Rational design of a multi-valent human papillomavirus vaccine by capsomere-hybrid co-assembly of virus-like particles.
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ABSTRACT:
SUBMITTER: Wang D
PROVIDER: S-EPMC7275066 | biostudies-literature |
REPOSITORIES: biostudies-literature
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2015-11-02 | E-MTAB-2948 | biostudies-arrayexpress
Project description:BACKGROUND:The 9-valent human papillomavirus vaccine (9vHPV) was approved for females and males aged 9 to 26 years in 2014. We analyzed postlicensure surveillance reports to the Vaccine Adverse Event Reporting System (VAERS). METHODS:We searched VAERS data for US reports of adverse events (AEs) after 9vHPV from December 2014 through December 2017. We calculated reporting rates and conducted empirical Bayesian data mining to identify disproportional reporting. Physicians reviewed reports for selected prespecified conditions. RESULTS:VAERS received 7244 reports after 9vHPV: 31.2% among females, 21.6% among males, and for 47.2%, sex was not reported. Overall, 97.4% of reports were nonserious. Dizziness, syncope, headache, and injection site reactions were most commonly reported; the most commonly reported AEs were similar between females and males. Two reports of death after 9vHPV were verified; no information in autopsy reports or death certificates suggested a causal relationship with vaccination. Approximately 28 million 9vHPV doses were distributed during the study period; crude AE reporting rates were 259 reports per million 9vHPV doses distributed for all reports and 7 per million doses distributed for serious reports. Syncope (a known AE associated with human papillomavirus vaccination) and several types of vaccine administration errors (eg, administered at wrong age) exceeded the statistical threshold for empirical Bayesian data mining findings. CONCLUSIONS:No new or unexpected safety concerns or reporting patterns of 9vHPV with clinically important AEs were detected. The safety profile of 9vHPV is consistent with data from prelicensure trials and from postmarketing safety data of its predecessor, the quadrivalent human papillomavirus vaccine.
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Project description:Sequence variability in surface-antigenic sites of pathogenic proteins is an important obstacle in vaccine development. Over 200 distinct genomic sequences have been identified for human papillomavirus (HPV), of which more than 18 are associated with cervical cancer. Here, based on the high structural similarity of L1 surface loops within a group of phylogenetically close HPV types, we design a triple-type chimera of HPV33/58/52 using loop swapping. The chimeric VLPs elicit neutralization titers comparable with a mix of the three wild-type VLPs both in mice and non-human primates. This engineered region of the chimeric protein recapitulates the conformational contours of the antigenic surfaces of the parental-type proteins, offering a basis for this high immunity. Our stratagem is equally successful in developing other triplet-type chimeras (HPV16/35/31, HPV56/66/53, HPV39/68/70, HPV18/45/59), paving the way for the development of an improved HPV prophylactic vaccine against all carcinogenic HPV strains. This technique may also be extrapolated to other microbes.
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Project description:Feline infectious peritonitis (FIP) is a grave and frequently lethal ailment instigated by feline coronavirus (FCoV) in wild and domestic feline species. The spike (S) protein of FCoV assumes a critical function in viral ingress and infection, thereby presenting a promising avenue for the development of a vaccine. In this investigation, an immunoinformatics approach was employed to ascertain immunogenic epitopes within the S-protein of FIP and formulate an innovative vaccine candidate. By subjecting the amino acid sequence of the FIP S-protein to computational scrutiny, MHC-I binding T-cell epitopes were predicted, which were subsequently evaluated for their antigenicity, toxicity, and allergenicity through in silico tools. Our analyses yielded the identification of 11 potential epitopes capable of provoking a robust immune response against FIPV. Additionally, molecular docking analysis demonstrated the ability of these epitopes to bind with feline MHC class I molecules. Through the utilization of suitable linkers, these epitopes, along with adjuvants, were integrated to design a multi-epitope vaccine candidate. Furthermore, the stability of the interaction between the vaccine candidate and feline Toll-like receptor 4 (TLR4) was established via molecular docking and molecular dynamics simulation analyses. This suggests good prospects for future experimental validation to ascertain the efficacy of our vaccine candidate in inducing a protective immune response against FIP.
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Project description:Vaccination against human papillomavirus (HPV) has been progressively implemented in most developed countries for approximately 10 years. In order to increase the protection of the vaccines, a 9-valent vaccine (HPV9) was developed, which provides protection against nine types of the virus. Studies evaluating its safety are rare. Thus, we performed a meta-analysis of three clinical trials assessing adverse effects on women randomly vaccinated with HPV9 or tetravalent vaccine (HPV4), with the objective of analyzing whether the HPV9 is as safe as HPV4. An electronic data search was performed through the PubMed, Embase, Scopus, Web of Science, and SciELO databases. The studies selected 27,465 women who received one of the two vaccines. Pain (OR 1.72; 95% CI 1.62-1.82) and erythema (OR 1.29; 95% CI 1.21-1.36) occurred significantly more in the HPV9 group. However, there was no significant difference between the groups for the following adverse effects: headache (OR 1.07; 95% CI 0.99-1.15), dizziness (OR 1.09; 95% CI 0.93-1.27), and fatigue (OR 1.09; 95% CI 0.91-1.30), and the occurrence of serious events related to vaccination was similarly rare among those vaccinated. Therefore, our findings demonstrate that HPV9 in female patients is as safe as the tetravalent vaccine.
