Both Humoral and Cellular Immunity Limit the Ability of Live Attenuated Influenza Vaccines to Promote T Cell Responses
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Abstract One potential advantage of live attenuated influenza vaccines (LAIVs) is their ability to establish both virus-specific Ab and tissue-resident memory T cells (TRM) in the respiratory mucosa. However, it is hypothesized that pre-existing immunity from past infections and/or immunizations prevents LAIV from boosting or generating de novo CD8+ T cell responses. To determine whether we can overcome this limitation, we generated a series of drifted influenza A/PR8 LAIVs with successive mutations in the hemagglutinin protein, allowing for increasing levels of escape from pre-existing Ab. We also inserted a CD8+ T cell epitope from the Sendai virus nucleoprotein (NP) to assess both generation of a de novo T cell response and boosting of pre-existing influenza-specific CD8+ T cells following LAIV immunization. Increasing the level of escape from Ab enabled boosting of pre-existing TRM, but we were unable to generate de novo Sendai virus NP+ CD8+ TRM following LAIV immunization in PR8 influenza-immune mice, even with LAIV strains that can fully escape pre-existing Ab. As these data suggested a role for cell-mediated immunity in limiting LAIV efficacy, we investigated several scenarios to assess the impact of pre-existing LAIV-specific TRM in the upper and lower respiratory tract. Ultimately, we found that deletion of the immunodominant influenza NP366–374 epitope allowed for sufficient escape from cellular immunity to establish de novo CD8+ TRM. When combined, these studies demonstrate that both pre-existing humoral and cellular immunity can limit the effectiveness of LAIV, which is an important consideration for future design of vaccine vectors against respiratory pathogens.Keywords:
Cellular immunity
Monoclonal antibody 2F5 recognizing the ELDKWA epitope on HIV-1 gp41 has a significant neutralization potency against 90% of the investigated viruses of African, Asian, American, and European strains, but the antibody responses to the epitope 2F5 in HIV-1-infected individuals were very low. We attempted to induce high levels of epitope-specific antibodies to ELDKWA and its three mutated epitopes by candidate epitope vaccines. The four candidate epitope vaccines all induced strong antibody responses at dilutions from about 1:6,400 to 1:25,600. We tested the cross-reactions between these antisera and four epitope peptides. The ELDKWA-specific antisera showed strong cross-reactivity with three neutralizing-resistant mutated epitopes which contain changes in the D or K positions of the epitope sequence. Virus variants containing these changes could escape neutralization by monoclonal antibody 2F5. In immunoblotting analysis, the ELDKWA, ELDEWA, and ELEKWA epitope specific antibodies all recognized rsgp41 which confirms that the antibodies against both mutated epitopes, ELDEWA and ELEKWA, could cross-react with the native epitope on rsgp41. Although it is not clear whether the polyclonal antibodies induced by the ELDKWA epitope vaccine could neutralize the mutated viruses containing these mutated epitopes, it is conceivable that epitope vaccines based on mutated epitopes could induce strong antibody responses with predefined epitope specificity to neutralize mutated viruse containing the mutated epitope. An epitope vaccine, using different epitopes including mutated epitopes, could provide a new concept for developing a new vaccine against HIV-1.
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Polyclonal antibodies
Epitope mapping
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Despite a publicly funded immunization program and continuous promotional efforts, vaccine uptake for seasonal influenza in Quebec (Canada) remains under its goal of 80%. Missed opportunities can explain the low influenza vaccine rates among chronically ill children. To address that, demonstration projects using the live attenuated influenza vaccine (LAIV) were implemented in 3 pediatric tertiary care hospitals to evaluate the feasibility and acceptability of implementing influenza immunization of chronically ill children in hospitals' outpatient clinics. A diary was used to document barriers and enabling factors regarding the implementation, and a questionnaire was distributed to healthcare professionals involved in the project in each hospital. Parent's knowledge, attitudes and behaviors (KAB) about influenza immunization and acceptability of immunization in outpatient clinics were also measured with a questionnaire. As part of the project, 2,478 children were immunized. Enabling factors included the financial support received from Quebec ministry of Health, the nasal mode of administration of the LAIV and the presence of a leader specifically dedicated to influenza immunization. Barriers to influenza immunization in outpatient clinics included difficulties of hiring extra staff to work in immunization clinics and additional tasks added to regular activities of the clinics. Results from both questionnaires illustrated a high level of acceptability of seasonal influenza immunization in hospitals' outpatient clinics by parents and healthcare professionals. Influenza immunization in pediatric tertiary care hospital is an effective way to reach chronically ill children and does not involve major feasibility or acceptability issues.
