scholarly journals A Nanoparticle-Based Trivalent Vaccine Targeting the Glycan Binding VP8* Domains of Rotaviruses

Viruses ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 72
Author(s):  
Ming Xia ◽  
Pengwei Huang ◽  
Xi Jiang ◽  
Ming Tan
Keyword(s):  
Low Income ◽  
Vaccine Candidate ◽  
Rotavirus Vaccine ◽  
Vaccine Production ◽  
Binding Function ◽  
Severe Gastroenteritis ◽  
New Type ◽  
Health Need ◽  
Trivalent Vaccine ◽  
Promising Vaccine Candidate

Rotavirus causes severe gastroenteritis in children. Although vaccines are implemented, rotavirus-related diarrhea still claims ~200,000 lives annually worldwide, mainly in low-income settings, pointing to a need for improved vaccine tactics. To meet such a public health need, a P24-VP8* nanoparticle displaying the glycan-binding VP8* domains, the major neutralizing antigens of rotavirus, was generated as a new type of rotavirus vaccine. We reported here our development of a P24-VP8* nanoparticle-based trivalent vaccine. First, we established a method to produce tag-free P24-VP8* nanoparticles presenting the VP8*s of P[8], P[4], and P[6] rotaviruses, respectively, which are the three predominantly circulating rotavirus P types globally. This approach consists of a chemical-based protein precipitation and an ion exchange purification, which may be scaled up for large vaccine production. All three P24-VP8* nanoparticle types self-assembled efficiently with authentic VP8*-glycan receptor binding function. After they were mixed as a trivalent vaccine, we showed that intramuscular immunization of the vaccine elicited high IgG titers specific to the three homologous VP8* types in mice. The resulted mouse sera strongly neutralized replication of all three rotavirus P types in cell culture. Thus, the trivalent P24-VP8* nanoparticles are a promising vaccine candidate for parenteral use against multiple P types of predominant rotaviruses.

scholarly journals Reduction in severity of all-cause gastroenteritis requiring hospitalisation in children vaccinated against rotavirus in Malawi

2021 ◽  
Author(s):  
Jonathan J Mandolo ◽  
Marc Henrion ◽  
Chimwemwe Mhango ◽  
End Chinyama ◽  
Richard Wachepa ◽  
...  
Keyword(s):  
Low Income ◽  
Severity Score ◽  
Age Groups ◽  
Rotavirus Vaccine ◽  
Low Income Country ◽  
Arm Circumference ◽  
Severity Scores ◽  
Severe Gastroenteritis ◽  
One Year ◽  
Mid Upper Arm Circumference

Background: Rotavirus is the major cause of severe gastroenteritis in children aged <5 years. Introduction of Rotarix rotavirus vaccine (RV1) in Malawi in 2012 has reduced rotavirus-associated hospitalisations and diarrhoeal mortality. However, RV1 impact on gastroenteritis severity remains unknown. We conducted a hospital-based surveillance study to assess RV1 impact on gastroenteritis severity in children aged <5 years, in Malawi. Methods: Stool samples were collected from children hospitalised with acute gastroenteritis from December 2011 to October 2019. Gastroenteritis severity was determined using Ruuska and Vesikari scores. Rotavirus was detected in stool using Enzyme Immunoassay. Rotavirus genotypes were determined using nested RT-PCR. Associations between RV1 vaccination and gastroenteritis severity were investigated using adjusted linear regression. Results: In total, 3,159 children were recruited. After adjusting for Mid-Upper Arm Circumference, age, weight, gender and receipt of other vaccines, all-cause gastroenteritis severity scores were 2.21 units lower (95% CI 1.85, 2.56; p<0.001) among RV1-vaccinated (n=2,224) compared to RV1-unvaccinated children (n=935); the decrease was comparable between rotavirus-positive and rotavirus-negative cases in all age groups. The reduction in severity score was observed against every rotavirus genotype, although the magnitude was smaller among those infected with G12P[6] compared to the remaining genotypes (p=0.011). Other than RV1 vaccination, age was the only variable associated with gastroenteritis severity. Each one-year increment in age was associated with a decrease of 0.43 severity score (95% CI 0.26, 0.60; p<0.001). Conclusion: Our findings provide additional evidence of RV1 impact in a high disease burden, low-income country, lending further support to rotavirus vaccine programme in Malawi.

Attenuation of a human rotavirus vaccine candidate did not correlate with mutations in the NSP4 protein gene.

