Identification of Putative Vaccine and Drug Targets against the Methicillin-Resistant Staphylococcus aureus by Reverse Vaccinology and Subtractive Genomics Approaches

Methicillin-resistant Staphylococcus aureus (MRSA) is an opportunistic pathogen and responsible for causing life-threatening infections. The emergence of hypervirulent and multidrug-resistant (MDR) S. aureus strains led to challenging issues in antibiotic therapy. Consequently, the morbidity and mortality rates caused by S. aureus infections have a substantial impact on health concerns. The current worldwide prevalence of MRSA infections highlights the need for long-lasting preventive measures and strategies. Unfortunately, effective measures are limited. In this study, we focus on the identification of vaccine candidates and drug target proteins against the 16 strains of MRSA using reverse vaccinology and subtractive genomics approaches. Using the reverse vaccinology approach, 4 putative antigenic proteins were identified; among these, PrsA and EssA proteins were found to be more promising vaccine candidates. We applied a molecular docking approach of selected 8 drug target proteins with the drug-like molecules, revealing that the ZINC4235426 as potential drug molecule with favorable interactions with the target active site residues of 5 drug target proteins viz., biotin protein ligase, HPr kinase/phosphorylase, thymidylate kinase, UDP-N-acetylmuramoyl-L-alanyl-D-glutamate-L-lysine ligase, and pantothenate synthetase. Thus, the identified proteins can be used for further rational drug or vaccine design to identify novel therapeutic agents for the treatment of multidrug-resistant staphylococcal infection.     

Correlates with Vaccine Protective Capacity and COVID-19 Disease Symptoms Identified by Serum Proteomics in Vaccinated Individuals

In the last two years, the coronavirus disease 19 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a scientific and social challenge worldwide. Vaccines have been the most effective intervention for reducing virus transmission and disease severity. However, genetic virus variants are still circulating among vaccinated individuals with different disease symptomatology. Understanding the protective- or disease-associated mechanisms in vaccinated individuals is relevant to advances in vaccine development and implementation. To address this objective, serum-protein profiles were characterized by quantitative proteomics and data-analysis algorithms in four cohorts of uninfected and SARS-CoV-2-infected vaccinated individuals with asymptomatic, non-severe, and severe disease symptomatology. The results show that immunoglobulins were the most overrepresented proteins in infected cohorts when compared to PCR-negative individuals. The immunoglobulin profile varied between different infected cohorts and correlated with protective- or disease-associated capacity. Overrepresented immunoglobulins in PCR-positive individuals correlated with protective response against SARS-CoV-2, other viruses, and thrombosis in asymptomatic cases. In non-severe cases, correlates of protection against SARS-CoV-2 and HBV together with risk of myasthenia gravis and allergy and autoantibodies were observed. Patients with severe symptoms presented risk for allergy, chronic idiopathic thrombocytopenic purpura, and autoantibodies. The analysis of underrepresented immunoglobulins in PCR-positive compared to PCR-negative individuals identified vaccine-induced protective epitopes in various coronavirus proteins, including the spike receptor-binding domain RBD. Non-immunoglobulin proteins were associated with COVID-19 symptoms and biological processes. These results evidence host-associated differences in response to vaccination and the possibility of improving vaccine efficacy against SARS-CoV-2.     

Studies on the Interaction Mechanism between the mRNA Vaccine against SARS-CoV-2 and the Immune System

Vaccines are an effective tool in the fight against infectious diseases. However, mathematical models of SARS-CoV-2 focus on the macroscopic situation, while articles on vaccines focus on effectiveness and safety. We develop four mathematical models to investigate the immune system and the microdynamics of antigens and viruses in individuals injected with mRNA vaccines. We first theoretically analyze the optimal model, calculate all equilibria, and prove that the disease-free equilibrium is globally asymptotically stable while the others are unstable. This suggests that after a certain period after vaccination, the infected cells and antigens will no longer exist in vivo and will be eliminated by the immune system over time or will die naturally. This theoretically proves the safety of the mRNA vaccines. Then, we use the differential algebra to analyze the structural identifiability of the models. We find that two of them are globally identifiable while the other two are unidentifiable, but once a certain parameter is fixed, then they are identifiable as well. To select the optimal model among four models, we use the Affine Invariant Ensemble Markov Chain Monte Carlo algorithm for data fitting and parameter estimation. We find that the roles of memory cells in killing infected cells and promoting immune cells and neutralizing antibodies in the process of mRNA vaccination are not significant and can be ignored in the modeling. On the other hand, the innate immunity of the human body plays an important role in this process. In addition, we also analyze the practical identifiability of the parameters of the optimal model. The results show that even if the structure of the system is globally identifiable, it does not ensure that all the parameters are practically identifiable. After random sampling and simulating the four unidentifiable parameters, we find that only two variables, infected cells II and antibodies, are sensitive to these unidentifiable parameters, but the results are still within acceptable ranges. This suggests that our fitting results are generally reliable. Finally, we simulate multiple booster injections and find that booster injections are indeed effective in maintaining antibody levels in vivo, which could otherwise gradually die off over time. Therefore, booster injections are beneficial to help the human body increase and maintain immunity.     

