Influenza A viruses (IAVs) are a major cause of respiratory illness and are responsible for yearly epidemics associated with more than 500,000 annual deaths globally. Novel IAVs may cause pandemic ...outbreaks and zoonotic infections with, for example, highly pathogenic avian influenza virus (HPAIV) of the H5N1 and H7N9 subtypes, which pose a threat to public health. Treatment options are limited and emergence of strains resistant to antiviral drugs jeopardize this even further. Like all viruses, IAVs depend on host factors for every step of the virus replication cycle. Host kinases link multiple signaling pathways in respond to a myriad of stimuli, including viral infections. Their regulation of multiple response networks has justified actively targeting cellular kinases for anti-cancer therapies and immune modulators for decades. There is a growing volume of research highlighting the significant role of cellular kinases in regulating IAV infections. Their functional role is illustrated by the required phosphorylation of several IAV proteins necessary for replication and/or evasion/suppression of the innate immune response. Identified in the majority of host factor screens, functional studies further support the important role of kinases and their potential as host restriction factors. PKC, ERK, PI3K and FAK, to name a few, are kinases that regulate viral entry and replication. Additionally, kinases such as IKK, JNK and p38 MAPK are essential in mediating viral sensor signaling cascades that regulate expression of antiviral chemokines and cytokines. The feasibility of targeting kinases is steadily moving from bench to clinic and already-approved cancer drugs could potentially be repurposed for treatments of severe IAV infections. In this review, we will focus on the contribution of cellular kinases to IAV infections and their value as potential therapeutic targets.
Recently, A/H5N1 influenza viruses were shown to acquire airborne transmissibility between ferrets upon targeted mutagenesis and virus passage. The critical genetic changes in airborne ...A/Indonesia/5/05 were not yet identified. Here, five substitutions proved to be sufficient to determine this airborne transmission phenotype. Substitutions in PB1 and PB2 collectively caused enhanced transcription and virus replication. One substitution increased HA thermostability and lowered the pH of membrane fusion. Two substitutions independently changed HA binding preference from α2,3-linked to α2,6-linked sialic acid receptors. The loss of a glycosylation site in HA enhanced overall binding to receptors. The acquired substitutions emerged early during ferret passage as minor variants and became dominant rapidly. Identification of substitutions that are essential for airborne transmission of avian influenza viruses between ferrets and their associated phenotypes advances our fundamental understanding of virus transmission and will increase the value of future surveillance programs and public health risk assessments.
•CD4+ and CD8+ T cells are important correlates of protection.•CD4+ T cells provide help to B cells and support CD8+ T cell expansion.•CD8+ T cell responses are highly cross-reactive and contribute ...to heterosubtypic protection.•TRM mediate protection at the site of influenza virus entry.
Influenza A and B virus infections are a major cause of respiratory disease in humans and are responsible for substantial morbidity and mortality worldwide. Vaccination against influenza mainly aims at the induction of virus neutralizing serum antibodies, which are an important correlate of protection provided that the antibodies match the strains causing the outbreaks antigenically. In addition, virus-specific T cells are known to contribute to protective immunity to influenza virus infections by limiting duration and severity of the disease. As the majority of virus-specific T cells recognize epitopes located in relatively conserved proteins, like the Nucleoprotein and Matrix 1 protein, they display a high degree of cross-reactivity with a wide range of influenza viruses, including newly emerging viruses of alternative subtypes. Advancing our understanding of influenza virus-specific T cell responses and their role in protective immunity against influenza will aid the rational design of novel vaccines that could induce robust, broad and long-lasting immune responses.
Here, we discuss the contribution of influenza virus-specific CD4+ and CD8+ T cells to protective immunity against influenza infection and the requirements and strategies for their induction by natural infection or vaccination, especially in children.
Highly pathogenic avian influenza A/H5N1 virus can cause morbidity and mortality in humans but thus far has not acquired the ability to be transmitted by aerosol or respiratory droplet ("airbome ...transmission") between humans. To address the concern that the virus could acquire this ability under natural conditions, we genetically modified A/H5N1 virus by site-directed mutagenesis and subsequent serial passage in ferrets. The genetically modified A/H5N1 virus acquired mutations during passage in ferrets, ultimately becoming airborne transmissible in ferrets. None of the recipient ferrets died after airborne infection with the mutant A/H5N1 viruses. Four amino acid substitutions in the host receptor-binding protein hemagglutinin, and one in the polymerase complex protein basic polymerase 2, were consistently present in airborne-transmitted viruses. The transmissible viruses were sensitive to the antiviral drug oseltamivir and reacted well with antisera raised against H5 influenza vaccine strains. Thus, avian A/H5N1 influenza viruses can acquire the capacity for airborne transmission between mammals without recombination in an intermediate host and therefore constitute a risk for human pandemic influenza.
