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NCT03527173

A Study to Evaluate the Efficacy, Safety and Immunogenicity of a Vaccine Designed to Protect Against Infection With Shigella Sonnei in Healthy Adults

Completed Phase 2 Results posted Last updated 28 July 2020
What this trial tests

Phase 2 trial testing S.sonnei vaccine in Dysentery, Bacillary in 71 participants. Completed in 11 November 2019.

Timeline
29 August 2018
Primary endpoint
8 May 2019
11 November 2019

Quick facts

Lead sponsorGlaxoSmithKline
PhasePhase 2
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingquadruple
Primary purposeprevention
Enrollment71
Start date29 August 2018
Primary completion8 May 2019
Estimated completion11 November 2019
Sites1 location across United States

Drugs / interventions tested

Conditions studied

Sponsor

GlaxoSmithKline — full company profile →

Who can join

Adults 18 to 50, any sex, with Dysentery, Bacillary. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Subjects With at Least One Episode of Shigellosis According to the Protocol Primary Case Definition Primary · Starting with the challenge visit (Day 57) and lasting up to the end of the inpatient stay (Day 64)

Attack rate of shigellosis expressed as percentage of subjects with at least one episode of shigellosis after challenge, and 90% confidence interval (CI) (Clopper-Pearson method). Episodes of shigellosis fulfilling primary case definition: Shedding of S. sonnei 53G accompanied by moderate or severe diarrhea OR shedding with oral temperature greater than or equal to (≥) 38.5°C. Moderate diarrhea consists of 4 to 5 loose or watery (Grade \[G\]3 to 5) stools or 400 to 800 grams of G3 to 5 stools within 24 hours. Severe diarrhea consists of 6 or more loose or watery (G3 to 5) stools or \> 800 gram

GroupValue95% CI
S. Sonnei Group46.931.5 – 62.7
Placebo Group42.926.9 – 60.0
Percentage of Subjects With at Least One Episode of Shigellosis According to Controlled Human Infection Model (CHIM) Working Group Case Definition for Shigellosis Secondary · Starting with the challenge visit (Day 57) and lasting up to the end of the inpatient stay (Day 64)

Percentage of subjects with shigellosis fulfilling the CHIM expert working group case definition for shigellosis, and 90% confidence interval (CI) (Clopper-Pearson method). According to the working group, the participant must fulfil any of the three following possible endpoints to qualify as having reached the CHIM case definition for this objective: 1. Severe diarrhea defined as \[\[≥ 6 loose stools in 24 hours\] OR \[˃800 grams loose stools in 24 hours\]; 2. Moderate diarrhea defined as \[4-5 loose stools in 24 hours OR 400-800 grams loose stools in 24 hours\] AND \[oral temperature \[≥ 38.0

GroupValue95% CI
S. Sonnei Group46.931.5 – 62.7
Placebo Group32.117.9 – 49.4
Percentage of Subjects With at Least One Episode of Shigellosis Secondary · Starting with the challenge visit (Day 57) and lasting up to the end of the inpatient stay (Day 64)

Percentage of subjects with shigellosis fulfilling the following definition of shigellosis (with 90% confidence interval (CI) - Clopper-Pearson method): 1) severe diarrhea OR 2) moderate diarrhea AND oral temperature ≥ 38.0 °C OR ≥ 1 moderate constitutional/enteric symptom OR 3) dysentery \[\[≥ 2 loose stools with gross blood (hemoccult positive) in 24 hours\] AND \[≥ 1 reportable constitutional/enteric symptom\]\].

GroupValue95% CI
S. Sonnei Group46.931.5 – 62.7
Placebo Group35.720.8 – 53.0
Percentage of Subjects With at Least One Episode of More Severe Shigellosis Secondary · Starting with the challenge visit (Day 57) and lasting up to the end of the inpatient stay (Day 64)

Percentage of subjects with more severe shigellosis fulfilling the following definition of more severe shigellosis (with 90% confidence interval (CI) - Clopper-Pearson method): 1) moderate OR severe diarrhea AND oral temperature ≥ 38.0 °C OR ≥ 1 severe constitutional/enteric symptom OR 2) dysentery \[\[≥ 2 loose stools with gross blood (hemoccult positive) in 24 hours\] AND \[oral temperature ≥ 38.0°C OR ≥ 1 severe constitutional/enteric symptom\]\].

