A Study to Determine If a New Shigella Vaccine is Safe, Induces Immunity and The Best Dose Among Kenyan Infants

Safety and Immunogenicity of a Shigella-Tetravalent Bioconjugate Vaccine: A Phase 1/2 Randomized Controlled and Age Descending Study Including Dose Finding in 9 Month Old Infants

In this study, the tetravalent bioconjugate candidate vaccine Shigella4V will be tested to obtain first-in-human data on its safety and immunogenicity in infants and to identify the preferred dose of Shigella4V in 9 month old infants.

Study Overview

• Status: Completed
• Conditions: Shigellosis
• Intervention / Treatment: Biological: Shigella 4V; Biological: MenACWY; Biological: Placebo; Biological: Rabies; Biological: Diphtheria, Tetanus and Pertussis (DTaP)

Detailed Description

Shigella4V is a tetravalent bioconjugate vaccine including O antigen-polysaccharides of the most predominant Shigella serotypes.

The study will be conducted in two steps. In Step1: safety and reactogenicity of the vaccine will be evaluated first in adults and subsequently in children and infants through an age-descending and dose escalation approach. In Step 2: in order to further evaluate safety and to identify the optimum immunogenic dose, infants will be randomised to receive 1 of 4 different vaccine doses or control vaccine.

Adults will receive a 2 dose schedule, children and infants will receive a 3 dose schedule. For each vaccine dose, formulation with and without Aluminium adjuvant will be tested.

• Study Type: Interventional
• Enrollment (Actual): 596
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Kenya
  • Kericho, Kenya, 1357-20200
    • Kenya Medical Research Institute (KEMRI)/ United States Army Medical Research Directorate- Kenya (USAMRD-K)
  • Kilifi, Kenya, 230-80108
    • KEMRI-Centre Geographic Medical Research-COAST (KEMRI-CGMRC)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 months to 50 years (Child, Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

All ages

• Healthy by medical history, laboratory findings and physical examination before entering into the study (Participants with a minor illness (such as mild diarrhoea, mild upper respiratory infection) without fever may be enrolled at the discretion of the investigator)
• Seronegative for HIV, hepatitis B and C (as per screening laboratory tests)
• Resident in the study area village during the whole trial period (Kilifi -Kilifi Health and Demographic Surveillance System (Described in more detail in the SSA); (Kericho-a 75km radius from the Kericho Clinical Research Centre).
• Previously completed routine primary vaccinations (6,10 and 14 weeks or thereabouts) to the best knowledge of the participant/parent/guardian.
• Signed/thumb written informed consent, in accordance with local practice, provided by adult volunteers (participants 18 years of age and older), parents or legal representatives for children and infants participants as applicable, who, in the opinion of the investigator, can and will comply with the requirements of the protocol
• Demonstrated comprehension of the protocol procedures by passing score of 90% or better on a written/verbal comprehension test.

Adults

• Female and male participants between, and including 18-50 years at the time of first vaccination

• Female participants of non-childbearing potential may be enrolled in the study. Non-childbearing potential is defined as pre-menarche, current bilateral tubal ligation or occlusion, hysterectomy, bilateral ovariectomy or post-menopause. Female volunteers of childbearing potential may be enrolled in the study if the participant: has a negative urine pregnancy test at the day of screening and vaccinations, respectively, and

  • agree to use effective contraception for 30 days prior to vaccination and
  • agree to continue contraception at least for 2 months after completion of vaccination series.

Children and Infants

• Female and male aged 9 months (+/- 1 month) old (infants) or between, and including, 2-5 years of age (children) at the time of the first vaccination
• Born full-term (i.e. after a gestation period of 37 to less than 42 completed weeks)

Exclusion Criteria:

All ages

• Any clinically significant deviation from the normal range in biochemistry or haematological blood tests.
• Suspected or known hypersensitivity (including allergy) to any of the vaccine components or to previous vaccine, or to medicinal products or medical equipment whose use is foreseen in this study
• Clinical conditions representing a contraindication to intramuscular vaccination and blood draws
• Any confirmed or suspected immunosuppressive or immune-deficient condition.
• Systemic administration of corticosteroids (PO/IV/IM): prednisone ≥20 mg/day, or equivalent for more than 14 consecutive days from birth (for infants) / within 90 days prior to informed consent. Inhaled except for doses > 800 mg/day and topical steroids are allowed.
• Administration of antineoplastic or radiotherapy from birth / within 90 days prior to informed consent. Participants may be on chronic or as needed medications if, in the opinion of the site principal investigator or appropriate sub-investigator, they pose no additional risk to participant safety or assessment of reactogenicity and immunogenicity and do not indicate a worsening of medical diagnosis or condition
• Known exposure to Shigella during lifetime of the subject
• Concurrently participating in another clinical study, or participation in the preceding month, at any time during the study period, in which the participant has been or will be exposed to an investigational or a non-investigational vaccine/product (pharmaceutical product or device)
• Acute disease and /or fever at the time of enrolment Note: enrolment may be postponed/delayed until such transient circumstances have terminated
• History of any malignancy of lymphoproliferative disorder
• Known to be part of study personnel or being a close family member to the personnel conducting this study.
• Previous history of significant persistent neutropenia, or drug related Neutropenia
• Adults with clinical wasting; children with weight-for-age Z score less than -3SD.
• History of any chronic or progressive disease (e.g., neoplasm, insulin dependent diabetes, cardiac, renal or hepatic disease) that according to judgment of the investigator could interfere with the study outcomes or pose a threat to the participant's health
• History of surgical splenectomy or Sickle cell disease (SCD test performed at KEMRI-CGMRC only).
• Administration of immunoglobulin and/or any blood products within the three months preceding the first dose of study vaccine
• Any medical, social condition, or occupational reason that, in the judgment of the investigator, is a contraindication to protocol participation or impairs the volunteer's/parent's/guardian's ability to give informed consent, increases the risk to the potential participant because of participation in the study, affect the ability of the volunteer to participate in the study or impair interpretation of the study data .

Adults

• Women who are breastfeeding
• History of chronic alcohol consumption and/or drug abuse. Chronic alcohol consumption is defined as: a prolonged period of frequent, heavy alcohol use; the inability to control drinking once it has begun; physical dependence manifested by withdrawal symptoms when the individual stops using alcohol; tolerance, or the need to use more and more alcohol to achieve the same effects; a variety of social and/or legal problems arising from alcohol use.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

