Periodic Reporting for period 2 - SHIGETECVAX (Early clinical development of a live, attenuated combination vaccine against Shigella and ETEC diarrhoea)
Período documentado: 2021-09-01 hasta 2023-02-28
Shigella and enterotoxigenic Escherichia coli (ETEC) are among the leading causes of diarrhoea worldwide especially in low- and middle-income countries (LMIC) where these pathogens account for about 200 million episodes of diarrhoea per year. Prolonged and/or repeated symptomatic episodes in childhood among those who survive infections can have long term consequences such as reduced cognitive development, poorer educational outcomes, reduced wages, and increased risk of non-communicable diseases in adulthood, further perpetuating the cycle of poverty in low-resource settings.
Vaccination against other pathogens causing diarrhoeal disease, such as cholera and rotavirus, has proven to be effective and has greatly contributed to reduce global mortality due to diarrhoea. There is currently no licenced vaccine for Shigella and ETEC. Therefore, development of an easy-to-administer and affordable Shigella-ETEC combination vaccine is warranted and may contribute to achieve the goal of the WHO/UNICEF Integrated Global Action Plan for the Prevention and Control of Pneumonia and Diarrhoea to reduce deaths from diarrhoea in children under 5 years of age to less than 1 per 1000 live births by 2025.
Accelerating the development of a combination vaccine suitable for use in limited resource settings for two of the major pathogens causing childhood diarrhoeal diseases (Shigella and ETEC) by the SHIGETECVAX consortium is expected to directly contribute to reducing the development time and cost when compared to advancing each program separately. The results of the activities proposed in this project will set the stage for further proof of concept clinical evaluation of the ShigETEC vaccine to provide a solution to the problems of these diarrhoeal diseases that affect millions of children at risk for death and long-term consequences of diarrhoeal illness, such as growth retardation and mental developmental impairments, in LMIC.
The SHIGETECVAX project aims to advance the ShigETEC vaccine candidate into early clinical development, with the goal to develop an effective vaccine suitable for different populations, in particular for paediatric use in LMIC.
Specific objectives are to:
1. Generate clinical trial material through cGMP manufacture of the ShigETEC vaccine for the first-in human Phase 1a study and testing in endemic country in the Phase 1b studies.
2. Conduct of a Phase 1a clinical trial in adult volunteers in Europe to determine safety, maximum tolerated dose, and optimal schedule of multiple doses of the orally administered ShigETEC vaccine based on safety and immunogenicity parameters.
3. Conduct a sero-epidemiology study to obtain samples from children and adults from Bangladesh infected with Shigella and ETEC and healthy adult controls to study. natural systemic and mucosal antibody responses to ShigETEC vaccine components.
4. Conduct an age descending Phase 1b clinical trial in Bangladeshi adults and three paediatric age groups orally immunized with ShigETEC or placebo to determine vaccine safety, shedding and immune responses.
5. Conduct comprehensive and comparative immune response profiling to reveal potential population differences in vaccine responses to the ShigETEC vaccine and compare vaccine induced and natural immune responses using a large panel of immune assays with standardized methodology.
6. Perform a feasibility study for heat-stable formulation in a multi-tablet presentation of ShigETEC for future paediatric use in LMIC.
Vaccination against other pathogens causing diarrhoeal disease, such as cholera and rotavirus, has proven to be effective and has greatly contributed to reduce global mortality due to diarrhoea. There is currently no licenced vaccine for Shigella and ETEC. Therefore, development of an easy-to-administer and affordable Shigella-ETEC combination vaccine is warranted and may contribute to achieve the goal of the WHO/UNICEF Integrated Global Action Plan for the Prevention and Control of Pneumonia and Diarrhoea to reduce deaths from diarrhoea in children under 5 years of age to less than 1 per 1000 live births by 2025.
Accelerating the development of a combination vaccine suitable for use in limited resource settings for two of the major pathogens causing childhood diarrhoeal diseases (Shigella and ETEC) by the SHIGETECVAX consortium is expected to directly contribute to reducing the development time and cost when compared to advancing each program separately. The results of the activities proposed in this project will set the stage for further proof of concept clinical evaluation of the ShigETEC vaccine to provide a solution to the problems of these diarrhoeal diseases that affect millions of children at risk for death and long-term consequences of diarrhoeal illness, such as growth retardation and mental developmental impairments, in LMIC.
The SHIGETECVAX project aims to advance the ShigETEC vaccine candidate into early clinical development, with the goal to develop an effective vaccine suitable for different populations, in particular for paediatric use in LMIC.
Specific objectives are to:
1. Generate clinical trial material through cGMP manufacture of the ShigETEC vaccine for the first-in human Phase 1a study and testing in endemic country in the Phase 1b studies.
2. Conduct of a Phase 1a clinical trial in adult volunteers in Europe to determine safety, maximum tolerated dose, and optimal schedule of multiple doses of the orally administered ShigETEC vaccine based on safety and immunogenicity parameters.
3. Conduct a sero-epidemiology study to obtain samples from children and adults from Bangladesh infected with Shigella and ETEC and healthy adult controls to study. natural systemic and mucosal antibody responses to ShigETEC vaccine components.
4. Conduct an age descending Phase 1b clinical trial in Bangladeshi adults and three paediatric age groups orally immunized with ShigETEC or placebo to determine vaccine safety, shedding and immune responses.
5. Conduct comprehensive and comparative immune response profiling to reveal potential population differences in vaccine responses to the ShigETEC vaccine and compare vaccine induced and natural immune responses using a large panel of immune assays with standardized methodology.
