Safety and Immunogenicity Study of Trivalent P2-VP8 Subun... | NCT02646891

NCT02646891

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Derived Section

Miscellaneous Info Module

Status Module

Name	Class
The Emmes Company, LLC	INDUSTRY

Description Module

Detailed Description

The P2-VP8 vaccine tested in this study was developed by Dr. Taka Hoshino at National Institute of Allergy and Infectious Diseases (NIAID). The monovalent (P[8]) vaccine previously tested consisted of bacteria-expressed VP8 subunit from the Wa strain of human rotaviruses (G1[P8]). A deoxyribonucleic acid (DNA) segment encoding the sequence of P2 epitope from tetanus toxin was fused to the VP8 sequence, resulting in this chimeric protein vaccine (P2-VP8). Dr. Hoshino's laboratory demonstrated in preclinical testing that the immunogenicity of these VP8 proteins could be significantly enhanced when fused with the P2 epitope of tetanus toxin, which exerts a strong T cell helper function. Further, immunization of neonatal piglets with a P2-VP8-P[8] chimeric protein conferred significant protection against experimental rotavirus gastroenteritis. Based on results of the initial first-in-human testing of the monovalent (P[8]) vaccine, a trivalent vaccine that includes antigens from P[4], P[6] and P[8] strains (DS-1, 1076 and Wa, respectively) has been developed to broaden responses for these 3 P-types, which together are responsible for the vast majority of global disease burden. The trivalent vaccine was assessed in this study.

The first clinical testing of the monovalent (P[8]) P2-VP8 subunit rotavirus vaccine was performed in 18-45 year old adults in North America. Overall, the vaccine was well-tolerated at all three dose levels, was associated with only mild transient local reactogenicity, and no safety concerns were identified. Almost all vaccine recipients demonstrated greater than 4-fold rise in IgG and IgA response to P2-VP8 antigen by enzyme-linked immunosorbent assay (ELISA) after three vaccinations: only one vaccine recipient did not demonstrate an immunoglobulin G (IgG) response (in the 30 µg group) and all vaccine recipients demonstrated immunoglobulin A (IgA) responses. Neutralizing antibody responses were also encouraging, with clear increases in geometric mean titers (GMTs) for all three dose levels at one month post-third study injection (Day 84) compared to pre-vaccination levels. Neutralizing antibody responses to heterologous rotavirus strains were most robust to P[8] strains, moderate to the P[4] strain and fairly limited to the P[6] strain.

Clinical testing of the monovalent (P[8]) P2-VP8 subunit rotavirus vaccine was initiated in South African toddlers and infants in 2014. The vaccine was generally well-tolerated at all three dose levels. In both toddlers and infants, when local reactogenicity was reported, it was transient, rarely greater than mild, and never severe. When present, systemic reactogenicity was also transient and generally mild, without discernable dose effect. In the dose-escalation phase of the testing in the infant cohorts, the study injections were paused temporarily due to findings of severe neutropenia on post-vaccination laboratory monitoring in three participants (two infants and one toddler) but were later resumed after the Safety Review Committee assessed that the data did not support relation to the study vaccine. The primary serology results in the infant cohorts were close to universal responses, with substantial increases in titer as demonstrated by mean-fold increase in GMT. In infants receiving the 30 µg dose, the GMT rose from a baseline value of 107 to a post-vaccination value of 9,583. Although not as dramatic as the IgG responses, there were good IgA responses to P2-VP8, with the seroresponse rate over 80% in infants receiving 30 µg of vaccine. The 60 µg dose did not appear to provide any better response than the 30 µg dose, although this study was not powered for that comparison.

In summary, the P2-VP8 monovalent vaccine was generally well-tolerated in healthy South African infants, and there was no evidence that the higher vaccine dose (60 µg) provided any benefit in serologic responses or impact on shedding of Rotarix compared to the lower dose (30 µg).