19

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NA (Non-adjuvanted) - very low dose - infants; Infants receive 3 very low doses of the non-adjuvanted investigational product	Biological: Shigella 4V; Non-adjuvanted and adjuvanted Shigella 4V administrated at 4 different doses: very low, low, medium and high.
Experimental: A (adjuvanted) - very low dose - infants; Infants receive 3 very low doses of the adjuvanted investigational product	Biological: Shigella 4V; Non-adjuvanted and adjuvanted Shigella 4V administrated at 4 different doses: very low, low, medium and high.
Experimental: NA (Non-adjuvanted) - low dose -infants; Infants receive 3 low doses of the non-adjuvanted investigational product	Biological: Shigella 4V; Non-adjuvanted and adjuvanted Shigella 4V administrated at 4 different doses: very low, low, medium and high.
Experimental: A (adjuvanted) - low dose - infants; Infants receive 3 low doses of the adjuvanted investigational product	Biological: Shigella 4V; Non-adjuvanted and adjuvanted Shigella 4V administrated at 4 different doses: very low, low, medium and high.
Experimental: NA (non-adjuvanted) - medium dose - infants; Infants receive 3 medium doses of the non-adjuvanted investigational product	Biological: Shigella 4V; Non-adjuvanted and adjuvanted Shigella 4V administrated at 4 different doses: very low, low, medium and high.
Experimental: A (adjuvanted) - medium dose - infants; Infants receive 3 medium doses of the adjuvanted investigational product	Biological: Shigella 4V; Non-adjuvanted and adjuvanted Shigella 4V administrated at 4 different doses: very low, low, medium and high.
Experimental: NA (non-adjuvanted) - medium dose - children; Children receive 3 medium doses of the non-adjuvanted investigational product	Biological: Shigella 4V; Non-adjuvanted and adjuvanted Shigella 4V administrated at 4 different doses: very low, low, medium and high.
Experimental: A (adjuvanted) - medium dose - children; Children receive 3 medium doses of the adjuvanted investigational product	Biological: Shigella 4V; Non-adjuvanted and adjuvanted Shigella 4V administrated at 4 different doses: very low, low, medium and high.
Experimental: NA (non-adjuvanted) - medium dose-adults; Adults receive 2 medium doses of the non-adjuvanted investigational product	Biological: Shigella 4V; Non-adjuvanted and adjuvanted Shigella 4V administrated at 4 different doses: very low, low, medium and high.
Experimental: A (adjuvanted) - medium dose - adults; Adults receive 2 medium doses of the adjuvanted investigational product	Biological: Shigella 4V; Non-adjuvanted and adjuvanted Shigella 4V administrated at 4 different doses: very low, low, medium and high.
Experimental: NA (non-adjuvanted) - high dose - infants; Infants receive 3 high doses of the non-adjuvanted investigational product	Biological: Shigella 4V; Non-adjuvanted and adjuvanted Shigella 4V administrated at 4 different doses: very low, low, medium and high.
Experimental: A (adjuvanted) - high dose - infants; Infants receive 3 high doses of the adjuvanted investigational product	Biological: Shigella 4V; Non-adjuvanted and adjuvanted Shigella 4V administrated at 4 different doses: very low, low, medium and high.
Experimental: NA (non-adjuvanted) - high dose - children; Chilldren receive 3 high doses of the non-adjuvanted investigational product	Biological: Shigella 4V; Non-adjuvanted and adjuvanted Shigella 4V administrated at 4 different doses: very low, low, medium and high.
Experimental: A (adjuvanted) - high dose - children; Chilldren receive 3 high doses of the adjuvanted investigational product	Biological: Shigella 4V; Non-adjuvanted and adjuvanted Shigella 4V administrated at 4 different doses: very low, low, medium and high.
Experimental: NA (non-adjuvanted) - high dose - adults; Adults receive 2 high doses of the non-adjuvanted investigational product	Biological: Shigella 4V; Non-adjuvanted and adjuvanted Shigella 4V administrated at 4 different doses: very low, low, medium and high.
Experimental: A (adjuvanted) - high dose - adults; Adults receive 2 high doses of the adjuvanted investigational product	Biological: Shigella 4V; Non-adjuvanted and adjuvanted Shigella 4V administrated at 4 different doses: very low, low, medium and high.
Experimental: MenACWY-Placebo; Adults receive one administration of MenACWY followed by one placebo administration	Biological: MenACWY; Control vaccine administrated to adults and infants; Biological: Placebo; Control administrated to adults
Other: Rabies; Children receive three administrations of Rabies	Biological: Rabies; Control vaccine administrated to children
Other: MenACWY-DTaP; Infants receive two administrations of MenACWY followed by DTaP administration	Biological: MenACWY; Control vaccine administrated to adults and infants; Biological: Diphtheria, Tetanus and Pertussis (DTaP); Control vaccine administrated to infants

