The challenges of creating a universal influenza vaccine

The lack of population immunity to the periodically emerging pandemic influenza strains makes influenza infection especially dangerous. The fragmented nature of the influenza virus genome contributes to the formation of influenza virus reassortants containing genomic fragments from different strains. This mechanism is the main reason for the natural influenza virus antigenic diversity as well as for the occurrence of influenza pandemics. Vaccination is the best measure to prevent the spread of influenza infection, but the efficacy of existing vaccines is not sufficient, especially for the elderly and small children. Specific immunity, developed after disease or immunization, poorly protects against infection by influenza viruses of another subtype. In this regard, there is an urgent need for a more effective universal influenza vaccine that provides a long-lasting broad cross-protective immunity, and is able to protect against influenza A and B viruses of all known subtypes. The basic approaches to as well as challenges of creating such a vaccine are discussed in this review.The lack of population immunity to the periodically emerging pandemic influenza strains makes influenza infection especially dangerous. The fragmented nature of the influenza virus genome contributes to the formation of influenza virus reassortants containing genomic fragments from different strains. This mechanism is the main reason for the natural influenza virus antigenic diversity as well as for the occurrence of influenza pandemics. Vaccination is the best measure to prevent the spread of influenza infection, but the efficacy of existing vaccines is not sufficient, especially for the elderly and small children. Specific immunity, developed after disease or immunization, poorly protects against infection by influenza viruses of another subtype. In this regard, there is an urgent need for a more effective universal influenza vaccine that provides a long-lasting broad cross-protective immunity, and is able to protect against influenza A and B viruses of all known subtypes. The basic approaches to as well as challenges of creating such a vaccine are discussed in this review

Enhanced CD8+ T-cell response in mice immunized with NS1-truncated influenza virus

Influenza viruses with truncated NS1 protein stimulate a more intensive innate immune response compared to their wild type counterparts. Here, we investigate how the shortening of the NS1 protein influence the immunogenicity of the conserved T-cellular epitopes of influenza virus. Using flow cytometry, we showed that the intraperitoneal immunization of mice with influenza virus encoding 124 N-terminal amino acid residues of the NS1 protein (A/PR8/NS124) induced higher levels of CD8+ T-cells recognizing immunodominant (NP366-374) and sub-immunodominant (NP161-175, NP196-210, HA323-337, HA474-483, NA427-433) epitopes compared to immunization with the virus expressing full-length NS1 (A/PR8/full NS). It is noteworthy that the response to the immunodominant influenza epitope NP366-374 was achieved with the lower immunization dose of A/PR8/NS124 virus compared to the reference wild type strain. Despite the fact that polyfunctional CD8+ effector memory T-lymphocytes simultaneously producing two (IFNγ and TNFα) or three (IFNγ, IL2, and TNFα) cytokines prevailed in the immune response to both viruses, the relative number of such T-cells was higher in A/PR8/NS124-immunized mice. Furthermore, we have found that polyfunctional populations of lymphocytes generated upon the immunization of mice with the mutant virus demonstrated an increased capacity to produce IFNγ compared to the corresponding populations derived from the A/PR8/full NS-immunized mice. Therefore, immunization with the attenuated influenza virus encoding truncated NS1 protein ensures a more potent CD8+ T-cell immune response.Influenza viruses with truncated NS1 protein stimulate a more intensive innate immune response compared to their wild type counterparts. Here, we investigate how the shortening of the NS1 protein influence the immunogenicity of the conserved T-cellular epitopes of influenza virus. Using flow cytometry, we showed that the intraperitoneal immunization of mice with influenza virus encoding 124 N-terminal amino acid residues of the NS1 protein (A/PR8/NS124) induced higher levels of CD8+ T-cells recognizing immunodominant (NP366-374) and sub-immunodominant (NP161-175, NP196-210, HA323-337, HA474-483, NA427-433) epitopes compared to immunization with the virus expressing full-length NS1 (A/PR8/full NS). It is noteworthy that the response to the immunodominant influenza epitope NP366-374 was achieved with the lower immunization dose of A/PR8/NS124 virus compared to the reference wild type strain. Despite the fact that polyfunctional CD8+ effector memory T-lymphocytes simultaneously producing two (IFNγ and TNFα) or three (IFNγ, IL2, and TNFα) cytokines prevailed in the immune response to both viruses, the relative number of such T-cells was higher in A/PR8/NS124-immunized mice. Furthermore, we have found that polyfunctional populations of lymphocytes generated upon the immunization of mice with the mutant virus demonstrated an increased capacity to produce IFNγ compared to the corresponding populations derived from the A/PR8/full NS-immunized mice. Therefore, immunization with the attenuated influenza virus encoding truncated NS1 protein ensures a more potent CD8+ T-cell immune response

