HealthyPhase 1/2NCT02646891
Safety and Immunogenicity Study of Trivalent P2-VP8 Subunit Rotavirus Vaccine in Adults, Toddlers and Infants
A Phase 1/2 study testing Trivalent P2-VP8 Subunit Rotavirus Vaccine in people with Healthy, run by PATH at 3 sites in South Africa.
Trial summary
This is is a study of a parenteral trivalent rotavirus vaccine (P2-VP8 subunit rotavirus vaccine). The study examined the safety and immunogenicity of three dose levels of this vaccine in healthy South African adults, toddlers and infants. Read more about this study
- Who is it for?
- Ages 6 weeks to 45 yearsHealthy volunteers can take part
- Conditions the study is for
- Healthy
- What is being tested?
- Trivalent P2-VP8 Subunit Rotavirus Vaccine
- Type of treatment
- Vaccines, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 618 participants
- Where
- 3 sitesSouth Africa
- Study dates
- 15 Feb 2016to 22 Dec 2017
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 weeks to 45 years
- All sexes
- Healthy volunteers accepted
- Child, Adult
Who may be able to join
- Healthy adults (≥ 18 and ≤ 45 years), toddlers (≥ 2 and ≤ 3 years), and infants (≥ 6 and ≤ 8 weeks)
- Participants will remain in the area during the study
- Females of childbearing potential must not be pregnant or breastfeeding, and willing to use adequate method of contraception during the trial.
Who cannot join
- Presence of fever or other acute illness
- concurrent participation in another clinical trial
- Presence of malnutrition or other systemic disorder.
- Infants with history of premature birth (< 37 week gestational age)
- History of congenital abdominal disorders or surgery
- Suspected or known impairment of immune function
Show all 16Show fewer
- Infants who have received rotavirus vaccine in the past
- Known sensitivity to any components of the vaccine
- History of anaphylactic reaction
- Major congenital or genetic defect
- Unwillingness to follow study schedule
- Receipt of immunoglobulin therapy or blood products in last 6 months
- History of chronic immunosuppressive medications (with the exception of inhaled or topical steroids)
- Any medical condition that, in the judgement of the investigator, would interfere with the protocol, or would interfere with participant's ability to adhere to the study protocol.
- Clinically significant screening laboratory value
- Human immunodeficiency virus (HIV) infection
Trial locations and contacts
3 sites in 1 country.
South Africa3 sites
Respiratory and Meningeal Pathogens Research Unit (RMPRU)
Johannesburg, Gauteng, 2013
Shandukani Research Centre
Johannesburg, 2001
Family Clinical Research Unit (FAM-CRU) Stellenbosch Univ
Stellenbosch, 7505
About this study
Official title: Phase I/II Double-blind, Randomized, Placebo-controlled, Descending Age, Dose-escalation Study of the Safety, and Immunogenicity of the Trivalent P2-VP8 Subunit Rotavirus Vaccine in Healthy South African Adults, Toddlers and Infants
This is is a study of a parenteral trivalent rotavirus vaccine (P2-VP8 subunit rotavirus vaccine). The study examined the safety and immunogenicity of three dose levels of this vaccine in healthy South African adults, toddlers and infants. Progression from one dose level to another and to the next age group population was based on the assessment of safety information from the lowest dose and older age group.
The primary safety hypothesis is that the P2-VP8 subunit rotavirus vaccine is safe and well-tolerated. The primary immunogenicity hypothesis is that the trivalent P2-VP8 subunit rotavirus vaccine is immunogenic in infant participants and will induce an immune response to at least 2 of the 3 strains in 60% or more of participants in at least one of the study groups.
Read the 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).
- Conditions
- Healthy
- Being tested
- Trivalent P2-VP8 Subunit Rotavirus Vaccine, Placebo
- Keywords
- Rotavirus Vaccine
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Trivalent P2-VP8 Subunit Rotavirus VaccineBiological
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).