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety - Solicited Local and Systemic Adverse Events (AEs)	Safety and tolerability of the candidate vaccine Shigella4V as determined by occurrence, severity and relationship of solicited AEs	during 7 days following each vaccination
Safety - Unsolicited Adverse Events (AEs)	Safety and tolerability of the candidate vaccine Shigella4V as determined by occurrence, severity and relationship of unsolicited AEs	during 28 days following each vaccination
Safety - Serious Adverse Events (SAEs)	Safety and tolerability of the candidate vaccine Shigella4V as determined by occurrence, severity and relationship of SAEs	throughout the study duration, up to 15 months
Immunology - change in serum immunoglobulin G (IgG)	Serum IgG responses and fold-increases between post- and pre-vaccination samples from infants of step 2, as determined by enzyme-linked immunosorbent assay (ELISA) against lipopolysaccharide (LPS) corresponding to the 4 Shigella serotypes included in the Shigella4V bioconjugate.	throughout the study, up to 15 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety - clinically significant changes in cell blood count (CBC) with differentials	Assess the safety of the candidate vaccine Shigella4V by measuring clinical significant changes in haematological safety parameters	throughout the study, up to 15 months
Safety - clinically significant changes in creatinine level	Assess the safety of the candidate vaccine Shigella4V by measuring clinical significant changes in biochemical safety parameters	throughout the study, up to 15 months
Safety - clinically significant changes in alanine aminotransferase (ALT) level	Assess the safety of the candidate vaccine Shigella4V by measuring clinical significant changes in biochemical safety parameters	throughout the study, up to 15 months
Safety - clinically significant changes in aspartate aminotransferase (AST) level	Assess the safety of the candidate vaccine Shigella4V by measuring clinical significant changes in biochemical safety parameters	throughout the study, up to 15 months
Immunogenicity - change is serum IgG	Serum IgG responses and fold-increases between post- and pre-vaccination samples from all participants of step 1, as determined by ELISA against LPS corresponding to the 4 Shigella serotypes included in the Shigella4V bioconjugate.	throughout the study, up to 15 months
Immunogenicity - change in anti-Shigella LPS antibody titre	Percentage of participants (from step 1 and 2) achieving at least a four-fold rise in anti-Shigella LPS antibody titre after each injection compared to baseline.	throughout the study, up to 15 months

Collaborators and Investigators

• Sponsor: LimmaTech Biologics AG
• Collaborators: KEMRI-Wellcome Trust Collaborative Research Program; Kenya Medical Research Institute
• Investigators: Principal Investigator: Mainga Hamaluba, MD, KEMRI/Welcome Trust Research Programme,Kilifi, Kenya; Principal Investigator: Josphat Kosgei, MD, Medical Research Institute, Kericho, Kenya

