Pneumonia and diarrhoeal diseases are, respectively, the first and third leading causes of death in children under the age of five years. These diseases were added to the scope of the EDCTP2 programme, and recent funding has established a portfolio of projects in this area, with a strong focus on vaccines – generally the most cost-effective way to control infection and minimise the long-term impact of disease on individuals.

Enterotoxigenic E. coli (ETEC) is an important cause of diarrhoeal disease in sub-Saharan Africa. A promising vaccine against ETEC has been developed, known as ETVAX, and EDCTP has funded studies to accelerate its introduction in the region.

Funded in 2019, the ShigOraVax study is evaluating a vaccine against the most common forms of Shigella, S. flexneri strains 2a, 3a and 6 and S. sonnei, all of which are associated with severe diarrhoeal disease. The project aims to develop a whole-cell inactivated vaccine that is protective against all these strains, can be administered orally, and is cheap and easy to manufacture. After safety studies in adults, it will then be tested in children.

Finally, the BabyGel study is exploring a simple intervention to reduce infant infections – giving pregnant women alcohol-based hand rub for household use, alongside educational guidance, after they have given birth.

The ETEC Vaccine Efficacy study is conducting a series of safety studies on ETVAX in adults and progressively younger children in Zambia. Assuming no safety issues arise, the project will then progress to a phase IIb study in infants in The Gambia. The related ETEC ETVAX study, awarded in 2019, is developing a new formulation better suited to young children, as well as a user-friendly tool for administering the vaccine. The new all-in-one formulation will then be tested in a phase III trial in Zambian infants.

Typhoid fever, caused by infections with Salmonella Typhi, causes more than 200,000 deaths every year. A typhoid conjugate vaccine, Typbar-TCV^®, has been licensed despite limited data on its efficacy. In the THECA study, a trial in Ghana will generate data on safety and efficacy and population-level protection, adding to the pool of African data provided by other ongoing trials. In addition, a complementary study in the Democratic Republic of the Congo will be embedded within a mass vaccination campaign, providing additional data on protection when the vaccine is used within routine public health systems, as well as insight into feasibility, programmatic challenges, and cost-effectiveness.

Group B streptococci can be transmitted to babies in the womb or during childbirth and can cause stillbirths and invasive disease in young infants. The PREPARE study, funded in 2019, is testing two vaccines that, when given to pregnant women, are designed to prevent the transmission of group B streptococci to their offspring.

Three ongoing trials are focusing on treatment of pneumonia in children. The PediCAP study is testing new treatment regimens, to optimise antibiotic use in young children. The COAST-Nutrition study is building on an existing major trial of oxygen therapy to determine whether greater use of nutritional supplements improves survival. The EMPIRICAL trial is evaluating whether treatment for TB and cytomegalovirus, a common and usually harmless virus, improves survival of HIV-infected infants with severe pneumonia; these infections are turning out to be an unexpectedly common cause of disease in such infants, so presumptive treatment even without formal diagnosis may enhance survival.

Importantly, the pneumonia studies are also building regional capacity in research on respiratory tract infections, of potential importance in the battle against COVID-19.

The project is conducting a series of safety studies on ETVAX in adults and progressively younger children in Zambia. Why is this important? And how does this project relate to the EDCTP-funded ETEC ETVAX project? 

ETVAX^® is Scandinavian Biopharma’s tailor-made vaccine against enterotoxigenic Escherichia coli (ETEC). ETEC is one of the most important pathogens causing diarrhoeal disease for which there is no vaccine, making it a priority pathogen for WHO. Nearly 600,000 deaths occur each year, approximately 9 percent of global infant mortality, which has an enormous physical and economic toll in low-resource countries. A recent report from Zambia showed that ETEC was among the top three enteric pathogens detected among children under 5 years presenting with moderate to severe diarrhoea, making ETEC a pathogen of public health importance in Zambia.

The EDCTP-funded programme addresses three priority research areas: field testing of vaccines against ETEC; gaining a better understanding of oral vaccine safety and immunogenicity in age groups at high risk for ETEC diarrhoea; and implementing new approaches and diagnostic tools for more sensitive and rapid detection of ETEC and other enteric pathogens in low- and middle-income countries.

The outcome of the programs will pave the way for the pivotal phase III trial, licensure of a first ETEC vaccine, and pre-qualification by WHO.

What comes next?

Despite all challenges associated with the COVID-19 pandemic, all cohorts have been enrolled and the first two cohorts have received all three vaccinations. Children in the third cohort have been given the first two vaccinations and will receive the third and final vaccination in August 2020.

Preliminary findings suggest promising immunogenicity results for the different antigens in the vaccine and confirm the favourable safety profile of ETVAX^®.

The Zambian study will be followed, as soon as the COVID-19 pandemic allows, by a phase IIb study in approximately 5,000 children 6-18 months of age in The Gambia. Enrolment is due to start in October 2020. The objective of the study is to investigate the protective efficacy of the vaccine over a 1–2-year period against moderate to severe diarrhoea caused by ETEC.

What progress was made in 2019?

