Safety and immunogenicity of a parenteral trivalent P2-VP8 subunit rotavirus vaccine: a multisite, randomised, double-blind, placebo-controlled trial.
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SUBMITTER: Groome MJ
PROVIDER: S-EPMC7322558 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundEfficacy of live oral rotavirus vaccines is reduced in low-income compared with high-income settings. Parenteral non-replicating rotavirus vaccines might offer benefits over oral vaccines. We assessed the safety and immunogenicity of the P2-VP8-P[8] subunit rotavirus vaccine at different doses in South African toddlers and infants.MethodsThis double-blind, randomised, placebo-controlled, dose-escalation trial was done at a single research unit based at a hospital in South Africa in healthy HIV-uninfected toddlers (aged 2 to <3 years) and term infants (aged 6 to <8 weeks, without previous rotavirus vaccination). Block randomisation (computer-generated, electronic allocation) was used to assign eligible toddlers (in a 6:1 ratio) and infants (in a 3:1 ratio) in each dose cohort (10 μg, followed by 30 μg, then 60 μg if doses tolerated) to parenteral P2-VP8-P[8] subunit rotavirus or placebo injection. The two highest tolerated doses were then assessed in an expanded cohort (in a 1:1:1 ratio). Parents of participants and clinical, data, and laboratory staff were masked to treatment assignment. P2-VP8-P[8] vaccine versus placebo was assessed first in toddlers (single injection) and then in infants (three injections 4 weeks apart). The primary safety endpoints were local and systemic reactions within 7 days after each injection, adverse events within 28 days after each injection, and all serious adverse events, assessed in toddlers and infants who received at least one dose. In infants receiving all study injections, primary immunogenicity endpoints were anti-P2-VP8-P[8] IgA and IgG and neutralising antibody seroresponses and geometric mean titres 4 weeks after the third injection. This trial is registered at ClinicalTrials.gov, number NCT02109484.FindingsBetween March 17, 2014, and Sept 29, 2014, 42 toddlers (36 to vaccine and six to placebo) and 48 infants (36 to vaccine and 12 to placebo) were enrolled in the dose-escalation phase, in which the 30 μg and 60 μg doses where found to be the highest tolerated doses. A further 114 infants were enrolled in the expanded cohort between Nov 3, 2014, and March 20, 2015, and all 162 infants (12 assigned to 10 μg, 50 to 30 μg, 50 to 60 μg, and 50 to placebo) were included in the safety analysis. Serum IgA seroresponses were observed in 38 (81%, 95% CI 67-91) of 47 infants in the 30 μg group and 32 (68%, 53-81) of 47 in the 60 μg group, compared with nine (20%, 10-35) of 45 in the placebo group; adjusted IgG seroresponses were seen in 46 (98%, 89-100) of 47 infants in the 30 μg group and 47 (100%; 92-100) of 47 in the 60 μg group, compared with four (9%, 2·5-21) of 45 in the placebo group; and adjusted neutralising antibody seroresponses against the homologous Wa-strain were seen in 40 (85%, 72-94) of 47 infants in both the 30 μg and 60 μg groups, compared with three (7%, 1·4-18) of 45 participants in the placebo group. Solicited reactions following any injection occurred with similar frequency and severity in participants receiving vaccine and those receiving placebo. Unsolicited adverse events were mostly mild and occurred at a similar frequency between groups. Eight serious adverse events (one with placebo, two with 30 μg, and five with 60 μg) occurred in seven infants within 28 days of any study injection, none of which were deemed related to study treatment.InterpretationThe parenteral P2-VP8-P[8] vaccine was well tolerated and immunogenic in infants, providing a novel approach to vaccination against rotavirus disease. On the basis of these results, a phase 1/2 trial of a trivalent P2-VP8 (P[4], P[6], and P[8]) subunit vaccine is underway at three sites in South Africa.FundingBill & Melinda Gates Foundation.