Publications and helpful links

General Publications

• GBD 2015 LRI Collaborators. Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory tract infections in 195 countries: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Infect Dis. 2017 Nov;17(11):1133-1161. doi: 10.1016/S1473-3099(17)30396-1. Epub 2017 Aug 23.
• Livio S, Strockbine NA, Panchalingam S, Tennant SM, Barry EM, Marohn ME, Antonio M, Hossain A, Mandomando I, Ochieng JB, Oundo JO, Qureshi S, Ramamurthy T, Tamboura B, Adegbola RA, Hossain MJ, Saha D, Sen S, Faruque AS, Alonso PL, Breiman RF, Zaidi AK, Sur D, Sow SO, Berkeley LY, O'Reilly CE, Mintz ED, Biswas K, Cohen D, Farag TH, Nasrin D, Wu Y, Blackwelder WC, Kotloff KL, Nataro JP, Levine MM. Shigella isolates from the global enteric multicenter study inform vaccine development. Clin Infect Dis. 2014 Oct;59(7):933-41. doi: 10.1093/cid/ciu468. Epub 2014 Jun 23.
• Mani S, Wierzba T, Walker RI. Status of vaccine research and development for Shigella. Vaccine. 2016 Jun 3;34(26):2887-2894. doi: 10.1016/j.vaccine.2016.02.075. Epub 2016 Mar 12.
• Ashkenazi S, Cohen D. An update on vaccines against Shigella. Ther Adv Vaccines. 2013 Sep;1(3):113-23. doi: 10.1177/2051013613500428.
• Kotloff KL, Nataro JP, Blackwelder WC, Nasrin D, Farag TH, Panchalingam S, Wu Y, Sow SO, Sur D, Breiman RF, Faruque AS, Zaidi AK, Saha D, Alonso PL, Tamboura B, Sanogo D, Onwuchekwa U, Manna B, Ramamurthy T, Kanungo S, Ochieng JB, Omore R, Oundo JO, Hossain A, Das SK, Ahmed S, Qureshi S, Quadri F, Adegbola RA, Antonio M, Hossain MJ, Akinsola A, Mandomando I, Nhampossa T, Acacio S, Biswas K, O'Reilly CE, Mintz ED, Berkeley LY, Muhsen K, Sommerfelt H, Robins-Browne RM, Levine MM. Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study. Lancet. 2013 Jul 20;382(9888):209-22. doi: 10.1016/S0140-6736(13)60844-2. Epub 2013 May 14.
• Anderson M, Sansonetti PJ, Marteyn BS. Shigella Diversity and Changing Landscape: Insights for the Twenty-First Century. Front Cell Infect Microbiol. 2016 Apr 19;6:45. doi: 10.3389/fcimb.2016.00045. eCollection 2016.
• Kotloff KL, Platts-Mills JA, Nasrin D, Roose A, Blackwelder WC, Levine MM. Global burden of diarrheal diseases among children in developing countries: Incidence, etiology, and insights from new molecular diagnostic techniques. Vaccine. 2017 Dec 14;35(49 Pt A):6783-6789. doi: 10.1016/j.vaccine.2017.07.036. Epub 2017 Jul 29.
• Juergens C, de Villiers PJ, Moodley K, Jayawardene D, Jansen KU, Scott DA, Emini EA, Gruber WC, Schmoele-Thoma B. Safety and immunogenicity of 13-valent pneumococcal conjugate vaccine formulations with and without aluminum phosphate and comparison of the formulation of choice with 23-valent pneumococcal polysaccharide vaccine in elderly adults: a randomized open-label trial. Hum Vaccin Immunother. 2014;10(5):1343-53. doi: 10.4161/hv.27998. Epub 2014 Feb 27.
• Bryant K, McVernon J, Marchant C, Nolan T, Marshall G, Richmond P, Marshall H, Nissen M, Lambert S, Aris E, Mesaros N, Miller J. Immunogenicity and safety of measles-mumps-rubella and varicella vaccines coadministered with a fourth dose of Haemophilus influenzae type b and Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine in toddlers: a pooled analysis of randomized trials. Hum Vaccin Immunother. 2012 Aug;8(8):1036-41. doi: 10.4161/hv.20357. Epub 2012 Aug 1.
• Miller E, Andrews N, Waight P, Findlow H, Ashton L, England A, Stanford E, Matheson M, Southern J, Sheasby E, Goldblatt D, Borrow R. Safety and immunogenicity of coadministering a combined meningococcal serogroup C and Haemophilus influenzae type b conjugate vaccine with 7-valent pneumococcal conjugate vaccine and measles, mumps, and rubella vaccine at 12 months of age. Clin Vaccine Immunol. 2011 Mar;18(3):367-72. doi: 10.1128/CVI.00516-10. Epub 2010 Dec 29.
• Taylor DN, Trofa AC, Sadoff J, Chu C, Bryla D, Shiloach J, Cohen D, Ashkenazi S, Lerman Y, Egan W, et al. Synthesis, characterization, and clinical evaluation of conjugate vaccines composed of the O-specific polysaccharides of Shigella dysenteriae type 1, Shigella flexneri type 2a, and Shigella sonnei (Plesiomonas shigelloides) bound to bacterial toxoids. Infect Immun. 1993 Sep;61(9):3678-87. doi: 10.1128/iai.61.9.3678-3687.1993.
• Ashkenazi S, Passwell JH, Harlev E, Miron D, Dagan R, Farzan N, Ramon R, Majadly F, Bryla DA, Karpas AB, Robbins JB, Schneerson R. Safety and immunogenicity of Shigella sonnei and Shigella flexneri 2a O-specific polysaccharide conjugates in children. J Infect Dis. 1999 Jun;179(6):1565-8. doi: 10.1086/314759.

Study record dates

Study Major Dates

• Study Start (Actual): September 2, 2019
• Primary Completion (Actual): September 1, 2022
• Study Completion (Actual): November 14, 2022

Study Registration Dates

• First Submitted: July 26, 2019
• First Submitted That Met QC Criteria: August 13, 2019
• First Posted (Actual): August 14, 2019

Study Record Updates

• Last Update Posted (Actual): July 30, 2024
• Last Update Submitted That Met QC Criteria: July 29, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Infections; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Enterobacteriaceae Infections; Dysentery; Dysentery, Bacillary
• Other Study ID Numbers: S4V01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No