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It is known that for achieving high affinity antibody responses, vaccines must be optimized for antigen dose/density, and the prime/boost interval should be at least 4 weeks. Similar knowledge is lacking for generating high avidity T‐cell responses. The functional avidity (FA) of T cells, describing responsiveness to peptide, is associated with the quality of effector function and the protective capacity in vivo. Despite its importance, the FA is rarely determined in T‐cell vaccination studies. We addressed the question whether different time intervals for short‐term homologous vaccinations impact the FA of CD8 T‐cell responses. Four‐week instead of 2‐week intervals between priming and boosting with potent subunit vaccines in C57BL/6 mice did not improve FA. Equally, similar FA was observed after vaccination with virus‐like particles displaying low versus high antigen densities. Interestingly, FA was stable in vivo but not in vitro, depending on the antigen dose and the time interval since T‐cell activation, as observed in murine monoclonal T cells. Our findings suggest dynamic in vivo modulation for equal FA. We conclude that low antigen density vaccines or a minimal 4‐week prime/boost interval are not crucial for the T‐cell's FA, in contrast to antibody responses. [ABSTRACT FROM AUTHOR]

Background: Influenza A(H5N1) virus and other avian influenza virus strains represent major pandemic threats. Like all influenza A virus strains, A(H5N1) viruses evolve rapidly. Innovative immunization strategies are needed to induce cross-protective immunity.Methods: Subjects primed with clade 1 H5 antigen, with or without adjuvant, and H5-naive individuals were boosted with clade 2 H5 antigen. The impact of priming on T cells capable of both proliferation and cytokine production after antigen restimulation was assessed.Results: Subjects previously vaccinated with clade 1 H5 antigen developed significantly enhanced clade 2 H5 cross-reactive T cell responses detectable 6 months after vaccination with clade 2 H5 antigen. Priming dose (15 µg vs 45 or 90 µg) had no effect on magnitude of heterotypic H5 T cell responses. In contrast, age at priming negatively modulated both the magnitude and duration of heterotypic H5 T cell responses. Elderly subjects developed significantly less heterotypic H5 T cell boosting, predominantly for T cells capable of cytokine production. Adjuvant had a positive albeit weaker effect than age. The magnitude of CD4(+) interferon-γ producing T cells correlated with H5 antibody responses.Conclusions: H5 heterotypic priming prior to onset of an A(H5N1) pandemic may increase magnitude and duration of immunity against a newly drifted pandemic H5 virus. [ABSTRACT FROM AUTHOR]

Vaccines against the HIV-1 virus offer the best hope for eliminating HIV-associated mortality. Recombinant adenovector type 5 (rAd5) vaccine is a potential candidate for preventive vaccine strategies. In this study, we evaluated the rAd5 prime/protein boost strategy in a murine model. We used rAd5 harboring single HIV-1 genes. These genes, including gag (p24) and exon1 of tat, were amplified from HIV-1 (clade A) RNA using nested PCR. Recombinant vectors were constructed, purified and then injected at 1012 viral particles into four groups, each comprising five mice. The groups were each assigned to receive one of rAd5 prime/protein boost Gag, Tat with and without recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF), and rAd5 with and without genes. The humoral responses were evaluated using ELISA and cellular immune responses checked by cell proliferation and ELISpot assays (IL-2, IL-4 and IFN-γ). It was shown that compared with the rAd5 injection alone, the rAd5 prime/protein boost plan increased cellular immunity (p= 0.009) as well as humoral immunity (p= 0.009). Moreover, rGM-CSF as an adjuvant enhanced cell-mediated immunity and increased IL-4 expression (p=0.032). The results revealed that the simultaneous use of multiple antigens and heterologous prime/boost strategy can enhance both humoral and cellular immune systems. Moreover, subcutaneous injection of rGM-CSF increases IL-4 production and shifts the immune pattern to Th2. These strategies can potentially be used to develop an efficient HIV-1 vaccine. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) is a worldwide problem which does not have an effective vaccine and more than 170 million people worldwide are chronically infected by HCV. T cell responses are associated with spontaneous clearance of HCV infection. We report here the development of recombinant Lambda bacteriophage nanoparticles encoding HCV Core antigen. The aim of this study was to investigate the antigen-specific immune responses triggered in mice by different prime-boost combinations of DNA and Lambda phage nanoparticles encoding the HCV Core. The homologous prime/boost with recombinant Lambda nanoparticles induced higher levels of cellular and humoral immune response than the DNA vaccines. However, a heterologous prime/boost of HCV Core protein, using DNA vaccine priming followed by Lambda boost, induced highest level of lymphocyte proliferation, CD8 lymphocytes with cytotoxic function, and shifting the immune response toward a T helper (Th1) pattern and in overall improved immunity. Our study provides a new, safe, and effective vaccine for the prime-boost regimen which augments robust immunity and highlights novel promising strategies in HCV vaccine development. [ABSTRACT FROM AUTHOR]