PlaceboBiological
Sodium Chloride 0.9%, USP for Injection
| Study group | Role | What they receive |
|---|---|---|
| Adults: Placebo | Placebo comparator | Adults received three intramuscular injections of placebo four weeks apart on Days 0, 28, and 56. Receives: 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. Receives: 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. Receives: Biological: Trivalent P2-VP8 Subunit Rotavirus Vaccine |
| Toddlers: Placebo | Placebo comparator | Toddlers received one intramuscular injection of placebo on Day 0. Receives: 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. Receives: Biological: Trivalent P2-VP8 Subunit Rotavirus Vaccine |
| Toddlers: 90 µg P2-VP8 | Experimental | Toddlers received one intramuscular injection of 90 µg trivalent P2-VP8 subunit rotavirus vaccine on Day 0. Receives: Biological: Trivalent P2-VP8 Subunit Rotavirus Vaccine |
| Infants: Placebo | Placebo comparator | Infants received three intramuscular injections of placebo four weeks apart on Days 0, 28, and 56. Receives: Biological: Placebo |
| Infants: 15 µg P2-VP8 | Experimental | Infants received three intramuscular injections of 15 µg trivalent P2-VP8 subunit rotavirus vaccine four weeks apart on Days 0, 28, and 56. Receives: Biological: Trivalent P2-VP8 Subunit Rotavirus Vaccine |
| Infants: 30 µg P2-VP8 | Experimental | Infants received three intramuscular injections of 30 µg trivalent P2-VP8 subunit rotavirus vaccine four weeks apart on Days 0, 28, and 56. Receives: Biological: Trivalent P2-VP8 Subunit Rotavirus Vaccine |
| Infants: 90 µg P2-VP8 | Experimental | Infants received three intramuscular injections of 90 µg trivalent P2-VP8 subunit rotavirus vaccine four weeks apart on Days 0, 28, and 56. Receives: Biological: Trivalent P2-VP8 Subunit Rotavirus Vaccine |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: Day 84
Number of Infants With Anti-P2-VP8 Immunoglobulin A (IgA) 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 final injection (Day 84). Measured by enzyme-linked immunosorbent assay (ELISA) to whole viral lysate.
Measured: Day 84
Number of Infants With Neutralizing Antibody Responses 4 Weeks After the Third Vaccination to Each Rotavirus Strain
Neutralizing antibody response was defined as a ≥ 2.7-fold rise in antibody titer between Baseline and 28 days after the final injection (Day 84). Neutralizing antibodies to each of the three rotavirus strains from which the vaccine antigens were derived (Wa, DS-1, and 1076) were measured using a validated assay. For infants, antibody titer was adjusted for decay in maternal antibodies.
Measured: Day 84
Anti-P2-VP8 Immunoglobulin G (IgG) Geometric Mean Titers Among Infants, by Vaccine Antigen
Measured by ELISA at Baseline, 28 days after the second injection (Day 56 pre-vaccination; secondary outcome) and 28 days after the third and final injection (Day 84; primary outcome).
Measured: Baseline and Days 56 (pre-vaccination) and 84
Anti-P2-VP8 Immunoglobulin A (IgA) Geometric Mean Titers Among Infants, by Vaccine Antigen
Measured by ELISA at Baseline, 28 days after the second injection (Day 56 pre-vaccination; secondary outcome) and 28 days after the third and final injection (Day 84; primary outcome).
Measured: Baseline and Days 56 (pre-vaccination) and 84
Geometric Mean Titers of Neutralizing Antibody Against Rotavirus Strains Among Infants
Neutralizing antibodies to each of the three rotavirus strains from which the vaccine antigens were derived (Wa, DS-1, and 1076) were measured at Baseline and 28 days after the second injection (Day 56 pre-vaccination; secondary outcome) and third injection (Day 84; primary outcome).
Measured: Baseline and Days 56 (pre-vaccination) and 84
Secondary outcomes (10)
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.
Measured: Up to 6 months after the last injection (224 days for adults and infants; 168 days for toddlers)
Number of Infants With Anti-P2-VP8 Immunoglobulin G (IgG) Seroresponse 4 Weeks After the Second Vaccination, by Vaccine Antigen
Seroresponse was defined as a four-fold rise or greater in antibody titer between Baseline and 28 days after the 2nd injection (Day 56). Measured by enzyme-linked immunosorbent assay (ELISA) and adjusted for decay in maternal antibodies. The estimated maternal antibody half-life was derived from linear regression of Log2 transformed titers in placebo recipients from the combined infant cohorts.
Measured: Day 56, pre-vaccination
Number of Infants With Anti-P2-VP8 Immunoglobulin A (IgA) Seroresponse 4 Weeks After the Second Vaccination, by Vaccine Antigen
Seroresponse was defined as a four-fold rise or greater in antibody titer between Baseline and 28 days after the second injection (Day 56). Measured by enzyme-linked immunosorbent assay (ELISA) to whole viral lysate.
Measured: Day 56, pre-vaccination
Number of Infants With Neutralizing Antibody Responses 4 Weeks After the Second Vaccination
Neutralizing antibody response was defined as a ≥ 2.7-fold rise in antibody titer between Baseline and 28 days after the second injection (Day 56). Neutralizing antibodies to each of the three rotavirus strains from which the vaccine antigens were derived (Wa, DS-1, and 1076) were measured using a validated assay. For infants, antibody titers were adjusted for decay in maternal antibodies.