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Project description:Bacteriophage Qbeta coat protein forms uniform virus-like particles when expressed recombinantly in a variety of organisms. We have inserted the IgG-binding Z domain at the carboxy terminus of the coat protein and coexpressed this chimeric subunit with native coat protein to create hybrid, IgG-binding virus-like particles. Extracellular osmolytes were found to have an effect on the efficiency of incorporation of fusion proteins into VLPs in Escherichia coli when a carbenicillin, but not a kanamycin, selection marker was used. The addition of sucrose to the growth medium decreased the incorporation efficiency; the osmoprotectant glycine betaine eliminated this effect. The decrease in efficiency was not observed when carbenicillin was omitted from the final expression culture. The addition of sodium chloride instead of sucrose gave rise to particles with a larger number of fusion proteins than the standard conditions. These results illustrate that cellular conditions should be taken into account even in apparently simple systems when natural or engineered protein nanoparticles are made.
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Project description:BackgroundWe estimated the potential impact and cost-effectiveness of providing 3-doses of nonavalent human papillomavirus (HPV) vaccine (9vHPV) to females aged 13-18 years who had previously completed a series of quadrivalent HPV vaccine (4vHPV), a strategy we refer to as "additional 9vHPV vaccination."MethodsWe used 2 distinct models: (1) the simplified model, which is among the most basic of the published dynamic HPV models, and (2) the US HPV-ADVISE model, a complex, stochastic, individual-based transmission-dynamic model.ResultsWhen assuming no 4vHPV cross-protection, the incremental cost per quality-adjusted life-year (QALY) gained by additional 9vHPV vaccination was $146 200 in the simplified model and $108 200 in the US HPV-ADVISE model ($191 800 when assuming 4vHPV cross-protection). In 1-way sensitivity analyses in the scenario of no 4vHPV cross-protection, the simplified model results ranged from $70 300 to $182 000, and the US HPV-ADVISE model results ranged from $97 600 to $118 900.ConclusionsThe average cost per QALY gained by additional 9vHPV vaccination exceeded $100 000 in both models. However, the results varied considerably in sensitivity and uncertainty analyses. Additional 9vHPV vaccination is likely not as efficient as many other potential HPV vaccination strategies, such as increasing primary 9vHPV vaccine coverage.
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Project description:Human papillomavirus (HPV) occurs in many types, some of which cause cervical, genital, and other cancers. While vaccination is available against the major cancer-causing HPV types, many others are not covered by these preventive measures. Herein, we present a bioinformatics study for the designing of multivalent peptide vaccines against multiple HPV types as an alternative strategy to the virus-like particle vaccines being used now. Our technique of rational design of peptide vaccines is expected to ensure stability of the vaccine against many cycles of mutational changes, elicit immune response, and negate autoimmune possibilities. Using the L1 capsid protein sequences, we identified several peptides for potential vaccine design for HPV 16, 18, 33, 35, 45, and 11 types. Although there are concerns about the epitope-binding affinities for the peptides identified in this process, the technique indicates possibilities of multivalent, adjuvanted, peptide vaccines against a wider range of HPV types, and tailor-made different combinations of the peptides to address frequency variations of types over different population groups as required for prophylaxis and at lower cost than are in use at the present time.
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Project description:We developed an epitope selection method for the design of MHC targeting peptide vaccines. The method utilizes predictions for several clinical checkpoint filters, including binding affinity, immunogenicity, antigenicity, half-life, toxicity, IFNγ release, and instability. The accuracy of the prediction tools for these filter variables was confirmed using experimental data obtained from the Immune Epitope Database (IEDB). We also developed a graphical user interface computational tool called 'PCOptim' to assess the success of an epitope filtration method. To validate the filtration methods, we used a large data set of experimentally determined, immunogenic SARS-CoV-2 epitopes, which were obtained from a meta-analysis. The validation process proved that placing filters on individual parameters was the most effective method to select top epitopes. For a proof-of-concept, we designed epitope-based vaccine candidates for squamous cell carcinoma, selected from the top mutated epitopes of the HRAS gene. By comparing the filtered epitopes to PCOptim's output, we assessed the success of the epitope selection method. The top 15 mutations in squamous cell carcinoma resulted in 16 CD8 epitopes which passed the clinical checkpoints filters. Notably, the identified HRAS epitopes are the same as the clinical immunogenic HRAS epitope-based vaccine candidates identified by the previous studies. This indicates further validation of our filtration method. We expect a similar turn-around for the other designed HRAS epitopes as a vaccine candidate for squamous cell carcinoma. Furthermore, we obtained a world population coverage of 89.45% for the top MHC Class I epitopes and 98.55% population coverage in the absence of the IFNγ release clinical checkpoint filter. We also identified some of the predicted human epitopes to be strong binders to murine MHC molecules, which provides insight into studying their immunogenicity in preclinical models. Further investigation in murine models could warrant the application of these epitopes for treatment or prevention of squamous cell carcinoma.
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