Safety and Immunogenicity Study of Trivalent P2-VP8 Subunit Rotavirus Vaccine in Adults, Toddlers and Infants
Condition: Healthy
Study type: Interventional
Phase: Phase 1/Phase 2

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. 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).
    

Intervention name(s): Trivalent P2-VP8 Subunit Rotavirus Vaccine; Placebo
Intervention type(s): Biological; Biological
Intervention description(s): 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).; Sodium Chloride 0.9%, USP for Injection
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Rotavirus Vaccine