Safety, Immunogenicity and Efficacy of GSK S. Aureus Candidate Vaccine (GSK3878858A) When Administered to Healthy Adults (Dose-escalation) and to Adults 18 to 64 Years of Age With a Recent S. Aureus Skin and Soft Tissue Infection (SSTI)

Phase 2CompletedNCT04420221

GlaxoSmithKline226 enrolled

Overview

The study evaluates the safety, immunogenicity, and efficacy of the GSK S. aureus candidate vaccine (GSK3878858A) when administered to two groups: healthy adults (dose-escalation phase) and adults aged 18 to 64 years with a recent S. aureus skin and soft tissue infection (SSTI). In the dose-escalation safety lead-in phase, the safety and immunogenicity of four different vaccine compositions are assessed in healthy adults. Once safety has been established in this phase, the second phase, known as the proof of principle (PoP) phase, will assess the safety, immunogenicity, and efficacy of the final vaccine composition in adults with a recent SSTI.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

QUADRUPLE

Enrollment

226

Conditions

Infections, Soft Tissue

Interventions

PlaceboBIOLOGICAL

One dose of placebo (saline solution for injection/ vial or prefilled syringe) at Day 1 for placebo Groups 1 to 3 (Dose-escalation epoch) and a series of 2 doses of placebo given approximately 2 months apart (Days 1 and 61) for placebo Group 4 (Dose-escalation epoch) and Group PoP: Placebo, administered intramuscularly.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 64 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: All participants must satisfy all the following criteria at study entry: * Participants who, in the opinion of the investigator, can and will comply with the requirements of the protocol (e.g. completion of the diary cards, return for follow-up visits). * Written or witnessed informed consent obtained from the participant prior to performance of any study specific procedure. * Participant satisfying screening requirements. * Participants who, after the nature of the study has been explained to them, have shown adequate comprehension of the study procedures and knowledge of study. * A male or female * Dose escalation and safety lead-in phase: Aged between 18 and 50 years of age, inclusive, at the time of first vaccination. * PoP phase: Aged between 18 and 64 years of age, inclusive, 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 participants of childbearing potential may be enrolled in the study, if the participant: * has practiced adequate contraception for 30 days prior to vaccination, * has a negative pregnancy test on the day of enrolment, and * has agreed to continue adequate contraception during the entire treatment period and for 2 months after completion of the vaccination series. Additional inclusion criteria only for participants to be enrolled in the dose-escalation safety lead-in screening epoch: \- Healthy participants as established by medical history, clinical examination and laboratory assessment. Additional inclusion criteria only for participants to be enrolled in the PoP screening epoch: \- Healthy participants as established by medical history and clinical examination before entering into the study with an ongoing SSTI suspected to be caused by S. aureus, as diagnosed by investigator (before randomization participants have to be treated until clinical resolution of culture confirmed SSTI caused by S. aureus). SSTI must be amenable to microbiological culturing per standard clinical practice (i.e. recovery of drainage sample from abscess or suppurative cellulitis). OR \- Healthy participants as established by medical history and clinical examination before entering into the study with an ongoing S. aureus SSTI (i.e. S. aureus is the most likely cause), as confirmed by a S. aureus positive culture performed outside the study procedures and not earlier than 30 days prior to Informed Consent Form signature. Before randomisation participants have to be treated until clinical resolution of the culture confirmed SSTI caused by S. aureus. These participants will be enrolled whether they have or have not already started specific treatment of the infection. In case they have not started the treatment, this will be then given in compliance with the standard medical practice for the management of S. aureus SSTIs and the choice and judgment of the most appropriate treatment will be applied