Early clinical development of a live, attenuated combination vaccine against Shigella and ETEC diarrhoea

Project Information

SHIGETECVAX

Grant agreement ID: 815568

DOI

10.3030/815568

Project closed

EC signature date 30 April 2019

Start date 1 September 2019

End date 31 March 2026

Funded under

• SOCIETAL CHALLENGES - Health, demographic change and well-being

Total cost

No data

EU contribution

€ 8 603 989,93

Coordinated by

EUROPEAN VACCINE INITIATIVE EV
Germany

Periodic Reporting for period 3 - SHIGETECVAX (Early clinical development of a live, attenuated combination vaccine against Shigella and ETEC diarrhoea)

Reporting period: 2023-03-01 to 2025-02-28

Summary of the context and overall objectives of the project

Shigella and enterotoxigenic Escherichia coli (ETEC) are among the leading causes of diarrhoea worldwide especially in low- and middle-income countries (LMIC). Prolonged and/or repeated symptomatic episodes in childhood among those who survive infections can have long term consequences such as reduced cognitive development, reduced wages, and increased risk of non-communicable diseases in adulthood.
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 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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

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. Results were published 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 amending the study protocol and informed consent, prepared before commencing the Sero-epidemiology study. The protocol and ICF were amended based on the findings of the phase 1a clinical trial in Europe and were submitted and approved by the iccdr,b Research Review Committee, the Ethical Review Committee and the Directorate General of Drug Administration. After receiving approval from the DSMB, 36 adult participants in 2 escalating dose cohorts were successfully randomized. A third adult cohort receiving the dose of the first children cohort of 2-5 years age group was also included following the DSMB advise to ensure safety in children. Subsequently, and after receiving DSMB permission, the study activities in group B 2-5 years age group(B1, B2 and B3) and C 12-23 months age group (C1 and C2) were completed.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

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).

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