Lay Title

A study of the safety and body’s response of a new vaccine against blood infection with Salmonella bacteria that are not of the typhoid type.

What is the problem/background?

Non-typhoidal Salmonellae are types of bacteria that can cause gut infections resulting in diarrhoea across the globe. However, under some circumstances, these bacteria can cause a more severe illness where infection spreads beyond the gut into the blood stream, a condition termed invasive non-typhoidal Salmonellosis (iNTS).

iNTS disease is an under-recognised cause of disease and death in sub-Saharan Africa. In these regions, it primarily occurs in young children, particularly those with malaria, malnutrition, HIV infection and other causes of low immunity. High death rates, difficulties in diagnosing this infection, increasing resistance of the bacteria to common antibiotics, and spread via contaminated food and water make development of an effective and affordable vaccine against iNTS a desirable public health intervention.

What questions are we trying to answer?

A new and innovative vaccine (iNTS-GMMA Vaccine), has been developed by GlaxoSmithKline (GSK) Vaccines Institute for Global health (GVGH). This vaccine is formed from outer surface particles of the Salmonella bacterium. This vaccine reveals components of the bacteria to the human immune system without the risk of causing infection or disease. The aim of this vaccine is to confer protection to the two most common African non-typhoidal Salmonella entericaserotypes causing iNTS disease i.e. Salmonella Enteritidis and Salmonella Typhimurium.  

The main objective of this trial is to evaluate the safety of the iNTS-GMMA vaccine in healthy adults in Kenya. The secondary objective is to investigate the human immune response to the iNTS-GMMA vaccine.

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

The study will be conducted at KEMRI-Wellcome Trust, Kilifi and participants will be invited to participate from locations within the Kilifi Health and Demographic Surveillance System (KHDSS). Healthy adult male and female volunteers aged 18 – 45 years will be invited to participate in the study and will undergo an informed consent process. 120 adults meeting inclusion criteria and having normal baseline investigations will be randomized to receive the experimental vaccine in full dose, medium dose or low dose or a control vaccine/placebo combination. The vaccine will be administered three times: at 0, 2 months and 6 months. The control vaccine (MenACWY conjugate vaccine GSK Menveo) will be administered once at 0 months, and a placebo administered at 2 and 6 months.

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

Each of the participants will undergo 11 scheduled visits, including a screening visit <=28 days prior to the first vaccination (visit 0), three vaccination visits (at 0, 2 and 6 months), 2 safety visits (scheduled 7 and 28 days after each vaccination), and one final visit 6 months after the third dose of vaccine.

Daily assessments for 6 days post vaccination will be completed at home by field workers using a standardized home visit worksheet. A day 7 and day 28 assessment will be completed at the study clinic.

A medical assessment including a physical examination will be performed during each clinic visit for assessment of safety. Blood draws for safety laboratory tests and/or iNTS GMMA vaccine induced immune responses will be performed at each clinic visit. The tests for safety assessments will require approximately 30 mls of blood (3mls per visit) and those for the assessments of immune response will require approximately 70mls of blood (10mls per visit). The screening visit will require 7mls of blood for safety screening. A separate consent will be requested for the additional 456ml blood (34-77mls per visit) to be collected for additional assessments of the body’s protective responses bringing the total volume requested to 560ml.

A stool sample will also be collected at each clinic visit A urine pregnancy test will be performed for females of childbearing potential at screening and at each vaccination visit, those with a positive test will not be vaccinated.

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

No direct benefits can be guaranteed to those involved. Participants who receive this vaccine may have an added benefit of protection against invasive NTS disease, if the vaccine proves to be protective; while those in the control arm who receive the Menveo vaccine will have added benefit of protection against meningococcal disease. Risks associated with injection such as pain will be minimised in this study by using trained staff who will follow specific procedures to minimize the discomfort and risks. Reimbursement for transport costs incurred to attend study visits will be given based on actual distance travelled using public transportation rates. Compensation for out of pocket expenses will be offered at the rate of Sh. 500 per scheduled visit. For clinic visits, refreshments will be provided. In addition, the study will cover costs for medical care for acute illnesses from the day of the first dose of the vaccine until the completion of the study follow-up.

How will the study benefit society?   

Results obtained will be useful in developing a safe and effective vaccine against non-typhoidal Salmonella with the aim of reducing Salmonella associated diseases and deaths.

When does the study start and finish?

The study will start once ethical approval is obtained and is expected to end in 36 months

Invasive non-typhoidal Salmonella disease causes a high burden of morbidity and mortality in sub-Saharan Africa, with a case fatality rate of 20%. Children under the age of 5 years, especially infants, and those with malnutrition and malaria infection are most affected. Adults with HIV infection are also at risk. The dominant serotypes causing iNTS are S.Typhimurium and S. Enteritidis. With limited access to laboratory microbiology services to isolate these pathogens and their increasing antimicrobial resistance, a vaccine would be a useful control measure.

A bivalent vaccine against both S. Typhimurium and S. Enteritidis has been developed by the GSK Vaccines Institute for Global Health, using a new technology that utilizes outer membrane vesicles derived from genetically-modified bacteria (the Generalized Modules for Membrane Antigens technology). This iNTS-GMMA vaccine has been shown to be immunogenic and non-toxic in animal studies. A first in human safety and reactogenicity study with this iNTS-GMMA vaccine is currently on-going in a UK cohort (Trial registration: ISRCTN51750695), . The early results from this study show that the majority of the adverse events observed were of mild intensity and that, to date, no Serious Adverse Events (SAEs) have been observed. The full results of this study may be available before the present study begins. 

The present study proposes to assess safety and immunogenicity of the iNTS-GMMA vaccine among healthy Kenyan adults. We propose to recruit 120 adults aged 18-55years and randomise them into 4 groups. In 3 groups we will administer the low, medium and full dose of the iNTS-GMMA vaccine and the control vaccine/placebo in the 4^th group. These will be administered in 3 doses on Day 0, at 2- months and 6- months. The participants will be followed up for safety assessments through daily home visits after each vaccination and during clinic visits on day 7 and day 28 after each vaccination, and a final clinic visit 6 months after the 3^rd vaccination. On the clinic visits, blood draws for immunogenicity assessments will also be performed. The results of the study will inform further clinical development including trials in young children, who are the target age-group for the vaccine.