Safety and Immunogenicity Study of Trivalent P2-VP8 Subunit Rotavirus Vaccine in 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.

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).

Eligibility Criteria:
Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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
* 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