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Adults: Placebo	Placebo Comparator	Adults received three intramuscular injections of placebo four weeks apart on Days 0, 28, and 56.	Biological: Placebo
Adults: 30 µg P2-VP8	Experimental	Adults received three intramuscular injections of 30 µg trivalent P2-VP8 subunit rotavirus vaccine four weeks apart on Days 0, 28, and 56.	Biological: Trivalent P2-VP8 Subunit Rotavirus Vaccine
Adults: 90 µg P2-VP8	Experimental	Adults received three intramuscular injections of 90 µg trivalent P2-VP8 subunit rotavirus vaccine four weeks apart on Days 0, 28, and 56.	Biological: Trivalent P2-VP8 Subunit Rotavirus Vaccine
Toddlers: Placebo	Placebo Comparator	Toddlers received one intramuscular injection of placebo on Day 0.	Biological: Placebo
Toddlers: 30 µg P2-VP8	Experimental	Toddlers received one intramuscular injection of 30 µg trivalent P2-VP8 subunit rotavirus vaccine on Day 0.	Biological: Trivalent P2-VP8 Subunit Rotavirus Vaccine

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Trivalent P2-VP8 Subunit Rotavirus Vaccine	Biological	Manufactured and supplied by the Walter Reed Army Institute of Research (WRAIR) Pilot Bioproduction Facility (BPF). The trivalent P2-VP8 vaccine was formulated as a sterile suspension containing a total of 360 µg of protein (120 µg of each P type) per mL adsorbed to aluminum hydroxide (1.125 mg of aluminum per mL in a phosphate buffer, pH 7).

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Number of Participants Experiencing Adverse Events (AE) Within 28 Days of Any Vaccination	Any symptom starting after 7 days post any study injection was recorded as an adverse event. A serious adverse event (SAE) is any event that occurred from the first dose of study drug that resulted in any of the following outcomes: Death Life-threatening AE Inpatient hospitalization or prolongation of existing hospitalization Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions Congenital abnormality or birth defect Important medical event that may not result in one of the above outcomes but may jeopardize the health of the study participant or require medical or surgical intervention to prevent one of the outcomes listed above. The severity of adverse events was graded from Mild (grade 1) to Life Threatening (grade 4). AEs related to study drug were those events for which there was a reasonable possibility that the study drug caused the event In the opinion of the site investigator.	Up to 28 days after any vaccination (up to Day 28 for toddlers and up to Day 84 for infants and adults)
Number of Participants With Local or Systemic Reactions Within 7 Day of Vaccination	Reactogenicity data (solicited signs or symptoms) were assessed for 7 days after each injection. Participants and parents were instructed to assess and record daily local reactions (injection site pain/tenderness, redness, swelling, itching), as well as systemic signs and symptoms (fever, headache, vomiting, nausea, fatigue, chills and myalgia for adults; and fever, vomiting, decreased appetite, irritability, and decreased activity for toddlers and infants) in a participant memory aid. Reactions were graded on a scale from mild (Grade 1) to life-threatening (Grade 4). The overall number of participants who experienced any local or systemic reaction is reported. Grades are based on maximum severity per participant.	7 days following each vaccination
Number of Infants With Anti-P2-VP8 Immunoglobulin G (IgG) Seroresponse 4 Weeks After the Third Vaccination, by Vaccine Antigen	Seroresponse was defined as a four-fold rise or greater in antibody titer between Baseline and 28 days after the third injection (Day 84). Measured by enzyme-linked immunosorbent assay (ELISA) and adjusted for decay in maternal IgG antibodies. The estimated maternal antibody half-life was derived from linear regression of Log2 transformed titers in placebo recipients from the combined infant cohorts.

