What is the problem/background?

Diarrhoea caused by the bacteria Shigella is a major public health problem. Shigella is the leading cause of moderate to severe diarrhoea in infants and children in low- and middle-income countries (LMICs) with approximately seventy-five million episodes of diarrhoea occurring annually mainly over the child’s first three years of life. There are 4 main different types of Shigella and one of these, Shigella sonnei, has been found to be a common cause of diarrhoea in Kenya. There are no vaccines available against the disease; however, a number are currently in development and being tested in clinical trials including in trials being conducted in Kenya. There is an urgent need to accelerate the development of these vaccines especially in the advent of resistance to drugs used to treat the disease. Thus, human infection studies (HISs) are needed to test the usefulness of candidate vaccines so that vaccines showing evidence of efficacy can then be prioritised for testing in Phase 2/3 clinical trials in the target age population. Furthermore, there is need to study how the humans respond against to infection and the association between these immune responses with protection may help better understand resistance and/or susceptibility, including characterizing and identifying potential targets for second- or third-generation vaccines. Human infection studies for Shigella have been an important tool in the advancing of the understanding of the disease, how immunity develops, and efficacy of interventions such as vaccines. These, however, have largely been undertaken in individuals not exposed to infection. Human infection studies have been undertaken using Shigella sonnei 53G strain in the USA and Thailand. The expansion of the Shigella HISs to areas where infection commonly occurs, like Kenya, will help address the need to facilitate greater use of the model as a tool to accelerate Shigella vaccine development. 

What questions are we trying to answer?

We wish to understand:

• Human and bacterial factors that determine how vulnerability to and recovery from disease develops.
• What dose of bacteria is required to reliably cause disease in ≥60% of the volunteers.
• How immunity develops in individuals who have past exposure to Shigella sonnei.

Where is the study taking place, how many people does it involve, and how are they selected?

The study will take place in Kilifi, Kenya. Kilifi County (Kilifi North, Kilifi Town, Kilifi South, and Mtwapa) will be where volunteers will be recruited and undergo the infection phase of the study. The study will involve the recruitment and screening of adults (18-45 years of age, up to 70 volunteers are required) from Kilifi County to determine eligibility for participation and past exposure to the strain of Shigella used for infection. This will be done after a programme of sensitisation and information giving about the study to local community leaders, as well local regulatory and ethical boards. The study will be conducted in two phases (A and B) where volunteers will be enrolled as follows:

1. Phase A (N = up to 40 volunteers) dose-finding: to determine the dose of Shigella sonnei 53G bacteria that will cause infection and result in diarrhoea in at least 60% of the volunteers. Volunteers in Phase A will be enrolled in successive cohorts each with N = 10 volunteers receiving a varying dose of Shigella sonnei 53G bacteria.

2. Phase B (N = 30 volunteers dose verification: further validation of the disease rate assessing infectivity of the dose in Phase A found to give rise to diarrhoea in ≥60% of the volunteers. Volunteers in Phase B will be enrolled into two successive cohorts with N = 15 volunteers in each cohort receiving the dose of bacteria found to reliably cause diarrhoea in ≥60% of volunteers.

For each of these phases, eligibility for enrolment will be based on the health status and level of past exposure to Shigella sonnei (determined by history or serology). To determine these, a clinical assessment and laboratory tests will be performed with blood, saliva, stool, and urine samples taken at the point of screening for each individual volunteer.

What does the study involve for those who are in it?

All volunteers will attend a screening visit to determine if they are eligible based on review of medical history, a clinical assessment including to check the functioning of the heart, and laboratory tests. For screening, a blood sample of 76 mL will be collected in addition to urine, saliva, and stool samples. For enrolment, volunteers with no exclusionary clinical disease and medical history will be considered and will be screened for past exposure to Shigella. Those that meet the eligibility criteria after screening (there will be screening events for each cohort of volunteers enrolled) will be asked to be part of the challenge phase of the study. In the infection phase, volunteers will be enrolled into Phase A or into Phase B of the study for Shigella infection and will stay at the in-patient challenge facility located within close proximity to KEMRI CGMRC in Kilifi County where they will remain for about 14 days as in-patients. Phase A will happen before Phase B.