1997 ◽  
Vol 71 (8) ◽  
pp. 6267-6270 ◽  
Author(s):  
R L Ward ◽  
B B Mason ◽  
D I Bernstein ◽  
D S Sander ◽  
V E Smith ◽  
...  
Keyword(s):  
Protein Gene ◽  
Vaccine Candidate ◽  
Rotavirus Vaccine ◽  
Human Rotavirus ◽  
Nsp4 Protein

scholarly journals The Rotavirus Vaccine Landscape, an Update

Pathogens ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 520
Author(s):  
Roberto Cárcamo-Calvo ◽  
Carlos Muñoz ◽  
Javier Buesa ◽  
Jesús Rodríguez-Díaz ◽  
Roberto Gozalbo-Rovira
Keyword(s):  
Developing Countries ◽  
Mortality Rate ◽  
Low Income ◽  
State Of The Art ◽  
The State ◽  
Cold Chain ◽  
Low Income Countries ◽  
Rotavirus Vaccine ◽  
Oral Vaccines

Rotavirus is the leading cause of severe acute childhood gastroenteritis, responsible for more than 128,500 deaths per year, mainly in low-income countries. Although the mortality rate has dropped significantly since the introduction of the first vaccines around 2006, an estimated 83,158 deaths are still preventable. The two main vaccines currently deployed, Rotarix and RotaTeq, both live oral vaccines, have been shown to be less effective in developing countries. In addition, they have been associated with a slight risk of intussusception, and the need for cold chain maintenance limits the accessibility of these vaccines to certain areas, leaving 65% of children worldwide unvaccinated and therefore unprotected. Against this backdrop, here we review the main vaccines under development and the state of the art on potential alternatives.

Protection Studies in Colostrum-Deprived Piglets of a Bovine Rotavirus Vaccine Candidate Using Human Rotavirus Strains for Challenge

1983 ◽  
Vol 148 (6) ◽  
pp. 1061-1068 ◽  
Author(s):  
G. Zissis ◽  
J. P. Lambert ◽  
P. Marbebant ◽  
D. Marissens ◽  
M. Lobmann ◽  
...  
Keyword(s):  
Vaccine Candidate ◽  
Rotavirus Vaccine ◽  
Bovine Rotavirus ◽  
Human Rotavirus

scholarly journals A Chimeric Protein That Functions as both an Anthrax Dual-Target Antitoxin and a Trivalent Vaccine

2010 ◽  
Vol 54 (11) ◽  
pp. 4750-4757 ◽  
Author(s):  
Gaobing Wu ◽  
Yuzhi Hong ◽  
Aizhen Guo ◽  
Chunfang Feng ◽  
Sha Cao ◽  
...  
Keyword(s):  
Protective Antigen ◽  
Vaccine Candidate ◽  
Lethal Factor ◽  
Lethal Dose ◽  
Chimeric Protein ◽  
Dominant Negative ◽  
Lethal Challenge ◽  
Edema Factor ◽  
Trivalent Vaccine

ABSTRACT Effective measures for the prophylaxis and treatment of anthrax are still required for counteracting the threat posed by inhalation anthrax. In this study, we first demonstrated that the chimeric protein LFn-PA, created by fusing the protective antigen (PA)-binding domain of lethal factor (LFn) to PA, retained the functions of the respective molecules. On the basis of this observation, we attempted to develop an antitoxin that targets the binding of lethal factor (LF) and/or edema factor (EF) to PA and the transportation of LF/EF. Therefore, we replaced PA in LFn-PA with a dominant-negative inhibitory PA (DPA), i.e., PAF427D. In in vitro models of anthrax intoxication, the LFn-DPA chimera showed 3-fold and 2-fold higher potencies than DPA in protecting sensitive cells against anthrax lethal toxin (LeTx) and edema toxin (EdTx), respectively. In animal models, LFn-DPA exhibited strong potency in rescuing mice from lethal challenge with LeTx. We also evaluated the immunogenicity and immunoprotective efficacy of LFn-DPA as an anthrax vaccine candidate. In comparison with recombinant PA, LFn-DPA induced significantly higher levels of the anti-PA immune response. Moreover, LFn-DPA elicited an anti-LF antibody response that could cross-react with EF. Mice immunized with LFn-DPA tolerated a LeTx challenge that was 5 times its 50% lethal dose. Thus, LFn-DPA represents a highly effective trivalent vaccine candidate for both preexposure and postexposure vaccination. Overall, we have developed a novel and dually functional reagent for the prophylaxis and treatment of anthrax.

scholarly journals Simultaneous Immunization with Multivalent Norovirus VLPs Induces Better Protective Immune Responses to Norovirus than Sequential Immunization

Viruses ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1018
Author(s):  
Maria Malm ◽  
Timo Vesikari ◽  
Vesna Blazevic
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Antibody Response ◽  
Vaccine Candidate ◽  
Serum Antibodies ◽  
Blocking Antibody ◽  
Alternative Approach ◽  
Sequential Boost ◽  
Trivalent Vaccine ◽  
Rotavirus Vp6

