistical obstacles related to the development of, and clinical use of, fungal vaccines will be discussed.

Combination of chemoprophylaxis with chloroquine and so-called ‘controlled human malaria infections’ has been shown to induce sustained and fully protective immunity against malaria in experimental settings. This opens possibilities of translating this approach into an effective and applicable strategy for the field. We review the different ways in which antimalarial drugs have been used for prevention of malaria in endemic settings and discuss the possibilities and challenges of applying a strategy of drug use and naturally acquired infection in the field.

Plague is an ancient, serious, infectious disease which is still endemic in regions of the modern world and is a potential biothreat agent. This paper discusses the natural history of the bacterium and its evolution into a flea-vectored bacterium able to transmit bubonic plague. It reviews the incidence of plague in the modern world and charts the history of vaccines which have been used to protect against the flea-vectored disease, which erupts as bubonic plague. Current approaches to vaccine development to protect against pneumonic, as well as bubonic, plague are also reviewed. The considerable challenges in achieving a vaccine which is licensed for human use and which will comprehensively protect against this serious human pathogen are assessed.

The discovery of the Campylobacter jejuni N-linked glycosylation system combined with its functional expression in Escherichia coli marked the dawn of a new era in glycoengineering. The process, termed protein glycan coupling technology (PGCT), has, in particular, been applied to the development of glycoconjugate vaccines. In this review, we highlight recent technical developments in this area, including the first structural determination of the coupling enzyme PglB, the use of glycotags for optimal glycan attachment and the possible applications of other glycosylation systems and how these may improve and extend PGCT.

Alum has been the most widely used adjuvant for over 80 years. Although there have been searches for alternative adjuvants, aluminium-containing adjuvants will continue to be used for many years due to their good track record of safety, low cost and adjuvanticity with a variety of antigens. For infections that can be prevented by induction of serum antibodies, aluminium-containing adjuvants formulated under optimal conditions are the adjuvants of choice. There are also some limitations of aluminium-containing adjuvants, which include local reactions, augmentation of IgE antibody responses, ineffectiveness for some antigens and inability to augment cell-mediated immune responses, especially cytotoxic T-cell responses. In this review, we describe the current knowledge regarding the mechanisms (both cellular and molecular) by which alum employs its adjuvant effect, although the final mechanism is not yet well-defined. Furthermore, we discuss how alum’s adjuvanticity could be improved.

The ISCOMATRIX adjuvant has antigen delivery and presentation properties as well as immunomodulatory capabilities, which combine to provide enhanced and accelerated immune responses. The responses are broad, including a range of subclasses of antibodies as well as CD4+ and CD8+ T-cells. A range of ISCOMATRIX vaccines (ISCOMATRIX adjuvant combined with antigen) have now been tested in clinical trials and have been shown to be generally safe and well tolerated as well as immunogenic, generating both antibody (Ab) and T-cell responses. The mechanisms by which ISCOMATRIX adjuvant facilitates its immune effects are the scope of significant study and indicate that ISCOMATRIX adjuvant (i) rapidly traffics antigen into the cytosol of multiple dendritic cell subsets, (ii) induces the induction of an array of cytokines and chemokines and (iii) links the innate and adaptive immune responses in vivo in a Toll-like-receptor-independent but MyD88-dependent manner. These data highlight the clinical utility of ISCOMATRIX adjuvant in the development of prophylactic and therapeutic vaccines for infectious disease.

Mobile drug-resistance genes with identical nucleic acid sequences carried by multidrug-resistant Escherichia coli strains that cause community-acquired infections are becomingly increasingly dispersed worldwide. Over a 2-year period, we analysed Gram-negative bacterial (GNB) pathogens from the blood of inpatients at an urban public hospital to determine what proportion of these isolates carried such globally dispersed drug-resistance genes. Of 376 GNB isolates, 167 (44 %) were Escherichia coli, 50 (13 %) were Klebsiella pneumoniae, 25 (7 %) were Pseudomonas aeruginosa, 25 (7 %) were Proteus mirabilis and 20 (5 %) were Enterobacter cloacae; the remainder (24 %) comprised 26 different GNB species. Among E. coli isolates, class 1 integrons were detected in 64 (38 %). The most common integron gene cassette configuration was dfrA17-aadA5, found in 30 (25 %) of 119 drug-resistant E. coli isolates and in one isolate of Moraxella morganii. Extended-spectrum β-lactamase (ESBL) genes were found in 16 E. coli isolates (10 %). These genes with identical sequences were found in nearly 40 % of bloodstream E. coli isolates in the study hospital, as well as in a variety of bacterial species from clinical and non-clinical sources worldwide. Thus, a substantial proportion of bloodstream infections among hospitalized patients were caused by E. coli strains carrying drug-resistance genes that are dispersed globally in a wide variety of bacterial species.