Enhancement of the immunogenicity of influenza A virus by the inhibition of immunosuppressive function of NS1 protein

The truncation of the nonstructural NS1 protein is a novel approach for the generation of immunogenic attenuated influenza viruses. However, the innate immune mechanisms that cause the increased immunogenicity of influenza viruses with altered NS1 proteins are poorly understood. The goal of this study was to compare the immune responses in mice immunized with two variants of the influenza A/Puerto Rico/8/1934 (A/PR8) virus: the wild type virus (А/PR8/full NS) and the variant with the NS1 protein shortened to 124 amino acid residues (А/PR8/NS124). The investigated parameters of immunity included cytokine production, the dynamic variation of the innate immune cell populations, and the rate of the influenza-specific T-cell responses. An intraperitoneal route of immunization was chosen due to the variability in the replication capacity of the investigated viruses in the respiratory tract. The levels of interferon β (IFNβ), tumor necrosis factor α (TNFα), monocyte chemo-attractant protein 1 (MCP1), interleukin 6 (IL6), and IL27 in peritoneal washings of mice immunized with А/PR8/NS124 were significantly higher compared to the mice immunized with the wild-type virus. The А/PR8/NS124 treated group showed a delayed attraction of monocytes and neutrophils as well as a more pronounced reduction in the percentage of dendritic cells in the peritoneal cavity. The expression level of the CD86 activation marker on the cells expressing the molecules of the major histocompatibility complex II (MHCII+) was significantly higher in mice immunized with А/PR8/NS124 than in the group immunized with А/PR8/full NS. Finally, immunization with А/PR8/NS124 led to an increased formation of influenza-specific CD8+ effector T-cells characterized by the simultaneous production of IFNγ, IL2, and TNFα. We hypothesize that elevated cytokine production, enhanced dendritic cell migration, and increased CD86 expression on antigen-presenting cells upon immunization with А/PR8/NS124 lead to a more effective presentation of viral antigens and, therefore, promote an increased antigen-specific CD8+ immune response.The truncation of the nonstructural NS1 protein is a novel approach for the generation of immunogenic attenuated influenza viruses. However, the innate immune mechanisms that cause the increased immunogenicity of influenza viruses with altered NS1 proteins are poorly understood. The goal of this study was to compare the immune responses in mice immunized with two variants of the influenza A/Puerto Rico/8/1934 (A/PR8) virus: the wild type virus (А/PR8/full NS) and the variant with the NS1 protein shortened to 124 amino acid residues (А/PR8/NS124). The investigated parameters of immunity included cytokine production, the dynamic variation of the innate immune cell populations, and the rate of the influenza-specific T-cell responses. An intraperitoneal route of immunization was chosen due to the variability in the replication capacity of the investigated viruses in the respiratory tract. The levels of interferon β (IFNβ), tumor necrosis factor α (TNFα), monocyte chemo-attractant protein 1 (MCP1), interleukin 6 (IL6), and IL27 in peritoneal washings of mice immunized with А/PR8/NS124 were significantly higher compared to the mice immunized with the wild-type virus. The А/PR8/NS124 treated group showed a delayed attraction of monocytes and neutrophils as well as a more pronounced reduction in the percentage of dendritic cells in the peritoneal cavity. The expression level of the CD86 activation marker on the cells expressing the molecules of the major histocompatibility complex II (MHCII+) was significantly higher in mice immunized with А/PR8/NS124 than in the group immunized with А/PR8/full NS. Finally, immunization with А/PR8/NS124 led to an increased formation of influenza-specific CD8+ effector T-cells characterized by the simultaneous production of IFNγ, IL2, and TNFα. We hypothesize that elevated cytokine production, enhanced dendritic cell migration, and increased CD86 expression on antigen-presenting cells upon immunization with А/PR8/NS124 lead to a more effective presentation of viral antigens and, therefore, promote an increased antigen-specific CD8+ immune response