| S-EPMC7771518 | biostudies-literature
Project description:Two currently licensed live oral rotavirus vaccines (Rotarix® and RotaTeq®) are highly efficacious against severe rotavirus diarrhea. However, the efficacy of such vaccines in selected low-income African and Asian countries is much lower than that in middle or high-income countries. Additionally, these two vaccines have recently been associated with rare case of intussusception in vaccinated infants. We developed a novel recombinant subunit parenteral rotavirus vaccine which may be more effective in low-income countries and also avert the potential problem of intussusception. Truncated recombinant VP8* (ΔVP8*) protein of human rotavirus strain Wa P[8], DS-1 P[4] or 1076 P[6] expressed in Escherichia coli was highly soluble and was generated in high yield. Guinea pigs hyperimmunized intramuscularly with each of the ΔVP8* proteins (i.e., P[8], P[4] or P[6]) developed high levels of homotypic as well as variable levels of heterotypic neutralizing antibodies. Moreover, the selected ΔVP8* proteins when administered to mice at a clinically relevant dosage, route and schedule, elicited high levels of serum anti-VP8* IgG and/or neutralizing antibodies. Our data indicated that the ΔVP8* proteins may be a plausible additional candidate as new parenteral rotavirus vaccines.
| S-EPMC3434302 | biostudies-literature
Project description:Currently available live oral rotavirus vaccines, Rotarix(®) and RotaTeq(®), are highly efficacious in developed countries. However, the immunogenicity and efficacy of such vaccines in some developing countries are low. We reported previously that bacterially-expressed rotavirus ΔVP8* subunit vaccine candidates with P[8], P[4] or P[6] specificity elicited high-titer virus neutralizing antibodies in animals immunized intramuscularly. Of note was the finding that antibodies induced with the P[8]ΔVP8* vaccine neutralized both homotypic P[8] and heterotypic P[4] rotavirus strains to high titer. To further improve its vaccine potential, a tetanus toxoid universal CD4(+) T cell epitope P2 was introduced into P[8] or P[6]ΔVP8* construct. The resulting recombinant fusion proteins expressed in Escherichia coli were of high solubility and were produced with high yield. Two doses (10 or 20 μg/dose) of the P2-P[8]ΔVP8* vaccine or P2-P[6]ΔVP8* vaccine with aluminum phosphate adjuvant elicited significantly higher geometric mean homologous neutralizing antibody titers than the vaccines without P2 in intramuscularly immunized guinea pigs. Interestingly, high levels of neutralizing antibody responses induced in guinea pigs with 3 doses of the P2-P[8]ΔVP8* vaccine persisted for at least 6 months. Furthermore, in the gnotobiotic piglet challenge study, three intramuscular doses (50 μg/dose) of the P2-P[8]ΔVP8* vaccine with aluminum phosphate adjuvant significantly delayed the onset of diarrhea and significantly reduced the duration of diarrhea and the cumulative diarrhea score after oral challenge with virulent human rotavirus Wa (G1P[8]) strain. The P2-P[8]ΔVP8* vaccine induced serum virus neutralizing antibody and VP4-specific IgG antibody production prechallenge, and primed the pigs for higher antibody and intestinal and systemic virus-specific IFN-γ producing CD4(+) T cell responses postchallenge. These two subunit vaccines could be used at a minimum singly or preferably in bivalent formulation to provide antigenic coverage of most of the G types of global importance.
| S-EPMC4104241 | biostudies-literature
Project description:The two currently available live oral rotavirus vaccines, Rotarix(®) and RotaTeq(®), are highly efficacious in the developed countries. However, the efficacy of such vaccines in resource deprived countries in Africa and Southeast Asia is low. We reported previously that a bacterially-expressed rotavirus P2-P[8] ΔVP8* subunit vaccine candidate administered intramuscularly elicited high-titers of neutralizing antibodies in guinea pigs and mice and significantly shortened the duration of diarrhea in neonatal gnotobiotic pigs upon oral challenge with virulent human rotavirus Wa strain. To further improve its vaccine potential and provide wider coverage against rotavirus strains of global and regional epidemiologic importance, we constructed 2 tandem recombinant VP8* proteins, P2-P[8] ΔVP8*-P[8] ΔVP8* and P2-P[8] ΔVP8*-P[6] ΔVP8* based on Escherichia coli expression system. The two resulting recombinant tandem proteins were highly soluble and P2-P[8] ΔVP8*-P[8] ΔVP8* was generated with high yield. Moreover, guinea pigs immunized intramuscularly by 3 doses of the P2-P[8] ΔVP8*-P[8] ΔVP8* or P2-P[8] ΔVP8*-P[6] ΔVP8* vaccine with aluminum phosphate adjuvant developed high titers of homotypic and heterotypic neutralizing antibodies against human rotaviruses bearing G1-G4, G8, G9 and G12 with P[8], P[4] or P[6] combination. The results suggest that these 2 subunit vaccines in monovalent or bivalent formulation can provide antigenic coverage to almost all the rotavirus G (VP7) types and major P (VP4) types of global as well as regional epidemiologic importance.