GroupValue95% CI
S. Sonnei Group15.66.4 – 30.1
Placebo Group14.35.0 – 29.8
Percentage of Subjects With Specific Disease Symptoms Secondary · Starting with the challenge visit (Day 57) and lasting up to the end of the inpatient stay (Day 64)

Percentage of subjects with 90% CI-Clopper-Pearson method was also measured for: shedding of S.sonnei strain 53G (defined as positivity of ≥1 stool sample by culture/quantitative Polymerase Chain Reaction/both); severe diarrhea; more severe diarrhea; dysentery; confirmed S.sonnei 53G shedding AND moderate or severe diarrhea OR dysentery OR presence of oral temperature ≥ 38.5°C OR presence of 1 or more severe intestinal symptoms (abdominal pain, cramping, nausea, vomiting, gas, and anorexia) abbreviated as "shedding of S.sonnei 53G and \[…"; disease not fulfilling the protocol primary case defi

Shedding of S. sonnei strain 53G
GroupValue95% CI
S. Sonnei Group96.986.0 – 99.8
Placebo Group10089.9 – 100.0
Severe diarrhea
GroupValue95% CI
S. Sonnei Group40.626.0 – 56.7
Placebo Group2512.4 – 41.9
More severe diarrhea
GroupValue95% CI
S. Sonnei Group34.420.6 – 50.4
Placebo Group17.97.3 – 33.9
Dysentery
GroupValue95% CI
S. Sonnei Group34.420.6 – 50.4
Placebo Group28.615.1 – 45.7
Shedding of S. sonnei 53G and […
GroupValue95% CI
S. Sonnei Group46.931.5 – 62.7
Placebo Group42.926.9 – 60.0
≥1 stool and no moderate/severe diarrhea evidence
GroupValue95% CI
S. Sonnei Group50.034.4 – 65.6
Placebo Group60.743.5 – 76.2
Any Abdominal pain
GroupValue95% CI
S. Sonnei Group50.034.4 – 65.6
Placebo Group46.430.1 – 63.4
Any Abdominal cramps
GroupValue95% CI
S. Sonnei Group53.137.3 – 68.5
Placebo Group50.033.3 – 66.7
Mean Number of Grade 3-5 Stools Per Subject Secondary · Starting with the challenge visit (Day 57) and lasting up to the end of the inpatient stay (Day 64)

The mean number of grade 3-5 stools (and standard deviation) were calculated per subject from challenge to discharge.

GroupValue95% CI
S. Sonnei Group28± 13.0
Placebo Group13.9± 6.6
Weight of Grade 3-5 Stools Secondary · Starting with the challenge visit (Day 57) and lasting up to the end of the inpatient stay (Day 64)

Mean and standard deviation (SD) of weights were expressed in grams. The following measures were calculated: mean and SD of the weight of grade 3-5 stools calculated on all subjects (Weight/all subjects), mean and SD of the weight of grade 3-5 stools calculated on subjects with at least one grade 3-5 stool (Weight/subj.with at least 1 grade 3-5 stool), Cumulative mean and SD weight of grade 3-5 stools per subjects, accumulated from challenge to discharge (Cumulative weight/all subjects).

Weight/all subjects
GroupValue95% CI
S. Sonnei Group87.4± 68.3
Placebo Group91.3± 54.7
Weight/subj. with at least 1 grade 3-5 stool
GroupValue95% CI
S. Sonnei Group127.2± 39.8
Placebo Group116.3± 28.5
Cumulative weight/all subjects
GroupValue95% CI
S. Sonnei Group1161.1± 1416.9
Placebo Group766.9± 884.9
Number of Subjects With Any Solicited Local Adverse Events (AEs) Secondary · During the 7-day period after each vaccination (vaccine/placebo administered at Day 1 and Day 29)

Solicited local AEs include: pain, erythema and induration at injection site. Any = occurrence of local adverse event regardless of intensity grade. Any erythema or induration at injection site is any symptom with a surface diameter greater than 25 millimeters.

Dose 1, Pain
GroupValue95% CI
S. Sonnei Group29
Placebo Group12
Dose 2, Pain
GroupValue95% CI
S. Sonnei Group24
Placebo Group5
Dose 1, Erythema
GroupValue95% CI
S. Sonnei Group0
Placebo Group0
Dose 2, Erythema
GroupValue95% CI
S. Sonnei Group0
Placebo Group0
Dose 1, Induration
GroupValue95% CI
S. Sonnei Group0
Placebo Group1
Dose 2, Induration
GroupValue95% CI
S. Sonnei Group0
Placebo Group0
Number of Subjects With Any Solicited Systemic AEs Secondary · During the 7-day period after each vaccination (vaccine/placebo administered at Day 1 and Day 29)

Solicited systemic AEs include: arthralgia, chills, fatigue, headache, malaise, myalgia, fever (oral temperature ≥ 38.0°C). Any = occurrence of systemic adverse event regardless of intensity and relation to study vaccination.