by the investigator, outside the study procedures. Exclusion Criteria: All participants at study entry * Body mass index (BMI) \>40 kg/m2 * History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccine * Hypersensitivity to latex * Recurrent history of uncontrolled neurological disorders or seizures * History of potential immune-mediated disease (pIMD) * Clinical conditions that in the investigator's opinion represent a contraindication to intramuscular vaccination and blood draws * Known bleeding diathesis or any condition that may be associated with a prolonged bleeding time * Use of any investigational or non-registered product (drug, vaccine or medical device) other than the study vaccine(s) within 30 days before the first dose of study vaccine(s)/placebo (Day -29 to Day 1), or during the study period * Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immune-modifying drugs during the period starting 3 months prior to the first vaccine/placebo dose * Cytotoxic therapy (e.g., medications used during cancer chemotherapy) * Administration of long-acting immune-modifying drugs at any time during the study period (e.g. infliximab) * Administration of immunoglobulins and/or any blood products or plasma derivatives within 3 months before the first dose of study vaccine or during the study period * Planned administration/administration of a vaccine not foreseen by the study protocol in the period starting 15 days before the first dose and ending 15 days after the last dose of vaccine(s) administration with the exception of any non-adjuvanted influenza vaccine which may be administered ≥7 days before or after each study vaccination \*In case an emergency mass vaccination for an unforeseen public health threat (e.g.: a pandemic) is organised by the public health authorities, outside the routine immunisation program, the time period described above can be reduced if necessary for that vaccine provided it is licensed and used according to its Product Information. * Concurrently participating in another clinical study, in which the participant has been or will be exposed to an investigational or a non-investigational vaccine/product (drug or medical device) * Received a vaccine against S. aureus * Pregnant or lactating female * Female planning to become pregnant or planning to discontinue contraceptive precautions before 2 months after completion of the vaccination series * History of chronic alcohol consumption and/or drug abuse * Any study personnel or immediate dependents, family, or household member All participants at the time of vaccination * Any clinically significant hematological (hemoglobin level, white blood cell, lymphocyte, neutrophil, eosinophil, platelet count and red blood cell count) and/or biochemical (alanine aminotransferase \[ALT\], aspartate aminotransferase \[AST\], creatinine) laboratory abnormality Additional exclusion criteria applied only for dose-escalation safety lead-in * Any active or ongoing illness at screening or time of injection * History of any serious chronic or progressive disease according to the judgment of the investigator Additional exclusion criteria applied only for PoP at study entry * Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination * Major congenital defects, as assessed by the investigator * Acute or chronic, clinically significant pulmonary, cardiovascular\*, hepatic or renal functional abnormality, neoplasm, diabetes type 1 and uncontrolled diabetes type 2\*, as determined by physical examination or laboratory screening tests \* Note: Well-controlled type 2 diabetes mellitus (HbA1c \<7%) and well-controlled arterial hypertension (blood pressure \<140/90 mmHg) can be considered for inclusion in the study. * Any behavioral or cognitive impairment or psychiatric disease that, in the opinion of the investigator, may interfere with the participant's ability to participate in the study * Individuals at risk for severe or life-threatening SSTIs (e.g., lymphatic or venous insufficiency, liver and kidney disease, IV drug use, etc.) * Any other clinical condition that, in the opinion of the investigator, might pose additional risk to the participant due to participation in the study Additional exclusion criteria applied only for PoP at vaccination \- Microbiological test results of drainage suggest that the SSTI etiology could be other than infection with S. aureus