| S-EPMC4635725 | biostudies-literature
Project description:In attempts to develop recombinant subunit vaccines against rotavirus disease, it was previously shown that the N-terminal truncated VP8* protein, VP8-1 (aa26-231), is a good vaccine candidate when used for immunization in combination with Freund's adjuvant. However, this protein stimulated only weak immune response when aluminum hydroxide was used as an adjuvant. In this study, the nontoxic B subunit of cholera toxin (CTB) was employed as intra-molecular adjuvant to improve the immunogenicity of VP8-1. Both, the N-terminal and C-terminal fusion proteins, were purified to homogeneity, at which stage they formed pentamers, and showed significantly higher immunogenicity and protective efficacy than a VP8-1/aluminum hydroxide mixture in a mouse model. Compared to VP8-1-CTB, CTB-VP8-1 showed higher binding activity to both, GM1 and the conformation sensitive neutralizing monoclonal antibodies specific to VP8. More importantly, CTB-VP8-1 elicited higher titers of neutralizing antibodies and conferred higher protective efficacy than VP8-1-CTB. Therefore, the protein CTB-VP8-1, with enhanced immunogenicity and immunoprotectivity, could be considered as a viable candidate for further development of an alternative, replication-incompetent, parenterally administered vaccine against rotavirus disease.
| S-EPMC5137547 | biostudies-literature
Project description:The epitopes of the HRV (human rotavirus), especially those involved in virus neutralization, have not been determined in their entirety, and would have significant implications for HRV vaccine development. In the present study, we report on the epitope mapping and identification of sequential neutralization epitopes, on the Wa strain HRV subunit protein VP8, using synthetic overlapping peptides. Polyclonal antibodies against recombinant Wa VP8 were produced previously in chicken, and purified from egg yolk, which showed neutralizing activity against HRV in vitro. Overlapping VP8 peptide fragments were synthesized and probed with the anti-VP8 antibodies, revealing five sequential epitopes on VP8. Further analysis suggested that three of the five epitopes detected, M1-L10, I55-D66 and L223-P234, were involved in virus neutralization, indicating that sequential epitopes may also be important for the HRV neutralization. The interactions of the antibodies with the five epitopes were characterized by an examination of the critical amino acids involved in antibody binding. Epitopes comprised primarily of hydrophobic amino acid residues, followed by polar and charged residues. The more critical amino acids appeared to be located near the centre of the epitopes, with proline, isoleucine, serine, glutamine and arginine playing an important role in the binding of antibody to the VP8 epitopes.
| S-EPMC1223744 | biostudies-other
Project description:Although live attenuated Rotavirus (RV) vaccines are available globally to provide protection against enteric RV disease, efficacy is substantially lower in low- to middle-income settings leading to interest in alternative vaccines. One promising candidate is a trivalent nonreplicating RV vaccine, comprising 3 truncated RV VP8 subunit proteins fused to the P2 CD4+ epitope from tetanus toxin (P2-VP8-P[4/6/8]). A wide variety of analytical techniques were used to compare the physicochemical properties of these 3 recombinant fusion proteins. Various environmental stresses were used to evaluate antigen stability and elucidate degradation pathways. P2-VP8-P[4] and P2-VP8-P[6] displayed similar physical stability profiles as function of pH and temperature while P2-VP8-P[8] was relatively more stable. Forced degradation studies revealed similar chemical stability profiles with Met1 most susceptible to oxidation, the single Cys residue (at position 173/172) forming intermolecular disulfide bonds (P2-VP8-P[6] was most susceptible), and Asn7 undergoing the highest levels of deamidation. These results are visualized in a structural model of the nonreplicating RV antigens. The establishment of key structural attributes of each antigen, along with corresponding stability-indicating methods, have been applied to vaccine formulation development efforts (see companion paper), and will be utilized in future analytical comparability assessments.
