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Introduction: Currently, several universal/broadly protective influenza virus vaccine candidates are under development. Many of these vaccines are based on strategies to induce protective antibody responses against the surface glycoproteins of antigenically and genetically diverse influenza viruses. These strategies might also be applicable to surface glycoproteins of a broad range of other important viral pathogens. Areas covered: Common strategies include sequential vaccination with divergent antigens, multivalent approaches, vaccination with glycan-modified antigens, vaccination with minimal antigens and vaccination with antigens that have centralized/optimized sequences. Here we review these strategies and the underlying concepts. Furthermore, challenges, feasibility and applicability to other viral pathogens are discussed. Expert commentary: Several broadly protective/universal influenza virus vaccine strategies will be tested in humans in the coming years. If successful in terms of safety and immunological readouts, they will move forward into efficacy trials. In the meantime, successful vaccine strategies might also be applied to other antigenically diverse viruses of concern. [ABSTRACT FROM PUBLISHER]

Current influenza virus vaccines contain H1N1 (phylogenetic group 1 hemagglutinin), H3N2 (phylogenetic group 2 hemagglutinin), and influenza B virus components. These vaccines induce good protection against closely matched strains by predominantly eliciting antibodies against the membrane distal globular head domain of their respective viral hemagglutinins. This domain, however, undergoes rapid antigenic drift, allowing the virus to escape neutralizing antibody responses. The membrane proximal stalk domain of the hemagglutinin is much more conserved compared to the head domain. In recent years, a growing collection of antibodies that neutralize a broad range of influenza virus strains and subtypes by binding to this domain has been isolated. Here, we demonstrate that a vaccination strategy based on the stalk domain of the H3 hemagglutinin (group 2) induces in mice broadly neutralizing anti-stalk antibodies that are highly cross-reactive to heterologous H3, H10, H14, H15, and H7 (derived from the novel Chinese H7N9 virus) hemagglutinins. Furthermore, we demonstrate that these antibodies confer broad protection against influenza viruses expressing various group 2 hemagglutinins, including an H7 subtype. Through passive transfer experiments, we show that the protection is mediated mainly by neutralizing antibodies against the stalk domain. Our data suggest that, in mice, a vaccine strategy based on the hemagglutinin stalk domain can protect against viruses expressing divergent group 2 hemagglutinins. [ABSTRACT FROM AUTHOR]

When signals are presented on the immediate high-frequency side of a pure-tone masker, it is not the signals, but rather combination tones, that are detected at masked threshold [Greenwood, J. Acoust. Soc. Am. 50, 502-543 (1971)]. At low to moderate masker intensities, the detected combination tone is 2f1 -f2, where f1 is the masker frequency and f2 is the signal frequency. At higher masker levels, the combination tone f2 - f1 becomes large enough to play a role. To investigate this role, the combination tones f2 - f1 and 2f1 - f2 were selectively masked in different low-frequency regions, to identify their effects. As has been known, the notch region on the high side of the pure-tone masking pattern creates a secondary peak, which shifts upward in frequency and height as masker intensity is raised. At masker levels sufficient to shift this secondary peak upward, beyond 1.5 times f1 (masker), both 2f1 - f2(C1) and 2f2 - f1(D1) are detected with about equal likelihood in the higher-frequency part of the notch region. Either C1, D1 or both may be detected since their intensities become quite similar at higher masker levels, as supported by more direct estimates [Greenwood, J. Acoust. Soc. Am. 52, 1137-1167 (1972); Hall, J. Acoust. Soc. Am. 51, 1863-1881 (1972)]. [ABSTRACT FROM AUTHOR]