Characterization of ShigETEC, a Novel Live Attenuated Combined Vaccine against Shigellae and ETEC

Harutyunyan, Shushan; Neuhauser, Irene; Mayer, Alexandra; Aichinger, Michael; Szijártó, Valéria; Nagy, Gábor; Nagy, Eszter; Girardi, Petra; Malinoski, Frank; Henics, Tamás

doi:10.3390/vaccines8040689

Cited by 24 publications

(19 citation statements)

References 35 publications

(27 reference statements)

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“…Other promising cellular approaches to ETEC vaccine development have been the construction of attenuated, hybrid Shigella vaccine vectors expressing ETEC antigens. The two lead candidates based on this approach are ShigETEC and CVD 1208S-122 [7] , [65] , [66] , Phase 1 testing of ShigETEC and CVD 1208S-122 will likely begin in 2021.…”

Section: Current Status Of Etec Vaccine Developmentmentioning

confidence: 99%

Enterotoxigenic Escherichia coli (ETEC) vaccines: Priority activities to enable product development, licensure, and global access

Khalil¹,

Walker

Porter³

et al. 2021

Vaccine

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Diarrhoeal disease attributable to enterotoxigenic Escherichia coli (ETEC) causes substantial morbidity and mortality predominantly in paediatric populations in low- and middle-income countries. In addition to acute illness, there is an increasing appreciation of the long-term consequences of enteric infections, including ETEC, on childhood growth and development. Provision of potable water and sanitation and appropriate clinical care for acute illness are critical to reduce the ETEC burden. However, these interventions are not always practical and may not achieve equitable and sustainable coverage. Vaccination may be the most cost-effective and equitable means of primary prevention; however, additional data are needed to accelerate the investment and guide the decision-making process for ETEC vaccines. First, to understand and quantify the ETEC disease burden, additional data are needed on the association between ETEC infection and physical and cognitive stunting as well as delayed educational attainment. Furthermore, the role of inappropriate or inadequate antibiotic treatment of ETEC-attributable diarrhoea may contribute to the development of antimicrobial resistance (AMR) and needs further elucidation. An ETEC vaccine that mitigates acute diarrhoeal illness and minimizes the longer-term disease manifestations could have significant public health impact and be a cost-effective countermeasure. Herein we review the ETEC vaccine pipeline, led by candidates compatible with the general parameters of the Preferred Product Characteristics (PPC) recently developed by the World Health Organization. Additionally, we have developed an ETEC Vaccine Development Strategy to provide a framework to underpin priority activities for researchers, funders and vaccine manufacturers, with the goal of addressing globally unmet data needs in the areas of research, product development, and policy, as well as commercialization and delivery. The strategy also aims to guide prioritization and co-ordination of the priority activities needed to minimize the timeline to licensure and use of ETEC vaccines, especially in in low- and middle-income countries, where they are most urgently needed.

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Section: Current Status Of Etec Vaccine Developmentmentioning

confidence: 99%

Enterotoxigenic Escherichia coli (ETEC) vaccines: Priority activities to enable product development, licensure, and global access

Khalil¹,

Walker

Porter³

et al. 2021

Vaccine

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“…This is the Shigella Truncated Mutant (STM), which utilizes genetically modified (Δwzy) inactivated bacteria retaining only one repeating unit of O antigen chain on the bacterial surface [ 48 ]. The other candidate, ShigETEC, is attenuated by the deletion of the T3SS and is engineered to not express any LPS-O antigens through a targeted deletion of the rfbF gene [ 49 , 50 , 51 ]. Both of these novel approaches increase exposure of conserved outer membrane proteins and could effectively provide a broad coverage Shigella vaccine with a single cell type.…”

Section: Shigella Componentmentioning

confidence: 99%

“…ShigETEC, the O-PS free Shigella vaccine construct described above, could also be a combined Shigella −ETEC vaccine, as it has been engineered to express toxin antigens for the LT and stable toxin (ST) of ETEC [ 49 , 50 , 51 ]. However, instead of CFA/I-CS antigens, this candidate relies on the homology between Shigella and ETEC surface proteins.…”

