BackgroundThe continuing morbidity and mortality associated with infection with malaria parasites highlights the urgent need for a vaccine. The efficacy of sub-unit vaccines tested in clinical trials in malaria-endemic areas has thus far been disappointing, sparking renewed interest in the whole parasite vaccine approach. We previously showed that a chemically attenuated whole parasite asexual blood-stage vaccine induced CD4+ T cell-dependent protection against challenge with homologous and heterologous parasites in rodent models of malaria.MethodsIn this current study, we evaluated the immunogenicity and safety of chemically attenuated asexual blood-stage Plasmodium falciparum (Pf) parasites in eight malaria-naïve human volunteers. Study participants received a single dose of 3 × 107 Pf pRBC that had been treated in vitro with the cyclopropylpyrolloindole analogue, tafuramycin-A.ResultsWe demonstrate that Pf asexual blood-stage parasites that are completely attenuated are immunogenic, safe and well tolerated in malaria-naïve volunteers. Following vaccination with a single dose, species and strain transcending Plasmodium-specific T cell responses were induced in recipients. This included induction of Plasmodium-specific lymphoproliferative responses, T cells secreting the parasiticidal cytokines, IFN-γ and TNF, and CD3+CD45RO+ memory T cells. Pf-specific IgG was not detected.ConclusionsThis is the first clinical study evaluating a whole parasite blood-stage malaria vaccine. Following administration of a single dose of completely attenuated Pf asexual blood-stage parasites, Plasmodium-specific T cell responses were induced while Pf-specific antibodies were not detected. These results support further evaluation of this chemically attenuated vaccine in humans.Trial registrationTrial registration: ACTRN12614000228684. Registered 4 March 2014.Electronic supplementary materialThe online version of this article (10.1186/s12916-018-1173-9) contains supplementary material, which is available to authorized users.

The Elizabethkingia genus has gained global attention in recent years as a sporadic, worldwide, nosocomial pathogen. Elizabethkingia spp. are intrinsically multidrug resistant, primarily infect immunocompromised individuals, and are associated with high mortality (∼20-40%). Yet, gaps remain in our understanding of transmission, global strain relatedness, antimicrobial resistance and effective therapy. Over a 16-year period 22 clinical and six hospital environmental isolates were collected from Queensland, Australia. Identification using the MALDI-TOF MS (VITEK® MS) and whole-genome sequencing was compared with a global strain dataset. Phylogenomic reconstruction robustly identified 22 E. anophelis, three E. miricola, two E. meningoseptica and one E. bruuniana, most of which branched as unique lineages. Global analysisrevealed some Australian E. anophelis isolates are genetically closely related to strains identified from the USA, England and Asia. Comparative genomics of clinical and environmental strains identified evidence of nosocomial transmission in patients, indicating probable infection from a hospital reservoir. Furthermore, broth microdilution against 39 antimicrobials revealed almost ubiquitous resistance to aminoglycosides, carbapenems, cephalosporins and penicillins. Like other international strains, our isolates expressed susceptibility to minocycline and levofloxacin and the less common trimethoprim/sulfamethoxazole. Our study demonstrates important new insights into the genetic diversity, environmental persistence, transmission of and potential effective therapy for Australian Elizabethkingia species.

The Elizabethkingia genus has gained global attention in recent years as a nosocomial pathogen. Elizabethkingia spp. are intrinsically multidrug resistant, primarily infect immunocompromised individuals, and are associated with high mortality (~20-40%). Although Elizabethkingia infections appear sporadically worldwide, gaps remain in our understanding of transmission, global strain relatedness and patterns of antimicrobial resistance. To address these knowledge gaps, 22 clinical isolates collected in Queensland, Australia, over a 16-year period along with six hospital environmental isolates were examined using MALDI-TOF MS (VITEK MS) and whole-genome sequencing to compare with a global strain dataset. Phylogenomic reconstruction against all publicly available genomes (n=100) robustly identified 22 E. anophelis, three E. miricola, two E. meningoseptica and one E. bruuniana from our isolates, most with previously undescribed diversity. Global relationships show Australian E. anophelis isolates are genetically related to those from the USA, England and Asia, suggesting shared ancestry. Genomic examination of clinical and environmental strains identified evidence of nosocomial transmission in patients admitted several months apart, indicating probable infection from a hospital reservoir. Furthermore, broth microdilution of the 22 clinical Elizabethkingia spp. isolates against 39 antimicrobials revealed almost ubiquitous resistance to aminoglycosides, carbapenems, cephalosporins and penicillins, but susceptibility to minocycline, levofloxacin and trimethoprim/sulfamethoxazole. Our study demonstrates important new insights into the genetic diversity, environmental persistence and transmission of Australian Elizabethkingia species. Furthermore, we show that Australian isolates are highly likely to be susceptible to minocycline, levofloxacin and trimethoprim/sulfamethoxazole, suggesting that these antimicrobials may provide effective therapy for Elizabethkingia infections.

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