Secondary Outcomes

Measure	Description	Time Frame
Number of Participants Experiencing Adverse Events (AE) Over the Entire Study Period	Any symptom starting after 7 days post any study injection was recorded as an adverse event. A serious adverse event (SAE) is any event that occurred from the first dose of study drug that resulted in any of the following outcomes: Death - Life-threatening AE Inpatient hospitalization or prolongation of existing hospitalization Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions Congenital abnormality or birth defect Important medical event that may not result in one of the above outcomes but may jeopardize the health of the study participant or require medical or surgical intervention to prevent one of the outcomes listed in the above definition of serious event. AEs related to study drug were those events for which there was a reasonable possibility that the study drug caused the event In the opinion of the site investigator.

Eligibility Module

Name	Affiliation	Role
Michelle Groom, MBBCh	Chris Hani Baragwanath Hospital	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
Respiratory and Meningeal Pathogens Research Unit (RMPRU)		Johannesburg	Gauteng	2013	South Africa

PubMed Identifier	Type	Citation	Retractions
32251641	Derived	Groome MJ, Fairlie L, Morrison J, Fix A, Koen A, Masenya M, Jose L, Madhi SA, Page N, McNeal M, Dally L, Cho I, Power M, Flores J, Cryz S. Safety and immunogenicity of a parenteral trivalent P2-VP8 subunit rotavirus vaccine: a multisite, randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2020 Jul;20(7):851-863. doi: 10.1016/S1473-3099(20)30001-3. Epub 2020 Apr 3.

Arm/Group Information

ID	Title	Description
FG000	Adult: Placebo	Adult participants who received three intramuscular injections of placebo four weeks apart on days 0, 28, and 56. Approximately half of the participants were compared to the arm receiving the 30 µg dose of P2-VP8; once the safety of this dose was established, the other half were compared to the arm receiving 90 µg.
FG001	Adult: P2-VP8 (30 µg)	Adult participants who received three intramuscular injections of Trivalent P2-VP8 Subunit Rotavirus Vaccine (30 µg) four weeks apart on days 0, 28, and 56.
FG002	Adult: P2-VP8 (90 µg)	Adult participants who received three intramuscular injections of Trivalent P2-VP8 Subunit Rotavirus Vaccine (90 µg) four weeks apart on days 0, 28, and 56.
FG003	Toddler: Placebo	Toddler participants who received one intramuscular injection of placebo on day 0. Approximately half of the participants were compared to the arm receiving the 30 µg dose of P2-VP8; once the safety of this dose was established, the other half were compared to the arm receiving 90 µg.
FG004	Toddler: P2-VP8 (30 µg)	Toddler participants who received one intramuscular injections of Trivalent P2-VP8 Subunit Rotavirus Vaccine (30 µg) on day 0.
FG005	Toddler: P2-VP8 (90 µg)	Toddler participants who received one intramuscular injection of Trivalent P2-VP8 Subunit Rotavirus Vaccine (90 µg) on day 0.
FG006	Infant: Placebo	Infant participants who received three intramuscular injections of placebo four weeks apart on days 0, 28, and 56. Approximately one third of the participants were compared to the arm receiving the 15 µg dose of P2-VP8; once the safety of the 15 µg dose was established, one third of the participants were compared to the arm receiving 30 µg; and the last third were compared to the arm receiving 90 µg after the safety of the 30 µg dose was established.
FG007	Infant: P2-VP8 (15 µg)	Infant participants who received three intramuscular injections of Trivalent P2-VP8 Subunit Rotavirus Vaccine (15 µg) four weeks apart on days 0, 28, and 56.
FG008	Infant: P2-VP8 (30 µg)	Infant participants who received three intramuscular injections of Trivalent P2-VP8 Subunit Rotavirus Vaccine (30 µg) four weeks apart on days 0, 28, and 56.
FG009	Infant: P2-VP8 (90 µg)	Infant participants who received three intramuscular injections of Trivalent P2-VP8 Subunit Rotavirus Vaccine (90 µg) four weeks apart on days 0, 28, and 56.

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Adults: Placebo	Adults received three intramuscular injections of placebo four weeks apart on Days 0, 28, and 56.
BG001	Adults: 30 µg P2-VP8	Adults received three intramuscular injections of 30 µg trivalent P2-VP8 subunit rotavirus vaccine four weeks apart on Days 0, 28, and 56.

