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The most effective measure to induce protection from influenza is vaccination. Thus, yearly vaccination is recommended, which, together with infections, establishes diverse repertoires of B cells, antibodies, and T cells. We examined the impact of this accumulated immunity on human responses in adults to split, subunit, and recombinant protein-based influenza vaccines. Enzyme-linked immunosorbent assay (ELISA) assays, to quantify serum antibodies, and peptide-stimulated CD4 T-cell cytokine ELISpots revealed that preexisting levels of hemagglutinin (HA)-specific antibodies were negatively associated with gains in antibody postvaccination, while preexisting levels of CD4 T cells were negatively correlated with vaccine-induced expansion of CD4 T cells. These patterns were seen independently of the vaccine formulation administered and the subjects' influenza vaccine history. Thus, although memory CD4 T cells and serum antibodies consist of components that can enhance vaccine responses, on balance, the accumulated immunity specific for influenza A H1 and H3 proteins is associated with diminished future responses. [ABSTRACT FROM AUTHOR]

Repeated infections with endemic human coronaviruses (hCoV) are thought to reflect lack of long-lasting protective immunity. We evaluated circulating human CD4 T cells collected prior to 2020 for reactivity towards hCoV spike proteins, probing for the ability to produce interferon-γ, interleukin-2, or granzyme B. We found robust reactivity to spike-derived epitopes, comparable to influenza, but highly variable abundance and functional potential across subjects, depending on age and viral antigen specificity. To explore potential of these memory cells to be recruited in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we examined the subjects for cross-reactive recognition of epitopes from SARS-CoV-2 nucleocapsid, membrane/envelope, and spike. Functional potential of these cross-reactive CD4 T cells was highly variable; nucleocapsid-specific CD4 T cells but not spike-reactive cells showed exceptionally high levels of granzyme production upon stimulation. These results are considered in light of recruitment of hCoV-reactive cells into responses to SARS-CoV infections or vaccinations. [ABSTRACT FROM AUTHOR]

Despite the benefits of yearly influenza vaccination, accumulating evidence suggests that diminished vaccine efficacy may be related to repeated vaccination. Although studied at the level of B-cell responses, CD4 T-cell responses have not yet been examined. In this study, we analyze CD4 T-cell responses to influenza vaccination in subjects who differ in their vaccine history. We find a striking disparity in their responses, with previously vaccinated subjects exhibiting significantly blunted CD4 T-cell responses and diminished antibody responses. These results suggest that limiting CD4 T-cell help mteaserrlie the diminished or altered antibody responses in repeatedly vaccinated subjects. [ABSTRACT FROM AUTHOR]

Potentially pandemic strains of influenza pose an undeniable threat to human populations. Therefore, it is essential to develop better strategies to enhance vaccine design and predict parameters that identify susceptible humans. CD4 T cells are a central component of protective immunity to influenza, delivering direct effector function and potentiating responses of other lymphoid cells. Humans have highly diverse influenza-specific CD4 T-cell populations that vary in stimulation history, specificity, and functionality. These complexities constitute a formidable obstacle to predicting immune responses to pandemic strains of influenza and derivation of optimal vaccine strategies. We suggest that more precise efforts to identify and enumerate both the positive and negative contributors of immunity in the CD4 T-cell compartment will aid in both predicting susceptible hosts and in development of vaccination strategies that will poise most human subjects to respond to pandemic influenza strains with protective immune responses. [ABSTRACT FROM AUTHOR]

There is limited information on the antigen specificity and functional potential of the influenza virus-specific CD4+ T-cell repertoire in humans. Here, enzyme-linked immunospot assays were used to examine circulating CD4+ T-cell specificities for influenza virus directly ex vivo in healthy adults. Our studies revealed CD4+ T-cell reactivity to multiple influenza virus proteins, including hemagglutinins, neuraminidases, M1 proteins, and nucleoproteins. Unexpectedly, the immunodominance hierarchies and functional potential of cells reactive toward influenza A virus were distinct from those toward influenza B virus. We also identified influenza virus-specific cells producing granzyme B. Our findings revealed individual and virus-specific patterns that may differentially poise humans to respond to infection or vaccination. [ABSTRACT FROM AUTHOR]