Human noroviruses (NoVs) are a genetically diverse, constantly evolving group of viruses. Here, we studied the effect of NoV pre-existing immunity on the success of NoV vaccinations with genetically close and distant genotypes. A sequential immunization as an alternative approach to multivalent NoV virus-like particles (VLPs) vaccine was investigated. Mice were immunized with NoV GI.3, GII.4-1999, GII.17, and GII.4 Sydney as monovalent VLPs or as a single tetravalent mixture combined with rotavirus VP6-protein. Sequentially immunized mice were primed with a trivalent vaccine candidate (GI.3 + GII.4-1999 + VP6) and boosted, first with GII.17 and then with GII.4 Sydney VLPs. NoV serum antibodies were analyzed. Similar NoV genotype-specific immune responses were induced with the monovalent and multivalent mixture immunizations, and no immunological interference was observed. Multivalent immunization with simultaneous mix was found to be superior to sequential immunization, as sequential boost induced strong blocking antibody response against the distant genotype (GII.17), but not against GII.4 Sydney, closely related to GII.4-1999, contained in the priming vaccine. Genetically close antigens may interfere with the immune response generation and thereby immune responses may be differently formed depending on the degree of NoV VLP genotype identity.

scholarly journals Evaluating strategies to improve rotavirus vaccine impact during the second year of life in Malawi

2019 ◽  
Vol 11 (505) ◽  
pp. eaav6419 ◽  
Author(s):  
Virginia E. Pitzer ◽  
Aisleen Bennett ◽  
Naor Bar-Zeev ◽  
Khuzwayo C. Jere ◽  
Benjamin A. Lopman ◽  
...  
Keyword(s):  
Low Income ◽  
Transmission Rate ◽  
Natural Infection ◽  
Vaccine Effectiveness ◽  
Low Income Countries ◽  
Rotavirus Vaccine ◽  
Second Year Of Life ◽  
Vaccine Impact ◽  
Second Year ◽  
Induced Immunity

Rotavirus vaccination has substantially reduced the incidence of rotavirus-associated gastroenteritis (RVGE) in high-income countries, but vaccine impact and estimated effectiveness are lower in low-income countries for reasons that are poorly understood. We used mathematical modeling to quantify rotavirus vaccine impact and investigate reduced vaccine effectiveness, particularly during the second year of life, in Malawi, where vaccination was introduced in October 2012 with doses at 6 and 10 weeks. We fitted models to 12 years of prevaccination data and validated the models against postvaccination data to evaluate the magnitude and duration of vaccine protection. The observed rollout of vaccination in Malawi was predicted to lead to a 26 to 77% decrease in the overall incidence of moderate-to-severe RVGE in 2016, depending on assumptions about waning of vaccine-induced immunity and heterogeneity in vaccine response. Vaccine effectiveness estimates were predicted to be higher among 4- to 11-month-olds than 12- to 23-month-olds, even when vaccine-induced immunity did not wane, due to differences in the rate at which vaccinated and unvaccinated individuals acquire immunity from natural infection. We found that vaccine effectiveness during the first and second years of life could potentially be improved by increasing the proportion of infants who respond to vaccination or by lowering the rotavirus transmission rate. An additional dose of rotavirus vaccine at 9 months of age was predicted to lead to higher estimated vaccine effectiveness but to only modest (5 to 16%) reductions in RVGE incidence over the first 3 years after introduction, regardless of assumptions about waning of vaccine-induced immunity.

scholarly journals A critical role for 14-3-3ζ protein in regulating the VWF binding function of platelet glycoprotein Ib-IX and its therapeutic implications

Blood ◽  
2005 ◽  
Vol 106 (6) ◽  
pp. 1975-1981 ◽  
Author(s):  
Kesheng Dai ◽  
Richard Bodnar ◽  
Michael C. Berndt ◽  
Xiaoping Du
Keyword(s):  
Platelet Adhesion ◽  
Critical Role ◽  
Antiplatelet Agent ◽  
Inhibitory Effect ◽  
Platelet Glycoprotein ◽  
Therapeutic Implications ◽  
Binding Function ◽  
Platelet Receptor ◽  
New Type ◽  
Von Willebrand

Abstract The platelet receptor for von Willebrand factor (VWF), glycoprotein (GP) Ib-IX, mediates platelet adhesion and activation. The cytoplasmic domains of the GPIb α and β subunits contain binding sites for the phosphorylation-dependent signaling molecule, 14-3-3ζ. Here we show that a novel membrane-permeable inhibitor of 14-3-3ζ-GPIbα interaction, MPαC, potently inhibited VWF binding to platelets and VWF-mediated platelet adhesion under flow conditions. MPαC also inhibited VWF-dependent platelet agglutination induced by ristocetin. Furthermore, activation of the VWF binding function of GPIb-IX induced by GPIbβ dephosphorylation is diminished by mutagenic disruption of the 14-3-3ζ binding site in the C-terminal domain of GPIbα, mimicking MPαC-induced inhibition, indicating that the inhibitory effect of MPαC is likely to be caused by disruption of 14-3-3ζ binding to GPIbα. These data suggest a novel 14-3-3ζ-dependent regulatory mechanism that controls the VWF binding function of GPIb-IX, and also suggest a new type of antiplatelet agent that may be potentially useful in preventing or treating thrombosis.

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