Volunteers will be asked to stay at the facility starting five days before infection (to undertake health checks to be sure they are well). During the first 5 days, a COVID-19 test will be performed. In addition, a blood sample will be taken to test for presence of antibiotics that might have impact on establishment of infection. If a volunteer is found to be infected with COVID-19 and/or have antibiotics in their blood, the volunteer will be discharged from the facility before receiving the Shigella germ. On the sixth day, all volunteers will be given a dose of the Shigella germ. After infection, volunteers will be checked regularly by the study doctors and nurses. Five days after the challenge (study day 6), all volunteers will be given a 3-day course of antibiotics to clear the Shigella from their body. After completion of the antibiotics and having 2 stool cultures showing the Shigella is out of their body, volunteers will be able to return home. If the study doctor thinks it is necessary, antibiotics may be started before day 6. The inpatient period will last approximately 14 days. To set up the human infection model we must first reliably induce an infection which will result in disease in ≥60% of the volunteers. We will:

1. For Phase A: Healthy volunteers, 18–45 years old, will be enrolled into at least one of three cohorts to be given different doses of Shigella sonnei 53G bacteria in suspension to drink. During this part of the study, we want to find out the dose of 53G needed to cause an infection in about 6 of every 10 people. As mentioned before, the study will occur at the challenge in-patient facility within proximity of KEMRI CGMRC in Kilifi County where volunteers will remain for about 14 days. All volunteers will be treated with an antibiotic if they meet criteria (early treatment) or on day 6 after drinking the bacterial suspension. If the study doctor thinks it is important for the health of the volunteer, antibiotics may be started before day 6. Volunteers will be monitored until they have cleared the infection (i.e., no Shigella bacteria being detected in two consecutive negative stool samples with resolution of symptoms). It is likely that some volunteers might require treatment before day 6 based on their clinical presentation (see section 6.1.6.5).

2. For Phase B: Based on results from Phase A, volunteers will be given the dose of 53G found to cause infection in about 6 of 10 recipients. The rest of Phase B will be the same as described above for Phase A. All volunteers will be treated with an antibiotic on day 6 after infection and will be monitored until they have cleared the infection (i.e., no Shigella bacteria being detected in stool based on two stools with consecutive negative results and resolved symptoms). It is likely that some volunteers might require treatment before day 6 based on their clinical presentation.

During the first 5 days at the in-patient facility, volunteers will be checked to be sure they are well. During this time, COVID-19 and antibiotic testing will be performed. If a volunteer is found to be infected with COVID-19, i.e., found to have detectable virus, the volunteer will be referred for management according to the guidelines at time of testing and discharged from the in-patient facility before receiving the Shigella germ. Five days before infection, all volunteers eligible for enrolment (both Phases A and B) will be invited to the inpatient facility for COVID-19 testing and enrolled for infection after a confirmed negative test result. Any volunteers who are found to be positive will be referred for management based on the prevailing guidelines and their participation in the study will be discontinued.

Multiple samples (blood, saliva, stool, and urine) will be taken for those enrolled for admission (both Phase A and B). For both phases, blood samples will be drawn as follows: five days before challenge (up to 9 mL); a day before challenge (71 mL); days one, two, and three (9 mL each day); day four (49 mL); day five (5 mL); day six (59 mL); day seven (5 mL); day eight (59 mL); day nine (5 mL); day fifteen (29 mL); day twenty-nine (49 mL); day fifty-seven (44 mL); and then at 6 months (day 181) and 12 months (day 366) (40 mL and 10 mL each time point, respectively). In addition, stool and saliva samples will be collected at various time points during the study. For the entire duration of the study (12-14 months), up to a total of 544 mL of blood per volunteer will be drawn for both Phase A and Phase B. The total volume of blood collected in the study is within the limits of the volume taken about the same as during a single unit of blood donation. In addition to blood sampling, clinical assessments will be repeated a day before infection, including collection of a urine sample. Observed antibiotic treatment for shigellosis will be given on day 6, or earlier if the participant meets early treatment criteria.