Dose 1, Arthralgia
GroupValue95% CI
S. Sonnei Group6
Placebo Group3
Dose 2, Arthralgia
GroupValue95% CI
S. Sonnei Group7
Placebo Group2
Dose 1, Chills
GroupValue95% CI
S. Sonnei Group5
Placebo Group2
Dose 2, Chills
GroupValue95% CI
S. Sonnei Group3
Placebo Group1
Dose 1, Fatigue
GroupValue95% CI
S. Sonnei Group6
Placebo Group8
Dose 2, Fatigue
GroupValue95% CI
S. Sonnei Group7
Placebo Group3
Dose 1, Headache
GroupValue95% CI
S. Sonnei Group10
Placebo Group8
Dose 2, Headache
GroupValue95% CI
S. Sonnei Group4
Placebo Group4
Number of Subjects With Any Unsolicited AEs During the 28-day Post-vaccination Period Secondary · During the 28-day period across doses (vaccine/placebo administered at Day 1 and Day 29)

An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to study vaccination.

GroupValue95% CI
S. Sonnei Group18
Placebo Group13
Number of Subjects With Any Unsolicited AEs During the 28-day Follow-up Period After Challenge Secondary · During the 28-day follow-up period after challenge (challenge administered at Day 57)

An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to study vaccination and/or challenge agent administration.

GroupValue95% CI
S. Sonnei Group20
Placebo Group17
Number of Subjects With Any Serious Adverse Events (SAEs) and Related SAEs Secondary · From Day 1 up to study end at Day 237

Serious adverse events (SAEs) assessed include medical occurrences that resulted in death, were life-threatening, required hospitalization or prolongation of hospitalization or resulted in disability/incapacity. Related SAEs = SAEs assessed by the investigator as related to the study vaccination and/or challenge agent administration.

Any SAE(s)
GroupValue95% CI
S. Sonnei Group0
Placebo Group1
Related SAE(s)
GroupValue95% CI
S. Sonnei Group0
Placebo Group0

Adverse events — posted to ClinicalTrials.gov

Time frame: Solicited AEs were collected within the 7-day post-vaccination period or 8-day post-challenge period. Unsolicited AEs were collected within the 28-day post-vaccination or post-challenge period. SAEs were collected from Day 1 up to study end at Day 237.. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

S. Sonnei Group
Serious: 0/36 (0%)
Deaths: 0/36
Placebo Group
Serious: 1/35 (3%)
Deaths: 0/35

Serious adverse events (4 terms)

ReactionSystemS. Sonnei GroupPlacebo Group
Carotid artery aneurysmNervous system disorders
Deep vein thrombosisVascular disorders
HaematomaVascular disorders
Pelvic venous thrombosisVascular disorders
Other adverse events (57 terms — click to expand)

ReactionSystemS. Sonnei GroupPlacebo Group
Injection site painGeneral disorders
MyalgiaMusculoskeletal and connective tissue disorders
DiarrhoeaGastrointestinal disorders
HeadacheNervous system disorders
MalaiseGeneral disorders
Abdominal painGastrointestinal disorders
FlatulenceGastrointestinal disorders
ArthralgiaMusculoskeletal and connective tissue disorders
Decreased appetiteMetabolism and nutrition disorders
FatigueGeneral disorders
ChillsGeneral disorders
NauseaGastrointestinal disorders
VomitingGastrointestinal disorders
PyrexiaGeneral disorders
Upper respiratory tract infectionInfections and infestations
Skin abrasionInjury, poisoning and procedural complications
Neutrophil count decreasedInvestigations
DyspepsiaGastrointestinal disorders
Back painMusculoskeletal and connective tissue disorders
InsomniaPsychiatric disorders
ProctalgiaGastrointestinal disorders
Anal injuryInjury, poisoning and procedural complications
Limb injuryInjury, poisoning and procedural complications
Skin lacerationInjury, poisoning and procedural complications
Lymph node painBlood and lymphatic system disorders
LymphadenopathyBlood and lymphatic system disorders
Ear congestionEar and labyrinth disorders
Ear painEar and labyrinth disorders
Aphthous ulcerGastrointestinal disorders
Diarrhoea haemorrhagicGastrointestinal disorders
Irritable bowel syndromeGastrointestinal disorders
ToothacheGastrointestinal disorders
IndurationGeneral disorders
CellulitisInfections and infestations
Fungal infectionInfections and infestations
InfluenzaInfections and infestations
LaryngitisInfections and infestations
SinusitisInfections and infestations
Tooth abscessInfections and infestations
Arthropod biteInjury, poisoning and procedural complications

Most-reported serious reactions: Carotid artery aneurysm, Deep vein thrombosis, Haematoma, Pelvic venous thrombosis.

Data from ClinicalTrials.gov NCT03527173 adverse events section.