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Epitope-vaccine is a newly developing vaccine which has many advantages comparied with to the traditional vaccine.The key step for designing epitope-vaccine is to screen epitopes.The epitope-screening methods include protein degration,peptide-probing scanning,epitope prediction by computer,et al.Usually,the epitope-vaccine needs combine some carriers to display immunologic activity,for example,lipid carriers,protein carriers,and adjuvant.In addition,researchers also use tandem repeat epitopes,conformational multiple antigen peptide(MAP) and epitope modifying to strengthen the immunological efficacity.The epitope-vaccine mainly contains viral epitope-vaccine,bacterial epitope-vaccine and epitope-vaccine for parasites.Although the researches on epitope-vaccine develop fast,some problems and challenges need to resolve impendingly.
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Abstract Objective An influenza pandemic may demand that a large number of influenza immunizations be rapidly given with limited resources. This study tested the utility and practicality of self-immunization with live attenuated influenza intranasal vaccine in a mass vaccination event. Methods The self-immunization clinic model was evaluated in a three-tiered fashion using student, first responder, and open community events. Results A single nurse was easily able to direct 89 people through the process of self-administration of the vaccine in a three-hour first-responder event and 122 people in a three-hour open community event. 96% of participants believed that they had performed the self-administration correctly, and the same percentage reported that they would like to receive influenza immunization by self-vaccination in the future. Conclusions The self-immunization clinic is a practical and potentially useful model in an influenza pandemic setting.
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A single antigen (SA) Luminex beads assay was used to detect antibody specificities of allosera and monoclonal antibodies. Potential antibody epitopes were mapped by comparing the protein sequence differences of a group of HLA alleles that are either recognized or unrecognized by tested samples. A total of 61 epitopes, including 43 one amino acid (AA) epitopes, 11 two AA epitopes, and 7 epitopes with more than two residues involved, were identified. Among 38 residues constituting DR epitopes, 26 of them located in beta1 domain and 12 located in beta2 domain. Only 42% of beta1 domain epitopes are surface residues, while 83% of beta2 domain epitopes are on an antigen surface. These findings imply that some polymorphic AA residues, especially those on beta1 domain, may be indirectly involved in antibody-antigen interactions. In conclusion, sequence comparison following SA beads tests provides an ideal approach for epitope identification of HLA-specific antibody. Certainly, these identified potential epitopes need to be further proved or disproved by other approaches, such as absorption/elution from SA beads or cell lines, each of which contains unique epitope pattern.
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Purpose of review To provide an update of current recommendations and research findings on universal annual influenza immunization of children. Recent findings The Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention and the American Academy of Pediatrics now recommend annual influenza vaccination for all children 6 months through 18 years. New research has examined the effect of 'herd immunity' associated with immunizing all school-aged children, the suboptimal antigenic match between the trivalent vaccine strains and circulating virus strains of last 2007–2008 influenza season, the efficacy of live attenuated influenza vaccine versus trivalent inactivated influenza vaccine, and the tolerance for influenza vaccine in infants less than 6 months of age. With a goal of improving the overall rates of influenza immunization and an eye toward the anticipated increase in volume with expansion of the universal recommendations in children, Advisory Committee on Immunization Practices and American Academy of Pediatrics emphasize the value of extending the timeframe for immunization beyond December and into April, establishing school-based immunization programs and other alternative vaccination sites outside medical homes, and conducting large, population-based studies that examine the overall impact of universal childhood influenza immunization. Summary Annual influenza vaccination recommendations have been expanded, and research continues on vaccine efficacy, administration, and cost associated with vaccinating all school-aged children.
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Linear epitope
Epitope mapping
Immunofluorescence
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Keyhole limpet hemocyanin
Epitope mapping
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Linear epitope
Bovine herpesvirus 1
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