The emergence of avian H7N9 viruses has raised concerns about its pandemic potential and prompted vaccine trials. At present, it is unknown whether there will be sufficient cross-reactive hemagglutinin (HA)-specific CD4 T-cell memory with seasonal influenza to facilitate antibody production to H7 HA. There has also been speculation that H7N9 will have few CD4 T-cell epitopes. In this study, we quantified the potential of seasonal influenza to provide memory CD4 T cells that can cross-reactively recognize H7 HA-derived peptides. These studies have revealed that many humans have substantial H7-reactive CD4 T cells, whereas up to 40% are lacking such reactivity. Correlation studies indicate that CD4 T cells reactive with H7 HA are drawn from reactivity generated from seasonal strains. Overall, our findings suggest that previous exposure of humans to seasonal influenza can poise them to respond to avian H7N9, but this is likely to be uneven across populations. [ABSTRACT FROM AUTHOR]

Introduction. Previous priming with avian influenza vaccines results in more rapid and more robust neutralizing antibody responses upon revaccination, but the role CD4+ T cells play in this process is not currently known. Methods. Human subjects previously enrolled in trials of inactivated influenza A(H5N1) vaccines and naive subjects were immunized with an inactivated subunit influenza A/Indonesia/5/05(H5N1) vaccine. Neutralizing antibody responses were measured by a microneutralization assay, and hemagglutinin (HA)-specific and nucleoprotein (NP)-specific CD4+ T-cell responses were quantified using interferon γ enzyme-linked immunosorbent spot assays. Results. While vaccination induced barely detectable CD4+ T-cell responses specific for HA in the previously unprimed group, primed subjects had readily detectable HA-specific memory CD4+ T cells at baseline and mounted a more robust response to HA-specific epitopes after vaccination. There were no differences between groups when conserved NP-specific CD4+ T-cell responses were examined. Interestingly, neutralizing antibody responses following revaccination were significantly higher in individuals who mounted a CD4+ T-cell response to the H5 HA protein, a correlation not observed for NP-specific responses. Conclusions. These findings suggest that prepandemic vaccination results in an enriched population of HA-specific CD4+ T cells that are recruited on rechallenge with a drifted vaccine variant and contribute to more robust and more rapid neutralizing antibody responses. [ABSTRACT FROM AUTHOR]

Background. The ability of influenza vaccines to elicit CD4+ T cells and the relationship between induction of CD4+ T cells and vaccine-induced neutralizing antibody responses has been controversial. The emergence of swine-origin 2009 pandemic influenza A virus subtype H1N1 (A[H1N1]pdm09) provided a unique opportunity to examine responses to an influenza vaccine composed of both novel and previously encountered antigens and to probe the relationship between B-cell and T-cell responses to vaccination.Methods. We tracked CD4+ T-cell and antibody responses of human subjects vaccinated with monovalent subunit A(H1N1)pdm09 vaccine. The specificity and magnitude of the CD4+ T-cell response was evaluated using cytokine enzyme-linked immunosorbent spot assays in conjugation with peptide pools representing distinct influenza virus proteins.Results. Our studies revealed that vaccination induced readily detectable CD4+ T cells specific for conserved portions of hemagglutinin (HA) and the internal viral proteins. Interestingly, expansion of HA-specific CD4+ T cells was most tightly correlated with the antibody response.Conclusions. These results indicate that CD4+ T-cell expansion may be a limiting factor in development of neutralizing antibody responses to pandemic influenza vaccines and suggest that approaches to facilitate CD4+ T-cell recruitment may increase the neutralizing antibody produced in response to vaccines against novel influenza strains. [ABSTRACT FROM AUTHOR]

Introduction: Previous priming with avian influenza vaccines results in more rapid and more robust neutralizing antibody responses upon revaccination, but the role CD4(+) T cells play in this process is not currently known., Methods: Human subjects previously enrolled in trials of inactivated influenza A(H5N1) vaccines and naive subjects were immunized with an inactivated subunit influenza A/Indonesia/5/05(H5N1) vaccine. Neutralizing antibody responses were measured by a microneutralization assay, and hemagglutinin (HA)-specific and nucleoprotein (NP)-specific CD4(+) T-cell responses were quantified using interferon γ enzyme-linked immunosorbent spot assays., Results: While vaccination induced barely detectable CD4(+) T-cell responses specific for HA in the previously unprimed group, primed subjects had readily detectable HA-specific memory CD4(+) T cells at baseline and mounted a more robust response to HA-specific epitopes after vaccination. There were no differences between groups when conserved NP-specific CD4(+) T-cell responses were examined. Interestingly, neutralizing antibody responses following revaccination were significantly higher in individuals who mounted a CD4(+) T-cell response to the H5 HA protein, a correlation not observed for NP-specific responses., Conclusions: These findings suggest that prepandemic vaccination results in an enriched population of HA-specific CD4(+) T cells that are recruited on rechallenge with a drifted vaccine variant and contribute to more robust and more rapid neutralizing antibody responses., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)