Outcomes

Primary Outcomes

Dose-escalation Safety lead-in: Number of Participants With Any and Grade 3 Solicited Administration Site Adverse Events (AEs) After Each Vaccination

The solicited administration site AE(s) assessed are pain, redness and swelling. Any = any solicited administration site AE, regardless of intensity; Grade 3 Pain at injection site = Severe, significant pain at rest, that prevents normal everyday activities; Grade 3 redness/swelling = greater than (\>)100 millimeter (mm) diameter.

Time frame: Within 7 days post vaccination (day of administration and 6 subsequent days post-each vaccination; Vaccination 1 on Day 1 and Vaccination 2 on Day 61)

PoP: Number of Participants With Any and Grade 3 Solicited Administration Site AEs After Each Vaccination

The solicited administration site AEs assessed are pain, redness and swelling. Any = any solicited administration site AE, regardless of intensity; Grade 3 Pain at injection site = Severe, significant pain at rest, that prevents normal everyday activities; Grade 3 redness/swelling = greater than (\>)100 millimeter (mm) diameter.

Time frame: Within 7 days post vaccination (day of administration and 6 subsequent days post-each vaccination; Vaccination 1 on Day 1 and Vaccination 2 on Day 61)

Dose-escalation Safety lead-in: Number of Participants With Any and Grade 3 Solicited Systemic AEs After Each Vaccination

The solicited systemic AE(s) assessed are headache, fatigue, nausea, vomiting, diarrhea, abdominal pain, myalgia, shivering and fever. Any = any solicited systemic AE regardless of intensity; Grade 3 headache/fatigue/nausea/abdominal pain/myalgia/shivering = Severe: Prevents daily activity. Grade 3 vomiting = Severe: 6 or more times in 24 hours or requires intravenous hydration. Grade 3 diarrhea = Severe: 6 or more loose stools in 24 hours or requires intravenous hydration. Grade 3 fever = body temperature greater than (\>) 40.0°C/104°F.

Time frame: Within 7 days post vaccination (day of administration and 6 subsequent days post-each vaccination; Vaccination 1 on Day 1 and Vaccination 2 on Day 61)

PoP: Number of Participants With Any and Grade 3 Solicited Systemic AEs After Each Vaccination

The solicited systemic AE(s) assessed are headache, fatigue, nausea, vomiting, diarrhea, abdominal pain, myalgia, shivering and fever were assessed. Any = any solicited systemic AE regardless of intensity; Grade 3 headache/fatigue/nausea/abdominal pain/myalgia/shivering = Severe: Prevents daily activity. Grade 3 vomiting = Severe: 6 or more times in 24 hours or requires intravenous hydration. Grade 3 diarrhea = Severe: 6 or more loose stools in 24 hours or requires intravenous hydration. Grade 3 fever = body temperature greater than (\>) 40.0°C/104°F.

Time frame: Within 7 days post vaccination (day of administration and 6 subsequent days post-each vaccination; Vaccination 1 on Day 1 and Vaccination 2 on Day 61)

Dose-escalation Safety lead-in: Number of Participants With Unsolicited AEs (Any, Grade 3, Related, Related Grade 3) After Each Vaccination

An unsolicited adverse event is defined as an adverse event that was not solicited using a Subject Diary and that was spontaneously communicated by a subject who has signed the informed consent. Any unsolicited AE, Grade 3 unsolicited AE, unsolicited AE causally related to the vaccination and Grade 3 unsolicited AE causally related to the vaccination were assessed. A grade 3 AE is an AE that prevents normal, everyday activities.

Time frame: During 30 days after each vaccination (day of administration and 29 subsequent days post-each vaccination; Vaccination 1 on Day 1 and Vaccination 2 on Day 61)

PoP: Number of Participants With Unsolicited AEs (Any, Grade 3, Related, Related Grade 3) After Each Vaccination

Time frame: During 30 days after each vaccination (day of administration and 29 subsequent days post-each vaccination; Vaccination 1 on Day 1 and Vaccination 2 on Day 61)

Dose-escalation Safety lead-in: Number of Participants With Serious AEs (SAEs) up to 1 Year Post First Vaccination

A SAE is defined as any untoward medical occurrence that, at any dose: resulted in death, was life threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment. A grade 3 SAE is a SAE that prevents normal, everyday activities.

Time frame: From Day 1 to Day 366

Dose-escalation Safety lead-in: Number of Participants With SAEs up to 1 Year Post Second Vaccination

Time frame: From Day 61 to Day 426 (post vaccination at Day 61)

PoP: Number of Participants With SAEs

Time frame: From Day 1 to Day 426

Dose-escalation Safety lead-in: Number of Participants With Potential Immune-mediated Diseases (pIMDs) up to 1 Year Post First Vaccination

pIMDs are defined as a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune aetiology.

Time frame: From Day 1 to Day 366

Dose-escalation Safety lead-in: Number of Participants With pIMDs up to 1 Year Post Second Vaccination

pIMDs are defined as a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune aetiology.

Time frame: From Day 61 to Day 426 (post vaccination at Day 61)

PoP: Number of Participants With Potential Immune-mediated Diseases (pIMDs)

pIMDs are defined as a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune aetiology.

