Protocol No: ECCT/20/03/01 Date of Protocol: 13-01-2020

Study Title:

A Phase 2a age descending study to investigate the safety and immunogenicity of the SF2a-TT15 synthetic carbohydrate-based conjugate vaccine against Shigella flexneri 2a in adult, children and infant target population in endemic countries.

Study Objectives:

1.1. Objectives 1.1.1. Primary objective 1. To evaluate the safety and tolerability of one dose of the SF2a-TT15 vaccine corresponding to an equivalent of 10 µg OS, formulated with Alhydrogel in adults and children and of two doses (2 µg and 10 µg OS) non-adjuvanted or adjuvanted in infants. 2. To evaluate the immunogenicity of the vaccine as measured by serum IgG against SF2a LPS in the infant target population. Note: 10 µg OS, is also named 10 µg OS dose formulated with Alhydrogel (also named alum or adjuvanted vaccine in table/figure below). 1.1.2. Secondary Objectives 1. To evaluate the bactericidal activity of the SF2a-specific IgG antibodies induced in infants after immunization with the 2 µg and 10 µg OS dose of the SF2a-TT15 conjugate vaccine adjuvanted or not. 2. To evaluate the immunogenicity of the vaccine as measured by serum IgG against SF2a LPS in the adult and children cohorts. 3. To evaluate any potential immunological impact of the SF2a-TT15 vaccine candidate on the MR vaccine immune response. 1.1.3. Exploratory Objectives  To investigate additional antibody response characteristics, including subclasses, recognition of a diversity of circulating SF2a strains, cross-reactivity towards other SF serotypes, and specific cell-mediated immunity markers.

Laymans Summary:

Lay Title: A study among adults, children and infants in Kenya to determine if a new type of glycoconjugate vaccine incorporating a synthetic carbohydrate component is safe and induces immunity against Shigella. Background Enteric infections (diarrheal diseases and dysentery) remain among the main causes of illness and death among children under 5 in low-income and middle-income countries (LIMCs), particularly in Sub-Saharan Africa. Vaccination is a highly effective intervention against enteric infections, as recently confirmed by rollout of rotavirus vaccination that has already reduced the burden of acute watery diarrhea. Recent studies in Sub-Saharan African have clearly shown that Shigella is one of the four major causative agents consistently causing most of the severe cases of diarrhea. Shigella infection is difficult to treat because (i) the bacterium induces a massive destruction of the intestinal tissue and infected individuals are thus less responsive to the salutary effects of oral rehydration, and (ii) the circulating Shigella strains are multi-resistant to most of the available antibiotics. As treatment options narrow, the need for a safe and effective broad spectrum Shigella vaccine becomes more pressing. What questions are we trying to answer? By performing this study, one wants to know if the vaccine candidate is safe and well-tolerated and induces the appropriate immune response to confer protection against Shigella infection in particular in infants that are the main target of the disease. Where is the study taking place, how many people does it involve and how are they selected? The study will be conducted at the KEMRI/WRP Project clinical Research Center in Kericho, Kenya. In total, 16 adults, 16 children aged 2-5 years and 200 infants aged 9 months +/- 1 month, will be enrolled in the study. The study participants will be healthy based on history, clinical and laboratory evaluations. What does the study involve for those who are in it? The vaccine will be tested in adults first, then in children and eventually in infants in Kenya (where Shigella infection is present), based on the safety/tolerability in each group before to moving to the other. Participants will be randomly assigned to receive the study vaccine or a placebo control (same solution but without the vaccine component). In each group, there will be 3 times more participants receiving the vaccine than the placebo. The participants will have to go through all the trial procedures including the 14 visits during a 16 months period.

Abstract of Study:

Several experimental Shigella vaccines are currently being tested with the aim to eventually license an efficient vaccine against bacillary dysentery, which is still a burden in low- middle-income countries. The Institut Pasteur aims to develop a 4-valent Shigella glycoconjugate vaccine based on the use of synthetic oligosaccharides mimicking the O-antigen (O-Ag) polysaccharide part of the bacterial lipopolysaccharides (LPS) which are the target of the protective antibody response. The rationale for this innovative vaccine design, emerging from chemical biology, is to overcome the limitations reported for conjugate vaccines generated from detoxified Shigella LPSs (lack of immunogenicity in the infants, use of antigens of biological origin), and to fulfill the increasing requirements from regulatory agencies for better-defined and safer molecules to be used in humans. A phase I clinical trial performed in healthy adults in Israel with SF2a-TT15 a monovalent vaccine of that type, targeting the predominant Shigella flexneri 2a (SF2a) serotype, has provided evidence for safety and immunogenicity. The objective of this study, sponsored by Institut Pasteur, is thus to assess the safety and immunogenicity of SF2a-TT15 in adult, children and infant target population in an endemic country (Kenya). Based on the data obtained during the phase 1 clinical trial, two doses of the vaccine, adjuvanted or not with Alhydrogel, will be tested in a cohort of 200 infants (9 months-old +/- 1 month) in total. To achieve this goal, an age-descending study will be implemented with two starting cohorts 16 adults 18-50 years-old and 16 children (2-5 years-old), who will sequentially receive the highest adjuvanted dose tested in the phase 1 trial to “confirm” safety and lack of reactogenicity of SF2-TT15. Moving from one cohort to another till the infant one will be dictated by safety/tolerability data. Thus, a total of 232 participants will be enrolled at the KEMRI – CRC at the Kericho Investigator site. The duration of the total study will be up to 24 months. The results obtained by performing this study will contribute to the selection of the best Shigella vaccine approach to be moved forward to eventually license an efficient vaccine.