Measured: Day 56, prevaccination
Number of Adults and Toddlers With Anti-P2-VP8 Immunoglobulin G (IgG) Seroresponse, by Vaccine Antigen
Seroresponse was defined as a four-fold rise or greater in IgG antibody titer between Baseline and 28 days after the final injection (Day 84 for adults and Day 28 for toddlers). Measured by enzyme-linked immunosorbent assay (ELISA).
Measured: Day 84 for adults; Day 28 for toddlers
Number of Adults and Toddlers With Anti-P2-VP8 Immunoglobulin A (IgA) Seroresponse, by Vaccine Antigen
Seroresponse was defined as a four-fold rise or greater in IgA antibody titer between Baseline and 28 days after the final injection (Day 84 for adults and Day 28 for toddlers). Measured by enzyme-linked immunosorbent assay (ELISA).
Measured: Day 84 for adults; Day 28 for toddlers
Number of Adults and Toddlers With Neutralizing Antibody Responses to Each Rotavirus Strain
Neutralizing antibody response was defined as a ≥ 2.7-fold rise in antibody titer between Baseline and 28 days after the final injection (Day 84 for adults and Day 28 for toddlers) for each of the three rotavirus strains from which the vaccine antigens were derived (Wa, DS-1, and 1076).
Measured: Day 84 for adults; Day 28 for toddlers
Anti-P2-VP8 Immunoglobulin G (IgG) Geometric Mean Titers Among Adults and Toddlers, by Vaccine Antigen
Measured at Baseline and 28 days after the final injection (Day 84 for adults; Day 28 for toddlers).
Measured: Baseline and Day 28 for toddlers or Day 84 for adults
Anti-P2-VP8 Immunoglobulin A (IgA) Geometric Mean Titers Among Adults and Toddlers, by Vaccine Antigen
Measured at Baseline and 28 days after the final injection (Day 84 for adults; Day 28 for toddlers).
Measured: Baseline and Day 28 for toddlers or Day 84 for adults
Geometric Mean Titers of Neutralizing Antibody Against Rotavirus Strains Among Adults and Toddlers
Measured at Baseline and 28 days after the final injection (Day 84 for adults; Day 28 for toddlers).
Measured: Baseline and Day 28 for toddlers or Day 84 for adults
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Jan 2016 (estimated)
- Study start15 Feb 2016
- Primary completion1 Sep 2017
- Study completion22 Dec 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for HealthyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 618 participants (actual)
Sponsor and investigators
- Lead sponsor
- PATH
- Sponsor type
- University, hospital or other
- Collaborators
- The Emmes Company, LLC
- Responsible party
- Sponsor
- Investigators
- Michelle Groom, MBBCh, Study chair, Chris Hani Baragwanath Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02646891
- Sponsor's protocol ID
- VAC-041
- Status last verified
- Jan 2019
- First submitted
- 4 Jan 2016
- Last updated
- 10 Mar 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No
Publications
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.
PubMed 32251641
Study at a glance
From the registry record, last updated by the sponsor on 10 Mar 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I/II Double-blind, Randomized, Placebo-controlled, Descending Age, Dose-escalation Study of the Safety, and Immunogenicity of the Trivalent P2-VP8 Subunit Rotavirus Vaccine in Healthy South African Adults, Toddlers and Infants
- ClinicalTrials.gov ID
- NCT02646891
- Acronym / sponsor ID
- VAC-041
- Conditions
- Healthy
- Keywords
- Rotavirus Vaccine
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 618 participants (actual)
- Lead sponsor
- PATHUniversity, hospital or other
- Collaborators
- The Emmes Company, LLC
- Study start
- 15 Feb 2016 (actual)
- Primary completion
- 1 Sep 2017 (actual)
- Study completion
- 22 Dec 2017 (actual)
- First posted
- 6 Jan 2016 (estimated)
- Results
- Posted 10 Mar 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is is a study of a parenteral trivalent rotavirus vaccine (P2-VP8 subunit rotavirus vaccine). The study examined the safety and immunogenicity of three dose levels of this vaccine in healthy South African adults, toddlers and infants. Progression from one dose level to another and to the next age group population was based on the assessment of safety information from the lowest dose and older age group.
The primary safety hypothesis is that the P2-VP8 subunit rotavirus vaccine is safe and well-tolerated. The primary immunogenicity hypothesis is that the trivalent P2-VP8 subunit rotavirus vaccine is immunogenic in infant participants and will induce an immune response to at least 2 of the 3 strains in 60% or more of participants in at least one of the study groups.