Time frame: From Day 1 to Day 426

Number of Participants With Maximum Toxicity Grade Increase From Baseline for Haematological and Biochemical Laboratory Parameters

The Biochemical parameters assessed were: Creatinine, Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) and the Haematological parameters assessed were: Haemoglobin, white blood cells (WBC) decrease, WBC increase, Neutrophils decrease, Platelets decrease, Lymphocytes decrease, Eosinophils increase. Hematological and biochemical laboratory results are defined as follows: \<parameter\>,\<grade at baseline\>,\<grade at visit\> (e.g. ALT, Grade 0, Grade 0), where Grade 0 = a non-missing parameter value for which grade could not be derived according to the grading scale and does not belong to Grade 1-4; Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life-Threatening. Grading following the FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (September 2007). Unknown = parameter value missing for the specified parameter.

Time frame: On Day 8 compared to Baseline (Day 1)

Number of Participants With Maximum Toxicity Grade Increase From Baseline for Haematological and Biochemical Laboratory Parameters

The Biochemical parameters assessed were: Creatinine, AST, ALT and the Haematological parameters assessed were: Haemoglobin, WBC decrease, WBC increase, Neutrophils decrease, Platelets decrease, Lymphocytes decrease, Eosinophils increase. Hematological and biochemical laboratory results are defined as follows: \<parameter\>,\<grade at baseline\>,\<grade at visit\> (e.g. ALT, Grade 0, Grade 0), where Grade 0 = a non-missing parameter value for which grade could not be derived according to the grading scale and does not belong to Grade 1-4; Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life-Threatening. Grading following the FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (September 2007). Unknown = parameter value missing for the specified parameter.

Time frame: On Day 68 compared to Baseline (Day 61)

Number of Participants With Haematological and Biochemical Laboratory Change From Baseline Values

The Biochemical parameters assessed were: Creatinine, AST, ALT and the Haematological parameters assessed were: Haemoglobin, WBC decrease, WBC increase, Neutrophils decrease, Platelets decrease, Lymphocytes decrease, Eosinophils increase. Hematological and biochemical laboratory results are defined as follows: \<parameter\>,\<any grade at baseline\>,\<grade at visit\> (e.g. ALT, Any, Grade 0), where Grade 0 = a non-missing parameter value for which grade could not be derived according to the grading scale and does not belong to Grade 1-4; Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life-Threatening. Grading following the FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (September 2007). Unknown = parameter value missing for the specified parameter.

Time frame: On Day 8

Number of Participants With Haematological and Biochemical Laboratory Change From Baseline Values

The Biochemical parameters assessed were: Creatinine, AST, ALT and the Haematological parameters assessed were: Haemoglobin, WBC decrease, WBC increase, Neutrophils decrease, Platelets decrease, Lymphocytes decrease, Eosinophils increase. Hematological and biochemical laboratory results are defined as follows: \<parameter\>,\<any grade at baseline\>,\<grade at visit\> (e.g. ALT, Any, Grade 0), where Grade 0 = a non-missing parameter value for which grade could not be derived according to the grading scale and does not belong to Grade 1-4; Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Potentially Life-Threatening. Grading following the FDA Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (September 2007). Unknown = parameter value missing for the specified parameter.

Time frame: On Day 68

Secondary Outcomes

Number of Participants With at Least One Culture Confirmed Case of Recurrent Staphylococcus Aureus (S. Aureus) Skin and Soft Tissue Infection (SSTI) - Interim Analysis

An interim analysis was performed after 13 cases of recurrent SA-SSTI were reported following 14 days from the study intervention dose 2.

Time frame: From Day 75 to Day 426

Number of Participants With at Least One Culture Confirmed Case of Recurrent S. Aureus SSTI - Final Analysis

After encountering futility at the interim analysis, an EOS analysis was conducted when at least one culture-confirmed case of recurrent SA-SSTI was identified 14 days after the second dose of the vaccine. For the final analysis, all the data collected by End of Study (EoS; Last Participant Last Visit) were analyzed for descriptive purposes.

Time frame: From Day 75 to Day 426

Number of Participants With at Least One Culture Confirmed Case of Recurrent S. Aureus SSTI - Final Analysis

An EOS analysis was conducted when at least one culture-confirmed case of recurrent SA-SSTI was identified 14 days after the first dose of the vaccine. For the final analysis, all the data collected by End of Study (EoS; Last Participant Last Visit) were analyzed for descriptive purposes.

Time frame: From Day 15 to Day 426