Background: We explored the concept of heterologous prime/boost vaccination using 2 therapeutic vaccines currently in clinical development aimed at treating chronically infected hepatitis C virus (HCV) patients: prime with a DNA-based vaccine expressing HCV genotype 1a NS3/4A proteins (ChronVac-C) and boost with a modified vaccinia virus Ankara vaccine expressing genotype 1b NS3/4/5B proteins (MVATG16643).Methods: Two ChronVac-C immunizations 4 weeks apart were delivered intramuscularly in combination with in vivo electroporation and subsequently 5 or 12 weeks later boosted by 3 weekly subcutaneous injections of MVATG16643. Two mouse strains were used, and we evaluated quality, magnitude, and functionality of the T cells induced.Results: DNA prime/MVA boost regimen induced significantly higher levels of interferon γ (IFN-γ) or interleukin 2 (IL-2) ELISpot responses compared with each vaccine alone, independent of the time of analysis and the time interval between vaccinations. Both CD8⁺ and CD4⁺ T-cell responses as well as the spectrum of epitopes recognized was improved. A significant increase in polyfunctional IFN-γ/tumor necrosis factor α (TNF-α)/CD107a⁺ CD8⁺ T cells was detected following ChronVac-C/MVATG16643 vaccination (from 3% to 25%), and prime/boost was the only regimen that activated quadrifunctional T cells (IFN-γ/TNF-α/CD107a/IL-2). In vivo functional protective capacity of DNA prime/MVA boost was demonstrated in a Listeria-NS3-1a challenge model.Conclusions: We provide a proof-of-concept that immunogenicity of 2 HCV therapeutic vaccines can be improved using their combination, which merits further clinical development. [ABSTRACT FROM AUTHOR]

Background. We explored the concept of heterologous prime/boost vaccination using 2 therapeutic vaccines currently in clinical development aimed at treating chronically infected hepatitis C virus (HCV) patients: prime with a DNA-based vaccine expressing HCV genotype 1a NS3/4A proteins (ChronVac-C) and boost with a modified vaccinia virus Ankara vaccine expressing genotype 1b NS3/4/5B proteins (MVATG16643).Methods. Two ChronVac-C immunizations 4 weeks apart were delivered intramuscularly in combination with in vivo electroporation and subsequently 5 or 12 weeks later boosted by 3 weekly subcutaneous injections of MVATG16643. Two mouse strains were used, and we evaluated quality, magnitude, and functionality of the T cells induced.Results. DNA prime/MVA boost regimen induced significantly higher levels of interferon γ (IFN-γ) or interleukin 2 (IL-2) ELISpot responses compared with each vaccine alone, independent of the time of analysis and the time interval between vaccinations. Both CD8+ and CD4+ T-cell responses as well as the spectrum of epitopes recognized was improved. A significant increase in polyfunctional IFN-γ/tumor necrosis factor α (TNF-α)/CD107a+ CD8+ T cells was detected following ChronVac-C/MVATG16643 vaccination (from 3% to 25%), and prime/boost was the only regimen that activated quadrifunctional T cells (IFN-γ/TNF-α/CD107a/IL-2). In vivo functional protective capacity of DNA prime/MVA boost was demonstrated in a Listeria-NS3-1a challenge model.Conclusions. We provide a proof-of-concept that immunogenicity of 2 HCV therapeutic vaccines can be improved using their combination, which merits further clinical development. [ABSTRACT FROM PUBLISHER]

Development of a vaccine against HIV remains a major target goal in the field. The recent success of mRNA vaccines against the coronavirus SARS-CoV-2 is pointing out a new era of vaccine designs against pathogens. Here, we have generated two types of mRNA vaccine candidates against HIV-1; one based on unmodified vectors and the other on 1-methyl-3′-pseudouridylyl modified vectors expressing a T cell multiepitopic construct including protective conserved epitopes from HIV-1 Gag, Pol and Nef proteins (referred to as RNA-TMEP and RNA-TMEPmod, respectively) and defined their biological and immunological properties in cultured cells and in mice. In cultured cells, both mRNA vectors expressed the corresponding protein, with higher levels observed in the unmodified mRNA, leading to activated macrophages with differential induction of innate immune molecules. In mice, intranodal administration of the mRNAs induced the activation of specific T cell (CD4 and CD8) responses, and the levels were markedly enhanced after a booster immunization with the poxvirus vector MVA-TMEP expressing the same antigen. This immune activation was maintained even three months later. These findings revealed a potent combined immunization regimen able to enhance the HIV-1-specific immune responses induced by an mRNA vaccine that might be applicable to human vaccination programs with mRNA and MVA vectors. [ABSTRACT FROM AUTHOR]