The Interleukin-33-Group 2 Innate Lymphoid Cell Axis Represents a Potential Adjuvant Target To Increase the Cross-Protective Efficacy of Influenza Vaccine.

Interleukin-33 (IL-33) is a multifunctional cytokine that mediates type 2-dominated immune responses. In contrast, the role of IL-33 during viral vaccination, which often aims to induce type 1 immunity, has not been fully investigated. Here, we examined the effects of IL-33 on influenza vaccine responses. We found that intranasal coadministration of IL-33 with an inactivated influenza virus vaccine increases vaccine efficacy against influenza virus infection, not only with the homologous strain but also with heterologous strains, including the 2009 H1N1 influenza virus pandemic strain. Cross-protection was dependent on group 2 innate lymphoid cells (ILC2s), as the beneficial effect of IL-33 on vaccine efficacy was abrogated in ILC2-deficient C57BL/6 Il7rCre/+ Rorafl/fl mice. Furthermore, mechanistic studies revealed that IL-33-activated ILC2s potentiate vaccine efficacy by enhancing mucosal humoral immunity, particularly IgA responses, potentially in a Th2 cytokine-dependent manner. Our results demonstrate that IL-33-mediated activation of ILC2s is a critical early event that is important for the induction of mucosal humoral immunity, which in turn is responsible for cross-strain protection against influenza. Thus, we reveal a previously unrecognized role for the IL-33-ILC2 axis in establishing broadly protective and long-lasting humoral mucosal immunity against influenza, knowledge that may help in the development of a universal influenza vaccine. IMPORTANCE Current influenza vaccines, although capable of protecting against predicted viruses/strains included in the vaccine, are inept at providing cross-protection against emerging/novel strains. Thus, we are in critical need of a universal vaccine that can protect against a wide range of influenza viruses. Our novel findings show that a mucosal vaccination strategy involving the activation of lung ILC2s is highly effective in eliciting cross-protective humoral immunity in the lungs. This suggests that the biology of lung ILC2s can be exploited to increase the cross-reactivity of commercially available influenza subunit vaccines.

LUNG group 2 innate lymphoid cells as a new adjuvant target to enhance intranasal vaccine efficacy against influenza.

Group 2 innate lymphoid cells (ILC2) are a relatively new class of innate immune cells. Lung ILC2 are early responders that secrete type 2 cytokines in response to danger 'alarmin' signals such as interleukin (IL)-33 and thymic stromal lymphopoietin. Being an early source of type 2 cytokines, ILC2 are a critical regulator of type 2 immune cells of both innate and adaptive immune responses. The immune regulatory functions of ILC2 were mostly investigated in diseases where T helper 2 inflammation predominates. However, in recent years, it has been appreciated that the role of ILC2 extends to other pathological conditions such as cancer and viral infections. In this review, we will focus on the potential role of lung ILC2 in the induction of mucosal immunity against influenza virus infection and discuss the potential utility of ILC2 as a target for mucosal vaccination.

Counter-rotating microplates at the Galapagos triple junction.

An 'incipient' spreading centre east of (and orthogonal to) the East Pacific Rise at 2 degrees 40' N has been identified as forming a portion of the northern boundary of the Galapagos microplate. This spreading centre was described as a slowly diverging, westward propagating rift, tapering towards the East Pacific Rise. Here we present evidence that the 'incipient rift' has also rifted towards the east and opens anticlockwise about a pivot at its eastern end. The 'incipient rift' then bounds a second microplate, north of the clockwise-rotating Galapagos microplate. The Galapagos triple junction region, in the eastern equatorial Pacific Ocean, thus consists of two counter-rotating microplates partly separated by the Hess Deep rift. Our kinematic solution for microplate motion relative to the major plates indicates that the two counter-rotating microplates may be treated as rigid blocks driven by drag on the microplates' edges3.

A Triple-challenge Mouse Model of Allergic Airway Disease, Primary Influenza Infection, and Secondary Bacterial Infection.

Asthma is a global problem that affects millions of individuals. An increased risk of respiratory viral and bacterial infections is one of the complications of asthma. We recently reported that mice with ovalbumin-induced allergic airway disease (AAD) are protected against influenza-Streptococcus pneumoniae co-infection. Here, we describe in detail a protocol on how to induce AAD and influenza-S. pneumoniae co-infection in mice and to evaluate the specific roles of asthma on immunity to viral and bacterial pathogens in the hope of translating findings to benefit asthmatic individuals.

Impact of Pre-Existing Immunity to Influenza on Live-Attenuated Influenza Vaccine (LAIV) Immunogenicity.