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).
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 10
| Arm | Type | Receives |
|---|---|---|
| Adults: Placebo | Placebo comparator | Biological: PlaceboAdults received three intramuscular injections of placebo four weeks apart on Days 0, 28, and 56. |
| Adults: 30 µg P2-VP8 | Experimental | Biological: Trivalent P2-VP8 Subunit Rotavirus VaccineAdults received three intramuscular injections of 30 µg trivalent P2-VP8 subunit rotavirus vaccine four weeks apart on Days 0, 28, and 56. |
| Adults: 90 µg P2-VP8 | Experimental | Biological: Trivalent P2-VP8 Subunit Rotavirus VaccineAdults received three intramuscular injections of 90 µg trivalent P2-VP8 subunit rotavirus vaccine four weeks apart on Days 0, 28, and 56. |
| Toddlers: Placebo | Placebo comparator | Biological: PlaceboToddlers received one intramuscular injection of placebo on Day 0. |
| Toddlers: 30 µg P2-VP8 | Experimental | Biological: Trivalent P2-VP8 Subunit Rotavirus VaccineToddlers received one intramuscular injection of 30 µg trivalent P2-VP8 subunit rotavirus vaccine on Day 0. |
| Toddlers: 90 µg P2-VP8 | Experimental | Biological: Trivalent P2-VP8 Subunit Rotavirus VaccineToddlers received one intramuscular injection of 90 µg trivalent P2-VP8 subunit rotavirus vaccine on Day 0. |
| Infants: Placebo | Placebo comparator | Biological: PlaceboInfants received three intramuscular injections of placebo four weeks apart on Days 0, 28, and 56. |
| Infants: 15 µg P2-VP8 | Experimental | Biological: Trivalent P2-VP8 Subunit Rotavirus VaccineInfants received three intramuscular injections of 15 µg trivalent P2-VP8 subunit rotavirus vaccine four weeks apart on Days 0, 28, and 56. |
| Infants: 30 µg P2-VP8 | Experimental | Biological: Trivalent P2-VP8 Subunit Rotavirus VaccineInfants received three intramuscular injections of 30 µg trivalent P2-VP8 subunit rotavirus vaccine four weeks apart on Days 0, 28, and 56. |
| Infants: 90 µg P2-VP8 | Experimental | Biological: Trivalent P2-VP8 Subunit Rotavirus VaccineInfants received three intramuscular injections of 90 µg trivalent P2-VP8 subunit rotavirus vaccine four weeks apart on Days 0, 28, and 56. |
Who may qualify
- Ages
- 6 weeks to 45 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult
Key inclusion criteria (3 listed)
- Healthy adults (≥ 18 and ≤ 45 years), toddlers (≥ 2 and ≤ 3 years), and infants (≥ 6 and ≤ 8 weeks)
- Participants will remain in the area during the study
- Females of childbearing potential must not be pregnant or breastfeeding, and willing to use adequate method of contraception during the trial.
Key exclusion criteria (16 listed)
- Presence of fever or other acute illness
- concurrent participation in another clinical trial
- Presence of malnutrition or other systemic disorder.
- Infants with history of premature birth (< 37 week gestational age)
- History of congenital abdominal disorders or surgery
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Trivalent P2-VP8 Subunit Rotavirus VaccineManufactured 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). | Biological | Adults: 30 µg P2-VP8, Adults: 90 µg P2-VP8, Infants: 15 µg P2-VP8, Infants: 30 µg P2-VP8, Infants: 90 µg P2-VP8, Toddlers: 30 µg P2-VP8, Toddlers: 90 µg P2-VP8 |
| PlaceboSodium Chloride 0.9%, USP for Injection | Biological | Adults: Placebo, Infants: Placebo, Toddlers: Placebo |
Primary outcome
Number of Participants Experiencing Adverse Events (AE) Within 28 Days of Any Vaccination
Time frame: Up to 28 days after any vaccination (up to Day 28 for toddlers and up to Day 84 for infants and adults)
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: 1. Death 2. Life-threatening AE 3. Inpatient hospitalization or prolongation of existing hospitalization 4. Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 5. Congenital abnormality or birth defect 6. 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.
Number of Participants With Local or Systemic Reactions Within 7 Day of Vaccination
Time frame: 7 days following each 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.
Number of Infants With Anti-P2-VP8 Immunoglobulin G (IgG) Seroresponse 4 Weeks After the Third Vaccination, by Vaccine Antigen
Time frame: Day 84
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.