Outbreaks caused by Klebsiella pneumoniae producing carbapenemases and other β-lactamases have been reported. Four neonates admitted to a neonatal intensive care unit (NICU) in a Chinese hospital developed respiratory infection while receiving intensive care. In all four cases, multidrug-resistant K. pneumoniae was isolated from multiple respiratory specimens, leading to additional characterization of these organisms and investigation of the local environment in the NICU. Multiple β-lactamase genes, including bla TEM-1, bla IMP-4, bla DHA-1 and bla CTX-M-14, as well as the quinolone resistance gene qnrB4, were harboured by transferable plasmids from all four clinical isolates. Furthermore, PFGE confirmed that three of the four clinical isolates from the patients and three K. pneumoniae isolates collected from the hands of health-care workers and an incubator in the NICU belonged to the same PFGE cluster, indicating that an outbreak due to multidrug-resistant K. pneumoniae carrying bla IMP-4 and bla DHA-1 occurred in this NICU. As far as is known, this is the first report of the co-existence of bla IMP-4 and bla DHA-1 in the same K. pneumoniae isolate. These data suggest that additional precautions are needed to prevent outbreaks of infection caused by multidrug-resistant K. pneumoniae resulting from environmental exposure in NICUs.

The molecular characterization of genotype P[6] rotavirus strains collected from children admitted to hospital with acute dehydrating diarrhoea during a 6-year surveillance period in Taiwan is described in this study. In total, three G4P[6] strains, one G5P[6] and one G12P[6] were characterized by sequencing and phylogenetic analysis of the VP4, VP7, VP6 and NSP4 genes. Whilst all four genes of the single Taiwanese G12P[6] strain clustered with the respective genes of globally common human rotavirus strains, the G4 and G5 strains showed remarkable similarities to porcine rotavirus strains and putative porcine-origin human P[19] strains reported previously from Taiwan. The overall proportion of porcine rotavirus-like strains in Taiwan remains around 1 % among hospitalized children; however, the circulation and sporadic transmission of these heterotypic strains from pigs to humans could pose a public-health concern. Therefore, continuation of strain monitoring is needed in the vaccine era to detect any possible vaccine breakthrough events associated with the introduction of such heterologous rotavirus strains.

The aim of this study was to evaluate Etest for detectability of linezolid-resistant meticillin-resistant Staphylococcus aureus (MRSA). The MIC of linezolid obtained by the Etest method in 18 linezolid-resistant strains of MRSA was compared with that obtained using standard agar and broth dilution methods according to Clinical and Laboratory Standards Institute guidelines. The mean linezolid MIC obtained by Etest in 18 linezolid-resistant strains of MRSA using Mueller–Hinton (MH) agar was 12.6-fold lower than that obtained by the agar dilution method, with the result that 78 % of the linezolid-resistant strains were incorrectly classified as linezolid-susceptible. The MIC of linezolid by Etest on brain–heart infusion (BHI) agar had a mean value 2.5-fold lower than that obtained by the agar dilution method, suggesting that replacing MH agar with BHI agar considerably improved the detectability of linezolid-resistant MRSA. Use of blood agar (MH agar supplemented with 5 % sheep blood) and 48 h of incubation resulted in 100 % agreement with the agar and broth dilution methods. Thus, this study revealed that the Etest on MH agar and BHI agar yielded false-negative results in a significant fraction of the linezolid-resistant MRSA. Hence, the use of blood agar and prolonged incubation is highly recommended for the accurate detection of linezolid-resistant MRSA using Etest.

The Candida parapsilosis group encompasses three species: C. parapsilosis,Candida orthopsilosis and Candida metapsilosis. These species are phenotypically indistinguishable, and molecular methods are needed for their detection. We analysed 152 unique blood culture isolates of the C. parapsilosis group obtained during 1997–2011. The isolates were screened by PCR amplification of the gene encoding secondary alcohol dehydrogenase, followed by digestion with the restriction enzyme BanI. Isolates with RFLP patterns distinct from those of the C. parapsilosis group were characterized as C. parapsilosis sensu stricto (90.8 %), C. orthopsilosis (8.6 %) and C. metapsilosis (0.6 %). Antifungal susceptibility tests indicated that all isolates were susceptible to itraconazole, amphotericin B and caspofungin. Although C. orthopsilosis and C. metapsilosis isolates were susceptible to fluconazole, higher MICs (≥2 mg l−1) were observed for C. orthopsilosis. Three isolates (2.0 %) of C. parapsilosis sensu stricto were resistant to voriconazole. Five C. parapsilosis isolates (3.3 %) were intermediate, and a single isolate (0.7 %) was resistant (MIC 16 mg l−1) to fluconazole. These data were confirmed using reference strains. It was observed that C. parapsilosis isolates were less susceptible to all triazoles, and this finding deserves further attention to assess the appearance of cross-resistance phenomena. In conclusion, C. metapsilosis and C. orthopsilosis are involved in a small but significant number of invasive infections in Brazil.

Against a background of point-source outbreaks of Pneumocystis pneumonia (PCP) in renal transplant units in Europe, we undertook a retrospective 3 year observational review of PCP in Northern Ireland. This showed an unexpected increase in incidence, with a mortality rate of 30 %. Fifty-one cases were confirmed compared to 10 cases confirmed in the preceding 7 years. Where undiagnosed HIV infection had previously been the main risk factor for PCP, this was now equally matched by chemotherapy for haematological and non-haematological malignancy and immune suppression for a range of autoimmune conditions. Congenital immunodeficiency and transplantation were less common predisposing factors, but renal grafts also showed a rising incidence. Asymptomatic carriage was uncommon. At presentation both upper and lower respiratory samples were of equal use in establishing the diagnosis, and treatment resulted in rapid clearance. These data suggest the need for considering PCP in at-risk patients, reviewing its mode of acquisition and whether iatrogenic colonization is a treatable pre-condition.