Apoferritin nanoparticle based dual-antigen influenza conjugate vaccine with potential cross-protective efficacy against heterosubtypic influenza virus

Ferritin nanoparticles with self-assembling properties have been widely explored as vaccine carrier by displaying foreign antigens through genetic fusion strategy. In the present work, an apoferritin (AFt) nanoparticle was tested as influenza vaccine carrier by chemically conjugating a matrix protein 2 ectodomain (M2e) antigen peptide or/and the full-length hemagglutinin (HA) antigen on the outer surface of the AFt, with heterobifunctional sSMCC or SM(PEG)24 containing PEG chain as linkers. To each AFt nanoparticle, about 30–32 M2e or 1.8 HA antigen could be coupled. The AFt-(PEG)₂₄-M2e, in which the M2e was coupled through SM(PEG)24 containing PEG chain, conferred higher protective efficacy in immunized mice than AFt-M2e did, but was less effective than AFt-(PEG)₂₄-HA. When both M2e and HA were coupled, the synthesized dual-antigen vaccine candidate AFt-(PEG)₂₄-M2e/HA elicited high level of M2e and HA antigen-specific antibodies and conferred 100% protection against lethal infection of homologous PR8 H1N1 virus strain and 70% protection against a heterologous A/FM/1/47 (FM1, H1N1) strain, which was more effective than the M2e or HA single antigen vaccine candidates. The potential cross-protective effect of the dual-antigen vaccine was further demonstrated by significant specific hemagglutination inhibition (HAI) titers in serum of the immunized mice against three other heterologous viral strains including A/Singapore/GP1908/2015 (IVR-180) H1N1, A/Anhui/1/2005 H5N1, and A/Hong Kong H3N2.     

Psychological and behavioral effects in epidemiological model with imperfect vaccination compartment

The aim of this paper is to investigate the dynamic of two SEIVS models, which incorporate an imperfect vaccination compartment. In this paper, we focus on the psychological inhibition effect of vaccinated individuals and the efficacy of vaccine on the spread of disease. For the susceptible individuals, we consider the psychological inhibition effect through the nonmonotone incidence rate. We find the disease‐free and the disease persistent conditions. We also give some numerical simulations to demonstrate the effect of behavioral change of the vaccinated individuals and the efficiency of vaccine. Copyright © 2015 John Wiley & Sons, Ltd.     

人丙型肝炎病毒研究进展

扼要介绍了近年来ＨＣＶ研究的进展，包括病毒形态、基因组结构、病毒蛋白质及其加工、病毒流行病学、病毒与肝癌关系、病毒抗体检测试剂的发展及疫苗研究，并对抗体检测试剂的发展趋势和目前疫苗研究中的问题进行了分析．     

Immunization Schedule of Liposomal Rabies Vaccine in Animals

The standard rabies vaccines recommended by WHO include Essen regimen, the Thai Red Cross two-site ID regimen and the eight-site ID regimen, and so on. The present schedules of rabies vaccine are all laborious and time consuming. We developed a new rabies vaccine with liposome as adjuvant(LipoRabV) and found that liposome could facilitate the inactivated rabies vaccine(RabV) to induce the more vigorous production of rabies virus neutra-lizing antibody(RVNA) in BALB/c mice and beagles. We established preliminary pre-and post-exposure prophylaxis schedules for LipoRabV. LipoRabV(0/14) could elicit similar RVNA level as RabV(0/7/28) by pre-exposure prophy-laxis schedules in mice and beagles. LipoRabV(0/3/14) could elicit higher RVNA level vs. RabV(0/3/7/14/28) in BALB/c. The data indicate that the three-shot liposome-enhanced rabies vaccine could achieve a higher protection rate(survival rate 56.2%) by post-exposure prophylaxis compared with that of the RabV group(survival rate 40.6%) in mice. The data also indicate that the three-inoculation liposome-enhanced rabies vaccine could achieve a survival rate of 80.0% vs. RabV(70.0%) by post-exposure prophylaxis in beagles. The results show that the immunization schedule for LipoRabV could be preliminarily determined at 0 and 14 d for pre-exposure prophylaxis and at 0, 3 and 14 d for post-exposure prophylaxis.     

Immunogenicity and Efficacy of Liposome-encapsulated Influenza Split Vaccine in BALB/c Mice

The cellular immunity of current influenza split vaccine is relatively low. It is necessary to develop a novel vaccine to improve the cellular immunity. Thes of this study prepared liposome-encapsulated influenza split vaccine and tested it in BALB/c mice. The mice were immunized once with 4 μg of haemagglutinin of monovalent A/New Caledonia/20/99(H1N1) encapsulated with liposomes or the split virus vaccine only through intrastomach injection. In a comparative study, it was observed that the liposome-encapsulated vaccine elicited a higher neutralizing antibody response, more effectively stimulated spleen cell proliferation, increased cell subsets like CD4 and CD4 /CD8 , and triggered IL-4 and IFN-γ production.     

日本血吸虫26ku谷胱甘肽S－转移酶Sj26抗原肽研究

多肽疫苗;日本血吸虫26ku谷胱甘肽S－转移酶Sj26抗原肽研究