Number of Infants With Anti-P2-VP8 Immunoglobulin A (IgA) Seroresponse 4 Weeks After the Third Vaccination, by Vaccine Antigen
Time frame: Day 84
Seroresponse was defined as a four-fold rise or greater in antibody titer between Baseline and 28 days after the final injection (Day 84). Measured by enzyme-linked immunosorbent assay (ELISA) to whole viral lysate.
Number of Infants With Neutralizing Antibody Responses 4 Weeks After the Third Vaccination to Each Rotavirus Strain
Time frame: Day 84
Neutralizing antibody response was defined as a ≥ 2.7-fold rise in antibody titer between Baseline and 28 days after the final injection (Day 84). Neutralizing antibodies to each of the three rotavirus strains from which the vaccine antigens were derived (Wa, DS-1, and 1076) were measured using a validated assay. For infants, antibody titer was adjusted for decay in maternal antibodies.
Anti-P2-VP8 Immunoglobulin G (IgG) Geometric Mean Titers Among Infants, by Vaccine Antigen
Time frame: Baseline and Days 56 (pre-vaccination) and 84
Measured by ELISA at Baseline, 28 days after the second injection (Day 56 pre-vaccination; secondary outcome) and 28 days after the third and final injection (Day 84; primary outcome).
Anti-P2-VP8 Immunoglobulin A (IgA) Geometric Mean Titers Among Infants, by Vaccine Antigen
Time frame: Baseline and Days 56 (pre-vaccination) and 84
Measured by ELISA at Baseline, 28 days after the second injection (Day 56 pre-vaccination; secondary outcome) and 28 days after the third and final injection (Day 84; primary outcome).
Geometric Mean Titers of Neutralizing Antibody Against Rotavirus Strains Among Infants
Time frame: Baseline and Days 56 (pre-vaccination) and 84
Neutralizing antibodies to each of the three rotavirus strains from which the vaccine antigens were derived (Wa, DS-1, and 1076) were measured at Baseline and 28 days after the second injection (Day 56 pre-vaccination; secondary outcome) and third injection (Day 84; primary outcome).
10 secondary outcomes
Number of Participants Experiencing Adverse Events (AE) Over the Entire Study Period
Time frame: Up to 6 months after the last injection (224 days for adults and infants; 168 days for toddlers)
Number of Infants With Anti-P2-VP8 Immunoglobulin G (IgG) Seroresponse 4 Weeks After the Second Vaccination, by Vaccine Antigen
Time frame: Day 56, pre-vaccination
Number of Infants With Anti-P2-VP8 Immunoglobulin A (IgA) Seroresponse 4 Weeks After the Second Vaccination, by Vaccine Antigen
Time frame: Day 56, pre-vaccination
Number of Infants With Neutralizing Antibody Responses 4 Weeks After the Second Vaccination
Time frame: Day 56, prevaccination
Number of Adults and Toddlers With Anti-P2-VP8 Immunoglobulin G (IgG) Seroresponse, by Vaccine Antigen
Time frame: Day 84 for adults; Day 28 for toddlers
Number of Adults and Toddlers With Anti-P2-VP8 Immunoglobulin A (IgA) Seroresponse, by Vaccine Antigen
Time frame: Day 84 for adults; Day 28 for toddlers
Number of Adults and Toddlers With Neutralizing Antibody Responses to Each Rotavirus Strain
Time frame: Day 84 for adults; Day 28 for toddlers
Anti-P2-VP8 Immunoglobulin G (IgG) Geometric Mean Titers Among Adults and Toddlers, by Vaccine Antigen
Time frame: Baseline and Day 28 for toddlers or Day 84 for adults
Anti-P2-VP8 Immunoglobulin A (IgA) Geometric Mean Titers Among Adults and Toddlers, by Vaccine Antigen
Time frame: Baseline and Day 28 for toddlers or Day 84 for adults
Geometric Mean Titers of Neutralizing Antibody Against Rotavirus Strains Among Adults and Toddlers
Time frame: Baseline and Day 28 for toddlers or Day 84 for adults
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Mar 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 32251641Groome 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Michelle Groom, MBBCh study chair
Chris Hani Baragwanath Hospital
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Trivalent P2-VP8 Subunit Rotavirus Vaccine in people with Healthy, run by PATH at 3 sites in South Africa.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 10 Mar 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in South Africa. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 10 Mar 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants Experiencing Adverse Events (AE) Within 28 Days of Any Vaccination (time frame: Up to 28 days after any vaccination (up to Day 28 for toddlers and up to Day 84 for infants and adults)). The study lists 8 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02646891, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Mar 2020.