| S-EPMC6941226 | biostudies-literature
Project description:Trivalent oral poliovirus vaccine (OPV) is known to interfere with monovalent rotavirus vaccine (RV1) immunogenicity. The interference caused by bivalent and monovalent OPV formulations, which will be increasingly used globally in coming years, has not been examined. We conducted a post hoc analysis to assess the effect of coadministration of different OPV formulations on RV1 immunogenicity.Healthy infants in Matlab, Bangladesh, were randomized to receive 3 doses of monovalent OPV type 1 or bivalent OPV types 1 and 3 at either 6, 8, and 10 or 6, 10, and 14 weeks of age or trivalent OPV at 6, 10, and 14 weeks of age. All infants received 2 doses of RV1 at about 6 and 10 weeks of age. Concomitant administration was defined as RV1 and OPV given on the same day; staggered administration as RV1 and OPV given ?1 day apart. Rotavirus seroconversion was defined as a 4-fold rise in immunoglobulin A titer from before the first RV1 dose to ?3 weeks after the second RV1 dose.There were no significant differences in baseline RV1 immunogenicity among the 409 infants included in the final analysis. Infants who received RV1 and OPV concomitantly, regardless of OPV formulation, were less likely to seroconvert (47%; 95% confidence interval, 39%-54%) than those who received both vaccines staggered ?1 day (63%; 57%-70%; P < .001). For staggered administration, we found no evidence that the interval between RV1 and OPV administration affected RV1 immunogenicity.Coadministration of monovalent, bivalent, or trivalent OPV seems to lower RV1 immunogenicity.NCT01633216.
| S-EPMC4755336 | biostudies-literature
Project description:BACKGROUND:Rotaviruses (RVs) are a major cause of acute children gastroenteritis. The rotavirus P [10] belongs to P[I] genogroup of group A rotaviruses that mainly infect animals, while the rotavirus P [10] was mainly identified from human infection. The rotavirus P [10] is an unusual genotype and the recognition pattern of cellular receptors remains unclear. METHODS:We expressed and purified the RV P [10] VP8* protein and investigated the saliva and oligosaccharide binding profiles of the protein. A homology model of the P [10] VP8* core protein was built and the superimposition structural analysis of P [10] VP8* protein on P [19] VP8* in complex with mucin core 2 was performed to explore the possible docking structural basis of P [10] VP8* and mucin cores. RESULTS:Our data showed that rotavirus P [10] VP8* protein bound to all ABO secretor and non-secretor saliva. The rotavirus P [10] could bind strongly to mucin core 2 and weakly to mucin core 4. The homology modeling indicated that RV P [10] VP8* binds to mucin core 2 using a potential glycan binding site that is the same to P [19] VP8* belonging to P[II] genogroup. CONCLUSION:Our results suggested an interaction of rotavirus P [10] VP8* protein with mucin core 2 and mucin core 4. These findings offer potential for elucidating the mechanism of RV A host specificity, evolution and epidemiology.
| S-EPMC6195756 | biostudies-literature
Project description:Rotaviruses infect cells by delivering into the cytosol a transcriptionally active inner capsid particle (a "double-layer particle": DLP). Delivery is the function of a third, outer layer, which drives uptake from the cell surface into small vesicles from which the DLPs escape. In published work, we followed stages of rhesus rotavirus (RRV) entry by live-cell imaging and correlated them with structures from cryogenic electron microscopy and tomography (cryo-EM and cryo-ET). The virus appears to wrap itself in membrane, leading to complete engulfment and loss of Ca2+ from the vesicle produced by the wrapping. One of the outer-layer proteins, VP7, is a Ca2+-stabilized trimer; loss of Ca2+ releases both VP7 and the other outer-layer protein, VP4, from the particle. VP4, activated by cleavage into VP8* and VP5*, is a trimer that undergoes a large-scale conformational rearrangement, reminiscent of the transition that viral fusion proteins undergo to penetrate a membrane. The rearrangement of VP5* thrusts a 250-residue, C-terminal segment of each of the three subunits outward, while allowing the protein to remain attached to the virus particle and to the cell being infected. We proposed that this segment inserts into the membrane of the target cell, enabling Ca2+ to cross. In the work reported here, we show the validity of key aspects of this proposed sequence. By cryo-EM studies of liposome-attached virions ("triple-layer particles": TLPs) and single-particle fluorescence imaging of liposome-attached TLPs, we confirm insertion of the VP4 C-terminal segment into the membrane and ensuing generation of a Ca2+ "leak". The results allow us to formulate a molecular description of early events in entry. We also discuss our observations in the context of other work on double-strand RNA virus entry.
| S-EPMC11020617 | biostudies-literature