Sponsor's own description

The purpose of this study is to evaluate the efficacy, safety and immunogenicity of the GSK3536852A vaccine, which was designed to protect against shigellosis caused by Shigella sonnei (S. sonnei) and is using the new Generalized Modules for Membrane Antigens (GMMA) platform technology developed by GlaxoSmithKline (GSK) Vaccines Institute for Global Health (GVGH). The study vaccine could be the stepping stone for the development of a multivalent broadly protective Shigella vaccine for vaccination of impoverished communities where shigellosis is endemic. However, a standalone monovalent vaccine against S. sonnei could be used to protect travelers against diarrheal shigellosis, as the vast majority of travelers' shigellosis is caused by S. sonnei, and even to protect infants in endemic regions where shigellosis is primarily caused by S. sonnei. The GSK3536852A vaccine has been tested in two Phase I dose escalation studies in Europe to assess its safety and immunogenicity via three routes of administration: intramuscular (IM), intranasal (IN) and intradermal (ID). The results from the first study (dose escalation with IM vaccination) have shown that the vaccine has an acceptable safety profile and is well-tolerated up to a dose of 100 micrograms (µg). The results from the second study (dose escalation with ID, IN and IM vaccination) showed that GSK3536852A vaccine is well-tolerated also when administered by the ID and IN routes of vaccination. However, immunogenicity data have shown that GSK3536852A vaccine administered by the ID and IN routes is not as immunogenic as GSK3536852A vaccine administered by the IM route. Therefore, it has been decided to proceed with the clinical development program of this vaccine only using the IM vaccination route. In terms of dosage, the regimen tested in Phase I studies (three doses given one month apart) did not show any significant benefit from the third dose in terms of immunogenicity, therefore a two dose schedule was selected for next studies. A Phase IIa study, conducted in endemic regions of Africa (i.e., Kenya), has been completed and confirmed the acceptable safety profile and immunogenicity of GSK3536852A vaccine. Performing this vaccine-human challenge study may give the opportunity to establish evidence of clinical protection induced by the candidate S. sonnei vaccine (GSK3536852A vaccine) at an early development stage.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Efficacy, safety, and immunogenicity of the <i>Shigella sonnei</i> 1790GAHB GMMA candidate vaccine: Results from a phase 2b randomized, placebo-controlled challenge study in adults.
    Frenck RW, Conti V, Ferruzzi P, Ndiaye AGW, et al · · 2021 · cited 57× · PMID 34430837 · DOI 10.1016/j.eclinm.2021.101076
  2. Induction of Broad Immunity against Invasive Salmonella Disease by a Quadrivalent Combination Salmonella MAPS Vaccine Targeting Salmonella Enterica Serovars Typhimurium, Enteritidis, Typhi, and Paratyphi A.
    Boerth EM, Gong J, Roffler B, Thompson CM, et al · · 2023 · cited 16× · PMID 38006003 · DOI 10.3390/vaccines11111671
  3. Putative correlates of protection against shigellosis assessing immunomarkers across responses to S. sonnei investigational vaccine.
    Conti V, Rossi O, Clarkson KA, Mancini F, et al · · 2024 · cited 10× · PMID 38459072 · DOI 10.1038/s41541-024-00822-2
  4. Safety and immunogenicity of the invasive non-typhoidal Salmonella (iNTS)-GMMA vaccine: a first-in-human, randomised, dose escalation trial.
    Hanumunthadu B, Demissie T, Greenland M, Skidmore P, et al · · 2025 · cited 4× · PMID 40907249 · DOI 10.1016/j.ebiom.2025.105903
  5. Protein-specific immune response elicited by the &lt;i&gt;Shigella sonnei&lt;/i&gt; 1790GAHB GMMA-based candidate vaccine in adults with varying exposure to &lt;i&gt;Shigella&lt;/i&gt;.
    Randall AZ, Conti V, Nakakana U, Liang X, et al · · 2025 · cited 3× · PMID 40237462 · DOI 10.1128/msphere.01057-24
  6. Shigella-Controlled Human Infection Models: Current and Future Perspectives.
    Clarkson KA, Porter CK, Talaat KR, Kapulu MC, et al · · 2024 · cited 3× · PMID 35616717 · DOI 10.1007/82_2021_248
  7. Development and Characterization of a 13-Plex Binding Assay to Detect <i>Shigella</i> Antibodies in Human Samples.
    Vezzani G, Mancini F, Raso MM, Giannelli C, et al · · 2024 · cited 2× · PMID 39660019 · DOI 10.1093/ofid/ofae675
  8. Evaluation of a Quadrivalent <i>Shigella flexneri</i> Serotype 2a, 3a, 6, and <i>Shigella sonnei</i> O-Specific Polysaccharide and IpaB MAPS Vaccine.
    Boerth EM, Gong J, Roffler B, Hancock Z, et al · · 2024 · cited 2× · PMID 39460258 · DOI 10.3390/vaccines12101091

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