During the in-patient period, if a volunteer develops signs and symptoms of COVID-19, samples will be taken for testing and if found to be positive (by PCR testing), they will be isolated and symptomatic management for coronavirus disease administered. At the same time, the volunteer will be treated with antibiotics against shigellosis as outlined in this protocol, after which he/she will exit the inpatient phase of the study (only after two stools with consecutive negative stool results and resolved symptoms) and be referred for management or managed based on the COVID-19 guidelines prevailing at the time of diagnosis. For infection control, volunteers will be released only after clearance of the S. sonnei 53G in their stool as evidenced by two negative stool culture results.

What are the benefits and risks/costs of the study for those involved? 

Human infection studies with Shigella have been conducted in healthy adults in the United States and Thailand and have been proven safe in these individuals. The risks relate to the development of shigellosis which is the primary objective of the study. Illness caused by Shigella ranges from mild (watery diarrhoea being the main symptom) to severe (fever and abdominal pain with frequent bloody stools containing mucus). Volunteers may complain of nausea, vomiting, headache, muscle and/or joint aches, and other symptoms associated with the disease. Symptoms typically are self-resolving in 5-7 days. However, administration of an effective antibiotic will significantly reduce, or eliminate, symptoms within 24 hours of initiation. There is potential risk of developing redness and swelling in various joints in the body, typically 1 to 3 weeks after the onset of diarrhoea. This risk is higher in persons with a particular genetic marker and therefore for this study, potential volunteers who are positive for this genetic marker will be excluded from participation. There is the possibility of increased risk of developing an intestinal disorder causing pain in the stomach, wind, diarrhoea, and constipation. There is the risk of pain, bruising, or infection at the site of venipuncture. There might be risks relating to the possibility of developing an allergic reaction or other side effects due to administration of the antibiotic treatment. There is also a risk of the study staff acquiring the infection from volunteers who will be administered the S. sonnei 53G strain. Therefore, proper personal protective equipment will be worn by staff, and good personal hygiene such as frequent hand washing will be followed by staff and volunteers.

Volunteers are required to be residents in the inpatient unit for safety monitoring and to reduce the risk of spreading the infection. This is a considerable cost to the volunteers on their time but is a requirement for the study to be successful. There are no direct benefits to individuals participating in this study other than gaining information about their health. There might be a perception of benefit from clinical assessment and laboratory screening. However, a successful outcome of the study could lead to the development of a model that will allow easier and more reproducible evaluation of preventive and therapeutic measures against disease due to S. sonnei. Despite there being no direct benefits to the study volunteers, all volunteers will have their transport costs reimbursed (a range between Ksh200 and Ksh1,000) and will be compensated for all out-of-pocket expenses for each study visit during the entire duration of the study (at a rate of Ksh500 for each clinic visit and at a rate of Ksh2,000 per overnight stay).

How will the study benefit society? 

This work is necessary for enhancing our understanding of how Shigella infection develops, the type of immunity involved, and the establishment of a model to test interventions such as vaccines in a population that has a high burden of infection with this bacterium and the resulting morbidity and mortality associated with both the acute and more long-term aspects of this disease, which would most benefit from a subsequent vaccine. The successful application of such interventions will benefit society by reducing diarrhoea attributed to S. sonnei, a major cause of illness, death, and impediment to national development. The establishment of this human infection model in Kenya provides a way of studying the disease in a very detailed way that is not possible in natural infections. In addition, the establishment of this model in Kenya will ultimately provide a pathway to support efforts to accelerate the efficacy testing of the most promising Shigella vaccine candidates, particularly providing an option for testing these vaccines against important types that lack the field incidence to be assessed in Phase 3 trials. 

When does the study start and finish?

The study will start upon receipt of ethical and regulatory clearance and activation by the study Sponsor. The duration of volunteer participation is 12-14 months from screening to final follow-up. Data collection, analysis, and write-up will take place over three years.