Multi-domain active sound control and noise shielding

This paper describes an active sound control methodology based on difference potentials. The main feature of this methodology is its ability to automatically preserve “wanted” sound within a domain while canceling “unwanted” noise from outside the domain. This method of preservation of the wanted sounds by active shielding control is demonstrated with various broadband and realistic sound sources such as human voice and music in multiple domains in a one-dimensional enclosure. Unlike many other conventional active control methods, the proposed approach does not require the explicit characterization of the wanted sound to be preserved. The controls are designed based on the measurements of the total field on the boundaries of the shielded domain only, which is allowed to be multiply connected. The method is tested in a variety of experimental cases. The typical attenuation of the unwanted noise is found to be about 20 dB over a large area of the shielded domain and the original wanted sound field is preserved with errors of around 1 dB and below through a broad frequency range up to 1 kHz. © 2011 Acoustical Society of Americ

Search for Sterile Neutrinos with a Radioactive Source at Daya Bay

The far site detector complex of the Daya Bay reactor experiment is proposed as a location to search for sterile neutrinos with > eV mass. Antineutrinos from a 500 kCi 144Ce-144Pr beta-decay source (DeltaQ=2.996 MeV) would be detected by four identical 20-ton antineutrino targets. The site layout allows flexible source placement; several specific source locations are discussed. In one year, the 3+1 sterile neutrino hypothesis can be tested at essentially the full suggested range of the parameters Delta m^2_{new} and sin^22theta_{new} (90% C.L.). The backgrounds from six nuclear reactors at >1.6 km distance are shown to be manageable. Advantages of performing the experiment at the Daya Bay far site are described

REFINED MODEL OF THE OPTICAL SYSTEM FOR SPACE MINI-VEHICLES WITH LASER PROPULSION

Simulation results for on-board optical system of a space mini-vehicle with laser propulsion are presented. This system gives the possibility for receiving theremote laser radiation power independently of a system telescope mutual orientation to the vehicle orbiting direction. The on-board optical system is designed with the use of such optical elements as optical hinges and turrets. The system incorporates the optical switch that is a special optical system adapting optically both receiving telescope and laser propulsion engines. Modeling and numerical simulation of the system have been performed with the use of ZEMAX software (Radiant Ltd). The object matter of calculations lied in size definition of system optical elements, requirements to accuracy of their manufacturing and reciprocal adjusting to achieve an efficient radiation energy delivery to laser propulsion engine. Calculations have been performed with account to the limitations on the mini-vehicle mass, its overall dimensions, and radiation threshold density of the optical elements utilized. The requirements to the laser beam quality at the entrance aperture of laser propulsion engine have been considered too. State-of-the-art optical technologies make it possible to manufacture space reflectors made of CO-115M glassceramics with weight-reducing coefficient of 0.72 and the radiation threshold of 5 J/cm2 for the radiation with a 1.064 microns wavelength at 10-20 ns pulse duration. The optimal diameter of a receiving telescope primary mirror has been 0.5 m when a coordinated transmitting telescope diameter is equal to 1 m. This provides the reception of at least 84% of laser energy. The main losses of radiation energy are caused by improper installation of receiving telescope mirrors and by in-process errors arising at manufacturing the telescope mirrors with a parabolic surface. It is shown that requirements to the in-process admissible errors for the on-board optical system elements and to their mutual adjustment accuracy are enhanced, but they are feasible at the same time. The proposed onboard optical system are usable both for space mini-vehicle with laser propulsion and for wireless technology of energy delivery through space with the use of lasers