During the previous influenza seasons, between 2010 and 2016, the live attenuated influenza vaccine (LAIV) provided variable efficacy against influenza in the U.S., causing the recommendation against the use of the LAIV. In striking contrast, pre-clinical studies have repeatedly demonstrated superior efficacy of LAIV against mismatched influenza viruses, compared to inactivated influenza vaccines (IIV). This disparity in reported vaccine efficacies between pre-clinical and clinical studies may in part be explained by limitations of the animal models of influenza. In particular, the absence of pre-existing immunity in animal models has recently emerged as a potential explanation for the discrepancies between preclinical findings and human studies. This commentary focuses on the potential impact of pre-existing immunity on LAIV induced immunogenicity with an emphasis on cross-protective immunity.

Impact of Pre-Existing Immunity on Live Attenuated Influenza Vaccine-Induced Cross-Protective Immunity.

The efficacy of the intranasally (i.n.) delivered live attenuated influenza vaccine (LAIV) is variable and, in some seasons, suboptimal. In this study, we report that LAIV exhibits cross-protective efficacy in mice, potentially associated with cellular immunity as opposed to antigen-specific antibody responses. However, pre-exposure to the intramuscularly (i.m.) delivered inactivated influenza vaccine (IIV) severely impaired LAIV-induced cross-protection against heterologous challenge, potentially by inhibiting replication of LAIV. Our findings suggest that pre-existing immunity afforded by IIV suppresses cross-protective T cell immunogenicity of LAIV.

Evaluation of Pneumococcal Surface Protein A as a Vaccine Antigen against Secondary Streptococcus pneumoniae Challenge during Influenza A Infection.

Secondary bacterial pneumonia is responsible for significant morbidity and mortality during seasonal and pandemic influenza. Due to the unpredictability of influenza A virus evolution and the time-consuming process of manufacturing strain-specific influenza vaccines, recent efforts have been focused on developing anti-Streptococcus pneumoniae immunity to prevent influenza-related illness and death. Bacterial vaccination to prevent viral-bacterial synergistic interaction during co-infection is a promising concept that needs further investigation. Here, we show that immunization with pneumococcal surface protein A (PspA) fully protects mice against low-dose, but not high-dose, secondary bacterial challenge using a murine model of influenza A virus-S. pneumoniae co-infection. We further show that immunization with PspA is more broadly protective than the pneumococcal conjugate vaccine (Prevnar). These results demonstrate that PspA is a promising vaccine target that can provide protection against a physiologically relevant dose of S. pneumoniae following influenza infection.

Allergic Airway Disease Prevents Lethal Synergy of Influenza A Virus-Streptococcus pneumoniae Coinfection.

Fatal outcomes following influenza infection are often associated with secondary bacterial infections. Allergic airway disease (AAD) is known to influence severe complications from respiratory infections, and yet the mechanistic effect of AAD on influenza virus-Streptococcus pneumoniae coinfection has not been investigated previously. We examined the impact of AAD on host susceptibility to viral-bacterial coinfections. We report that AAD improved survival during coinfection when viral-bacterial challenge occurred 1 week after AAD. Counterintuitively, mice with AAD had significantly deceased proinflammatory responses during infection. Specifically, both CD4+ and CD8+ T cell interferon gamma (IFN-γ) responses were suppressed following AAD. Resistance to coinfection was also associated with strong transforming growth factor ß1 (TGF-ß1) expression and increased bacterial clearance. Treatment of AAD mice with IFN-γ or genetic deletion of TGF-ß receptor II expression reversed the protective effects of AAD. Using a novel triple-challenge model system, we show for the first time that AAD can provide protection against influenza virus-S. pneumoniae coinfection through the production of TGF-ß that suppresses the influenza virus-induced IFN-γ response, thereby preserving antibacterial immunity.IMPORTANCE Asthma has become one of the most common chronic diseases and has been identified as a risk factor for developing influenza. However, the impact of asthma on postinfluenza secondary bacterial infection is currently not known. Here, we developed a novel triple-challenge model of allergic airway disease, primary influenza infection, and secondary Streptococcus pneumoniae infection to investigate the impact of asthma on susceptibility to viral-bacterial coinfections. We report for the first time that mice recovering from acute allergic airway disease are highly resistant to influenza-pneumococcal coinfection and that this resistance is due to inhibition of influenza virus-mediated impairment of bacterial clearance. Further characterization of allergic airway disease-associated resistance against postinfluenza secondary bacterial infection may aid in the development of prophylactic and/or therapeutic treatment against coinfection.