Section: Etec Componentmentioning

confidence: 99%

“…The strain contains a RfbF deletion that renders it rough, i.e., not expressing the serotype-determining O-PS. ETEC coverage is anticipated from homology existing between Shigella and ETEC [59,60], as well as the LT/ST chimeric toxoid expressed [51]. As stated above, the extent that the homology present in Shigella will contribute to protection against major ETEC strains remains to be determined.…”

mentioning

confidence: 99%

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Vaccines for Protecting Infants from Bacterial Causes of Diarrheal Disease

et al. 2021

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The global diarrheal disease burden for Shigella, enterotoxigenic Escherichia coli (ETEC), and Campylobacter is estimated to be 88M, 75M, and 75M cases annually, respectively. A vaccine against this target trio of enteric pathogens could address about one-third of diarrhea cases in children. All three of these pathogens contribute to growth stunting and have demonstrated increasing resistance to antimicrobial agents. Several combinations of antigens are now recognized that could be effective for inducing protective immunity against each of the three target pathogens in a single vaccine for oral administration or parenteral injection. The vaccine combinations proposed here would result in a final product consistent with the World Health Organization’s (WHO) preferred product characteristics for ETEC and Shigella vaccines, and improve the vaccine prospects for support from Gavi, the Vaccine Alliance, and widespread uptake by low- and middle-income countries’ (LMIC) public health stakeholders. Broadly protective antigens will enable multi-pathogen vaccines to be efficiently developed and cost-effective. This review describes how emerging discoveries for each pathogen component of the target trio could be used to make vaccines, which could help reduce a major cause of poor health, reduced cognitive development, lost economic productivity, and poverty in many parts of the world.

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“…Oral vaccination induced significant levels of S. flexneri 2a-specific IgG and IgA, with cross-reactive antibodies against several strains of Shigella and an enteroinvasive E. coli (EIEC) strain, suggesting that vaccination against multiple related enteric pathogens is plausible [32]. In fact, another potential cross-protective live-attenuated strain of S. flexneri 2a was created by removing genes involved in LPS O-antigen expression (rfbF), invasins (ipaB and ipaC), and ShET-1 enterotoxin expression (setBA) while simultaneously expressing two fused enterotoxigenic E. coli (ETEC) antigens: heat-labile enterotoxin subunit B (LT-B) and detoxified heat-stable toxin (ST) [33]. This vaccine strain, ShigETEC, was found to be non-invasive, non-pathogenic, and protected mice from a lethal intranasal challenge with both S. sonnei and S. flexneri 6.…”

Section: Inactivated Whole-cells and Live-attenuated Vaccines (Lavs)mentioning

confidence: 99%

Recent Progress in Shigella and Burkholderia pseudomallei Vaccines

et al. 2021

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Significant advancement has been made in the development of vaccines against bacterial pathogens. However, several roadblocks have been found during the evaluation of vaccines against intracellular bacterial pathogens. Therefore, new lessons could be learned from different vaccines developed against unrelated intracellular pathogens. Bacillary dysentery and melioidosis are important causes of morbidity and mortality in developing nations, which are caused by the intracellular bacteria Shigella and Burkholderia pseudomallei, respectively. Although the mechanisms of bacterial infection, dissemination, and route of infection do not provide clues about the commonalities of the pathogenic infectious processes of these bacteria, a wide variety of vaccine platforms recently evaluated suggest that in addition to the stimulation of antibodies, identifying protective antigens and inducing T cell responses are some additional required elements to induce effective protection. In this review, we perform a comparative evaluation of recent candidate vaccines used to combat these two infectious agents, emphasizing the common strategies that can help investigators advance effective and protective vaccines to clinical trials.

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Characterization of ShigETEC, a Novel Live Attenuated Combined Vaccine against Shigellae and ETEC

Cited by 24 publications

References 35 publications

Enterotoxigenic Escherichia coli (ETEC) vaccines: Priority activities to enable product development, licensure, and global access

Enterotoxigenic Escherichia coli (ETEC) vaccines: Priority activities to enable product development, licensure, and global access

Vaccines for Protecting Infants from Bacterial Causes of Diarrheal Disease

Recent Progress in Shigella and Burkholderia pseudomallei Vaccines

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