Проблема создания универсальной противогриппозной вакцины

Periodically emerging new influenza strains along with the lack of population immunity to these new viruses can lead to a pandemic, making influenza infection especially dangerous. The fragmented nature of the influenza virus genome contributes to the formation of influenza virus reassortants containing genomic fragments from different strains. This mechanism is one of the reasons for the existing influenza virus antigenic diversity in nature and the occurrence of influenza pandemics. Vaccination is the best measure to prevent the spread of influenza infection, however, the efficacy of existing vaccines is not sufficient, especially for the elderly and small children. Specific immunity developed after disease or immunization poorly protects against infection by influenza viruses of another subtype. In this regard, there is an urgent need for a more effective universal influenza vaccine that provides a long-lasting wide cross-protective immunity, and is able to resist to influenza A and B viruses of all known subtypes. Basic approaches and challenges in creating such a vaccine are discussed in this review.Периодически появляющиеся новые пандемические штаммы вируса гриппа А, к которым отсутствует популяционный иммунитет, превращают грипп в особо опасную инфекцию. Сегментированная природа генома вируса гриппа способствует образованию реассортантов – вирусов, в состав которых входят геномные сегменты разных штаммов, принадлежащих одному роду. Именно механизм реассортации является основной причиной антигенного разнообразия вирусов гриппа в природе и появления штаммов, вызывающих пандемии в человеческой популяции. Лучшим средством предотвращения распространения гриппозной инфекции считается вакцинация. Однако эффективность известных на сегодняшний день вакцин недостаточна, особенно при иммунизации пожилых людей и маленьких детей. Специфический иммунитет, вырабатываемый после перенесенного заболевания или вакцинации одним подтипом вируса гриппа, слабо защищает от инфекции вирусом другого подтипа. В связи с этим не потерял актуальности вопрос разработки эффективной универсальной гриппозной вакцины, которая будет индуцировать широкий кросс-протективный длительный иммунитет как к вирусам гриппа А различных подтипов, так и к вирусам гриппа В. Основные подходы к созданию такой вакцины и проблемы их реализации рассматриваются в данном обзоре

Spin light of neutrino in gravitational fields

We predict a new mechanism for the spin light of neutrino ($SL\nu$) that can be emitted by a neutrino moving in gravitational fields. This effect is studied on the basis of the quasiclassical equation for the neutrino spin evolution in a gravitational field. It is shown that the gravitational field of a rotating object, in the weak-field limit, can be considered as an axial vector external field which induces the neutrino spin procession. The corresponding probability of the neutrino spin oscillations in the gravitational field has been derived for the first time. The considered in this paper $SL\nu$ can be produced in the neutrino spin-flip transitions in gravitational fields. It is shown that the total power of this radiation is proportional to the neutrino gamma factor to the fourth power, and the emitted photon energy, for the case of an ultra relativistic neutrino, could span up to gamma-rays. We investigate the $SL\nu$ caused by both gravitational and electromagnetic fields, also accounting for effects of arbitrary moving and polarized matter, in various astrophysical environments. In particular, we discuss the $SL\nu$ emitted by a neutrino moving in the vicinity of a rotating neutron star, black hole surrounded by dense matter, as well as by a neutrino propagating in the relativistic jet from a quasar.Comment: 14 pages in LaTex with 1 eps figure; derivation of the neutrino spin oscillations probability in gravitational fields and several clarifying notes are added, typos correcte

Silver-doped Calcium Phosphate bone cements with antibacterial properties

Calcium phosphate bone cements (CPCs) with antibacterial properties are demanded for clinical applications. In this study, we demonstrated the use of a relatively simple processing route based on preparation of silver-doped CPCs (CPCs-Ag) through the preparation of solid dispersed active powder phase. Real-time monitoring of structural transformations and kinetics of several CPCs-Ag formulations (Ag = 0 wt %, 0.6 wt % and 1.0 wt %) was performed by the Energy Dispersive X-ray Diffraction technique. The partial conversion of β-tricalcium phosphate (TCP) phase into the dicalcium phosphate dihydrate (DCPD) took place in all the investigated cement systems. In the pristine cement powders, Ag in its metallic form was found, whereas for CPC-Ag 0.6 wt % and CPC-Ag 1.0 wt % cements, CaAg(PO₃)₃ was detected and Ag (met.) was no longer present. The CPC-Ag 0 wt % cement exhibited a compressive strength of 6.5 ± 1.0 MPa, whereas for the doped cements (CPC-Ag 0.6 wt % and CPC-Ag 1.0 wt %) the reduced values of the compressive strength 4.0 ± 1.0 and 1.5 ± 1.0 MPa, respectively, were detected. Silver-ion release from CPC-Ag 0.6 wt % and CPC-Ag 1.0 wt % cements, measured by the Atomic Emission Spectroscopy, corresponds to the average values of 25 µg/L and 43 µg/L, respectively, rising a plateau after 15 days. The results of the antibacterial test proved the inhibitory effect towards pathogenic Escherichia coli for both CPC-Ag 0.6 wt % and CPC-Ag 1.0 wt % cements, better performances being observed for the cement with a higher Ag-content