6. Perform a feasibility study for heat-stable formulation in a multi-tablet presentation of ShigETEC for future paediatric use in LMIC.
In advancing the early clinical development of this live, attenuated combination vaccine against Shigella and ETEC diarrhoea, in the first 24 months of the project, the ShigETEC drug product was successfully manufactured, labelled, packaged and stability was confirmed. The first-in-human Phase 1a clinical trial to assess safety and tolerability of ShigETEC was conducted at the University of Debrecen, Hungary. The study was conducted in two stages; Stage 1 as a single, dose escalating study and Stage 2 as a multidose study using the optimal dose defined in Stage 1. Taken together, the safety and immunogenicity results have confirmed the selection of a safe and likely effective dose and vaccination schedule to use in further clinical development of ShigETEC, incl. the Phase 1b study in Bangladesh.
The sero-epidemiology study was conducted in Bangladesh in adult and paediatric patients infected with Shigella or ETEC as well as in healthy adult controls. Enrolment and follow-up of the participants were successfully completed by March 2021. Clinical samples were characterized for natural systemic and mucosal antibody responses to the ShigETEC vaccine components. Publication of the results is planned in 2023. These results inform about natural immune response to the vaccine antigens, which will help predict critical vaccine responses for this and future generations of Shigella and ETEC vaccines.
The phase Ib clinical trial was initiated by preparing and submitting the study protocol, informed consent and study related documents to iccdr,b Ethical Review Committee (ERC) and Research Review Committee (RRC). After approval from ERC and RRC, the regulatory folder was submitted and approved by the governmental body, the Directorate General of Drug Administration.
The sero-epidemiology study was conducted in Bangladesh in adult and paediatric patients infected with Shigella or ETEC as well as in healthy adult controls. Enrolment and follow-up of the participants were successfully completed by March 2021. Clinical samples were characterized for natural systemic and mucosal antibody responses to the ShigETEC vaccine components. Publication of the results is planned in 2023. These results inform about natural immune response to the vaccine antigens, which will help predict critical vaccine responses for this and future generations of Shigella and ETEC vaccines.
The phase Ib clinical trial was initiated by preparing and submitting the study protocol, informed consent and study related documents to iccdr,b Ethical Review Committee (ERC) and Research Review Committee (RRC). After approval from ERC and RRC, the regulatory folder was submitted and approved by the governmental body, the Directorate General of Drug Administration.
The WHO Diarrhoeal Disease Fact Sheet, 2017 demonstrated the importance and threat from diarrhoeal diseases by high global disease burden of 1.7 billion cases each year. The 2015 Global Burden of Disease Study showed that worldwide diarrhoeal diseases ranked ninth among the causes of death for all ages, and fourth among children under 5 years old, accounting for an estimated 500 000 deaths in this age group in a total of 1.3 million deaths.
Diarrhoeal diseases are also the second most common cause of stunting and loss of disability-adjusted life-years (2.39 billion years lived with disability). Of the wide array of pathogens causing childhood diarrhoea, the ones causing by far the most cases of moderate-to-severe diarrhoea cases are rotavirus (for which vaccines are available now), Cryptosporidium, ETEC, and Shigella. Consequently, in combination with other measures, the development of a combined vaccine, as proposed in the SHIGETECVAX project, will be an important contribution to interventions targeting these major pathogens and will substantially reduce burden of childhood diarrhoeal diseases.
Furthermore, recent impact studies indicated that combination vaccines – such as the proposed ETEC and Shigella vaccine - would have the greatest impact on saving lives and promoting the health of infants and children in the developing world and consequently would be commended from the perspective of cost-effectiveness. In addition, adding protection against these pathogens through an oral vaccine regimen would avoid the expanding complexity of and parental concerns about multiple injections in the already crowded EPI schedule.
Beyond helping to achieve sustainable development goal (SDG) 3, improving health and well-being clearly are central measures of progress in achieving other SDGs, health being a precondition as well as an outcome of successful sustainable development. Improving health and well-being by reducing the disease burden of diarrhoeal diseases, will consequently have a direct positive impact on achieving SDG 1 (no poverty), SDG 5 (gender equality), SDG 10 (reduced inequalities) and SDG 13 (climate action).
Diarrhoeal diseases are also the second most common cause of stunting and loss of disability-adjusted life-years (2.39 billion years lived with disability). Of the wide array of pathogens causing childhood diarrhoea, the ones causing by far the most cases of moderate-to-severe diarrhoea cases are rotavirus (for which vaccines are available now), Cryptosporidium, ETEC, and Shigella. Consequently, in combination with other measures, the development of a combined vaccine, as proposed in the SHIGETECVAX project, will be an important contribution to interventions targeting these major pathogens and will substantially reduce burden of childhood diarrhoeal diseases.
Furthermore, recent impact studies indicated that combination vaccines – such as the proposed ETEC and Shigella vaccine - would have the greatest impact on saving lives and promoting the health of infants and children in the developing world and consequently would be commended from the perspective of cost-effectiveness. In addition, adding protection against these pathogens through an oral vaccine regimen would avoid the expanding complexity of and parental concerns about multiple injections in the already crowded EPI schedule.
Beyond helping to achieve sustainable development goal (SDG) 3, improving health and well-being clearly are central measures of progress in achieving other SDGs, health being a precondition as well as an outcome of successful sustainable development. Improving health and well-being by reducing the disease burden of diarrhoeal diseases, will consequently have a direct positive impact on achieving SDG 1 (no poverty), SDG 5 (gender equality), SDG 10 (reduced inequalities) and SDG 13 (climate action).