The programme started in 2019 with a phase I age-descending trial in Zambia, as a sequel to the already successful age-descending phase I/II trial in 500 Bangladeshi participants. The main objectives of the trial in Zambia were to establish the safe and immunogenic dose of the vaccine in young children (6-23 months of age) as well as to explore potential benefits of a third booster dose. The study included 40 healthy adults, followed by 60 children aged 10-23 months of age and 146 children 6-9 months of age.

During 2019 the enrolment and vaccination of the first cohort of adult participants was completed. The first children’s cohort (the oldest age group) was then enrolled and the children received their first two vaccinations during 2019 (and the last one in January–March 2020). The children cohorts received two doses of placebo, 1/8 or 1/4 of the adult dose of ETVAX^® together with 2.5 µg of dmLT (an adjuvant) followed by a booster dose.

The project is collecting essential data to advance the development of vaccines against Shigella. Why is this important? 

Shigella is one of the leading causes of diarrhoeal deaths in children under 5 years and still no vaccine is available. The project aims at establishing clinical proof of concept for an oral tetravalent vaccine, designed to ensure maximum uptake in low-resource settings, that will cover most of the pathogenic strains of Shigella. Moreover, the project will also address the lack of accurate data on disease burden by generating epidemiological data in children living in Burkina Faso and Zambia.

What comes next?

Work on the immunological assays will continue. The protocol and the surveillance tools to determine the incidence of shigellosis in children under 5 living in Burkina Faso and Zambia will be finalised and submitted to regulators before the start of the epidemiological study. We will also continue work on the protocol and other documents required for the phase Ia/Ib trial.

In addition, capacity-building activities will be implemented, with the selection of master’s and PhD students and preparation for the establishment of a controlled human infection model in Zambia and Burkina Faso.

What progress was made in 2019?

All project-related activities were discussed in depth during the kick-off meeting that was organised in Burkina Faso, just after the project’s official start in October 2019. The project governance has been established. Development of immunological assays to assess immune responses after vaccination has started at the University of Gothenburg. We have also begun to prepare the protocol for the phase Ia/Ib clinical trial and for epidemiological studies.

What are the main challenges for treating hospitalised children with severe pneumonia? How will the project address these issues? 

Pneumonia is the single largest infectious cause of death in children worldwide – accounting for 15% of all deaths of children under 5 years old, particularly in sub-Saharan Africa and southern Asia.

According to current WHO recommendations, children affected by pneumonia often receive intravenous antibiotics for several days and, especially in low- and middle-income countries, are hospitalised. This has a big impact on families and their finances, and exposes infants to the risk of hospital-acquired infections.

The scientific question PediCAP is addressing is whether it is safe and equally effective to implement a rapid step down to oral antibiotics, with early discharge for children who are making a good clinical recovery on intravenous antibiotics. The study also aims to define the overall optimal choice of oral antibiotic step down (amoxicillin vs co-amoxicillin), dose, and total duration of treatment, taking into account the efficacy, toxicity, costs, selection for drug resistance and reduction of hospital-acquired infection.

The ultimate goal of PediCAP is to help to define the optimal antibiotic treatment for children hospitalised with severe/very severe pneumonia in low- and middle-income countries, to address the lack of recent data to inform global guidance and local clinical decision-making.

PediCAP will also create an infrastructure that links study sites in order to share knowledge and promote capacity development.

What comes next?

The PediCAP Consortium is working closely with sites on COVID-19 risk assessments in all the involved countries and on all the participating teams. We are currently working with all partners to define a safe environment for families and all the teams for the conduct of the trial. We hope to have a virtual opening of sites to recruitment in late 2020.

What progress was made in 2019?

The PediCAP project started in April 2019, working with partners in Zimbabwe, Uganda, Zambia and South Africa. The teams reached the goal of finalising the trial protocol in June 2019. The second half of the year has seen the five recruiting partners working on ethics and regulatory submissions, with sites now completing this process. In parallel, the pharmacokinetic, microbiology and health economic analysis teams have made great progress on their programmes of work.

The EMPIRICAL trial is evaluating whether treatment for TB and cytomegalovirus improves survival of HIV-infected infants with severe pneumonia. Why is this approach important and how will it make a significant impact in this field?

Despite the high mortality associated with tuberculosis and cytomegalovirus, in many resource-limited settings there is no diagnosis in place and available diagnostic tools perform poorly. Therefore treatment is not started or started very late. Our hypothesis is that empirical treatment against cytomegalovirus and tuberculosis – i.e. beginning treatment before formal diagnosis – improves survival of HIV-infected infants with severe pneumonia.

What comes next?

Now that the protocol is approved, the next step is recruiting into the trial. It is a complex trial because we are dealing with hospitalised and very sick children. Recruiting has started but has been influenced by the COVID-19 pandemic, so we also have to adapt the study to the new situation. It is also very important to support three young researchers from the EMPIRICAL consortia to apply for EDCTP fellowships.

What progress was made in 2019?

During the first year of the project, all partners have demonstrated expertise and capability to collaborate. We managed to design a feasible protocol and standard operational procedures, with clear worksheets. Thanks to all these factors, we were able to get the trial protocol approved without extra delay by local ethics and regulatory authorities. In addition, the study drugs were purchased to be available for the trial.