Current influenza virus vaccines are annually reformulated to elicit protection by generating an immune response toward the virus strains that are predicted to circulate in the upcoming influenza ...season. These vaccines provide limited protection in cases of antigenic mismatch, when the vaccine and the circulating viral strains differ. The emergence of unexpected pandemic viruses presents an additional challenge to vaccine production. To increase influenza virus preparedness, much work has been dedicated to the development of a universal vaccine. Focusing on regions of viral proteins that are highly conserved across virus subtypes, vaccine strategies involving the matrix 2 protein, stalk domain of the hemagglutinin, and multivalent approaches have provided broad-based protection in animal models and show much promise. This review summarizes the most encouraging advances in the field with a focus on novel vaccine designs that have yielded promising preclinical and clinical data.
Influenza viruses are important pathogens which pose an ongoing threat to public health due to their ability to mutate and evade immunity elicited by prior infection or vaccination. Their ...evolutionary diversity is facilitated by the plasticity of the antigenically variable head domain of the major surface glycoprotein, hemagglutinin (HA), which tolerates the accumulation of extensive mutations. To date, vaccines have focused on eliciting largely strain-specific immune responses toward the HA head. However, novel universal influenza vaccines aim to refocus immunity toward the immunosubdominant but conserved influenza virus HA stalk domain. Such vaccines could provide heterologous protection against diverse influenza viruses.
Influenza virus is a master of evolution and immune evasion. Coughlan and Palese review current vaccines that largely elicit strain-specific immune responses, offering little protection from newly emerging pandemic viruses. They also discuss a new class of “universal” influenza vaccine which targets regions common to multiple influenza viruses.
Newcastle disease virus (NDV) is an avian paramyxovirus, which has been demonstrated to possess significant oncolytic activity against mammalian cancers. This review summarizes the research leading ...to the elucidation of the mechanisms of NDV-mediated oncolysis, as well as the development of novel oncolytic agents through the use of genetic engineering. Clinical trials utilizing NDV strains and NDV-based autologous tumor cell vaccines will expand our knowledge of these novel anticancer strategies and will ultimately result in the successful use of the virus in the clinical setting.
Killed and live influenza virus vaccines are effective in preventing and curbing the spread of disease, but new technologies such as reverse genetics could be used to improve them and to shorten the ...lengthy process of preparing vaccine seed viruses. By taking advantage of these new technologies, we could develop live vaccines that would be safe, cross-protective against variant strains, and require less virus per dose than conventional vaccines. Furthermore, pandemic vaccines against highly virulent strains such as the H5N1 virus can only be generated by reverse genetics techniques. Other technologic breakthroughs should result in effective adjuvants for use with killed and live vaccines, increasing the number of available doses. Finally, universal influenza virus vaccines seem to be within reach. These new strategies will be successful if they are supported by regulatory agencies and if a robust market for influenza virus vaccines against inter-pandemic and pandemic threats is made and sustained.
Influenza B viruses cause seasonal epidemics and are a considerable burden to public health. However, protection by current seasonal vaccines is suboptimal due to the antigenic changes of the ...circulating strains. In this study, we report a novel universal influenza B virus vaccination strategy based on "mosaic" hemagglutinins. We generated mosaic B hemagglutinins by replacing the major antigenic sites of the type B hemagglutinin with corresponding sequences from exotic influenza A hemagglutinins and expressed them as soluble trimeric proteins. Sequential vaccination with recombinant mosaic B hemagglutinin proteins conferred cross-protection against both homologous and heterologous influenza B virus strains in the mouse model. Of note, we rescued recombinant influenza B viruses expressing mosaic B hemagglutinins, which could serve as the basis for a universal influenza B virus vaccine.
This work reports a universal influenza B virus vaccination strategy based on focusing antibody responses to conserved head and stalk epitopes of the hemagglutinin. Recombinant mosaic influenza B hemagglutinin proteins and recombinant viruses have been generated as novel vaccine candidates. This vaccine strategy provided broad cross-protection in the mouse model. Our findings will inform and drive development toward a more effective influenza B virus vaccine.
Preexisting lymphocytic infiltration of tumors is associated with superior prognostic outcomes in a variety of cancers. Recent studies also suggest that lymphocytic responses may identify patients ...more likely to benefit from therapies targeting immune checkpoints, suggesting that therapeutic efficacy of immune checkpoint blockade can be enhanced through strategies that induce tumor inflammation. To achieve this effect, we explored the immunotherapeutic potential of oncolytic Newcastle disease virus (NDV). We find that localized intratumoral therapy of B16 melanoma with NDV induces inflammatory responses, leading to lymphocytic infiltrates and antitumor effect in distant (nonvirally injected) tumors without distant virus spread. The inflammatory effect coincided with distant tumor infiltration with tumor-specific CD4(+) and CD8(+) T cells, which was dependent on the identity of the virus-injected tumor. Combination therapy with localized NDV and systemic CTLA-4 blockade led to rejection of preestablished distant tumors and protection from tumor rechallenge in poorly immunogenic tumor models, irrespective of tumor cell line sensitivity to NDV-mediated lysis. Therapeutic effect was associated with marked distant tumor infiltration with activated CD8(+) and CD4(+) effector but not regulatory T cells, and was dependent on CD8(+) cells, natural killer cells, and type I interferon. Our findings demonstrate that localized therapy with oncolytic NDV induces inflammatory immune infiltrates in distant tumors, making them susceptible to systemic therapy with immunomodulatory antibodies, which provides a strong rationale for investigation of such combination therapies in the clinic.
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