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type	Title	Description	Population Description	Reporting Status	Anticipated Posting Date	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Time Frame	Units Analyzed	Denominator Units Selected	Arm/Group Information	Denominators	Classes	Analyses
Primary	Number of Participants Experiencing Adverse Events (AE) Within 28 Days of Any Vaccination	Any symptom starting after 7 days post any study injection was recorded as an adverse event. A serious adverse event (SAE) is any event that occurred from the first dose of study drug that resulted in any of the following outcomes: Death Life-threatening AE Inpatient hospitalization or prolongation of existing hospitalization Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions Congenital abnormality or birth defect Important medical event that may not result in one of the above outcomes but may jeopardize the health of the study participant or require medical or surgical intervention to prevent one of the outcomes listed above. The severity of adverse events was graded from Mild (grade 1) to Life Threatening (grade 4). AEs related to study drug were those events for which there was a reasonable possibility that the study drug caused the event In the opinion of the site investigator.	Safety population included all participants who were randomized and received at least one injection of the study drug.	Posted		Count of Participants		Participants		Up to 28 days after any vaccination (up to Day 28 for toddlers and up to Day 84 for infants and adults)

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Adult: Placebo	Adult participants who received three intramuscular injections of placebo four weeks apart on days 0, 28, and 56. Approximately half of the participants were compared to the arm receiving the 30 µg dose of P2-VP8; once the safety of this dose was established, the other half were compared to the arm receiving 90 µg.

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Diarrhoea	Gastrointestinal disorders	MedDRA (Unspecified)	Systematic Assessment

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Lymphadenopathy	Blood and lymphatic system disorders	MedDRA (Unspecified)	Systematic Assessment

Title	Organization	Phone	Extension	Email
Jorge Flores	PATH	(202) 822-0033		jeflores@path.org

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Jun 21, 2016	Jan 2, 2019	Prot_000.pdf
SAP	No	Yes	No	Statistical Analysis Plan	Aug 24, 2017	Jan 2, 2019	SAP_001.pdf

ID	Title	Description
OG000	Adults: Placebo	Adults received three intramuscular injections of placebo four weeks apart on Days 0, 28, and 56.
OG001	Adults: 30 µg P2-VP8	Adults received three intramuscular injections of 30 µg trivalent P2-VP8 subunit rotavirus vaccine four weeks apart on Days 0, 28, and 56.
OG002	Adults: 90 µg P2-VP8	Adults received three intramuscular injections of 90 µg trivalent P2-VP8 subunit rotavirus vaccine four weeks apart on Days 0, 28, and 56.
OG003	Toddlers: Placebo	Toddlers received one intramuscular injection of placebo on Day 0.
OG004	Toddlers: 30 µg P2-VP8	Toddlers received one intramuscular injection of 30 µg trivalent P2-VP8 subunit rotavirus vaccine on Day 0.
OG005	Toddlers: 90 µg P2-VP8	Toddlers received one intramuscular injection of 90 µg trivalent P2-VP8 subunit rotavirus vaccine on Day 0.
OG006	Infants: Placebo	Infants received three intramuscular injections of placebo four weeks apart on Days 0, 28, and 56.
OG007	Infants: 15 µg P2-VP8	Infants received three intramuscular injections of 15 µg trivalent P2-VP8 subunit rotavirus vaccine four weeks apart on Days 0, 28, and 56.
OG008	Infants: 30 µg P2-VP8	Infants received three intramuscular injections of 30 µg trivalent P2-VP8 subunit rotavirus vaccine four weeks apart on Days 0, 28, and 56.
OG009	Infants: 90 µg P2-VP8	Infants received three intramuscular injections of 90 µg trivalent P2-VP8 subunit rotavirus vaccine four weeks apart on Days 0, 28, and 56.