In July 2022, the ongoing monkeypox (MPX) outbreak was declared a public health emergency of international concern. Modified vaccinia Ankara-Bavarian Nordic (MVA-BN, also known as Imvamune, JYNNEOS ...or Imvanex) is a third-generation smallpox vaccine that is authorized and in use as a vaccine against MPX. To date, there are no data showing MPX virus (MPXV)-neutralizing antibodies in vaccinated individuals nor vaccine efficacy against MPX. Here we show that MPXV-neutralizing antibodies can be detected after MPXV infection and after historic smallpox vaccination. However, a two-shot MVA-BN immunization series in non-primed individuals yields relatively low levels of MPXV-neutralizing antibodies. Dose-sparing of an MVA-based influenza vaccine leads to lower MPXV-neutralizing antibody levels, whereas a third vaccination with the same MVA-based vaccine significantly boosts the antibody response. As the role of MPXV-neutralizing antibodies as a correlate of protection against disease and transmissibility is currently unclear, we conclude that cohort studies following vaccinated individuals are necessary to assess vaccine efficacy in at-risk populations.
The molecular basis of antigenic drift was determined for the hemagglutinin (HA) of human influenza A/H3N2 virus. From 1968 to 2003, antigenic change was caused mainly by single amino acid ...substitutions, which occurred at only seven positions in HA immediately adjacent to the receptor binding site. Most of these substitutions were involved in antigenic change more than once. Equivalent positions were responsible for the recent antigenic changes of influenza B and A/H1N1 viruses. Substitution of a single amino acid at one of these positions substantially changed the virus-specific antibody response in infected ferrets. These findings have potentially far-reaching consequences for understanding the evolutionary mechanisms that govern influenza viruses.
Abstract Since inactivated influenza vaccines mainly confer protective immunity by inducing strain-specific antibodies to the viral hemagglutinin, these vaccines only afford protection against ...infection with antigenically matching influenza virus strains. Due to the continuous emergence of antigenic drift variants of seasonal influenza viruses and the inevitable future emergence of pandemic influenza viruses, there is considerable interest in the development of influenza vaccines that induce broader protective immunity. It has long been recognized that influenza virus-specific CD8+ T cells directed to epitopes located in the relatively conserved internal proteins can cross-react with various subtypes of influenza A virus. This implies that these CD8+ T cells, induced by prior influenza virus infections or vaccinations, could afford heterosubtypic immunity. Furthermore, influenza virus-specific CD4+ T cells have been shown to be important in protection from infection, either via direct cytotoxic effects or indirectly by providing help to B cells and CD8+ T cells. In the present paper, we review the induction of virus-specific T cell responses by influenza virus infection and the role of virus-specific CD4+ and CD8+ T cells in viral clearance and conferring protection from subsequent infections with homologous or heterologous influenza virus strains. Furthermore, we discuss vector-based vaccination strategies that aim at the induction of a cross-reactive virus-specific T cell response.
Background. Influenza-related morbidity and mortality remain high. Seasonal vaccination is the backbone of influenza management but does not always result in protective antibody titers. Nonspecific ...effects of BCG vaccination related to enhanced function of myeloid antigen-presenting cells have been reported. We hypothesized that BCG vaccination could also enhance immune responses to influenza vaccination. Methods. Healthy volunteers received either live attenuated BCG vaccine (n = 20) or placebo (n = 20) in a randomized fashion, followed by intramuscular injection of trivalent influenza vaccine 14 days later. Hemagglutinationinhibiting (HI) antibodies and cellular immunity measured by ex vivo leukocyte responses were assessed. Results. In BCG-vaccinated subjects, HI antibody responses against the 2009 pandemic influenza A(H1N1) vaccine strain were significantly enhanced, compared with the placebo group, and there was a trend toward more-rapid seroconversion. Additionally, apart from enhanced proinflammatory leukocyte responses following BCG vaccination, nonspecific effects of influenza vaccination were also observed, with modulation of cytokine responses against unrelated pathogens. Conclusions. BCG vaccination prior to influenza vaccination results in a more pronounced increase and accelerated induction of functional antibody responses against the 2009 pandemic influenza A(H1N1) vaccine strain. These results may have implications for the design of vaccination strategies and could lead to improvement of vaccination efficacy.
Currently, infections with SARS-Coronavirus-2 (SARS-CoV-2), the causative agent of the COVID-19 pandemic, are responsible for substantial morbidity and mortality worldwide. Older adults subjects > ...60 years of age account for > 95% of the over one million fatal cases reported to date. It is unclear why in this age group SARS-CoV-2 infection causes more severe disease than in young adults. We hypothesized that differences in SARS-CoV-2 cross-reactive cellular immunity induced after infection with human coronaviruses (HCoVs), like OC43 and NL63, were at the basis of the differential mortality (and morbidity) observed after SARS-CoV-2 infection, because a small proportion of HCoV-specific T cells cross-react with SARS-CoV-2. Our data demonstrate that pre-existing T cell immunity induced by circulating human alpha- and beta-HCoVs is present in young adult individuals, but virtually absent in older adult subjects. Consequently, the frequency of cross-reactive T cells directed to the novel pandemic SARS-CoV-2 was minimal in most older adults. To the best of our knowledge, this is the first time that the presence of cross-reactive T cells to SARS-CoV-2 is compared in young and older adults. Our findings provide at least a partial explanation for the more severe clinical outcome of SARS-CoV-2 infection observed in the elderly. Moreover, this information could help to design efficacious vaccines for this age group, aiming at the induction of cell-mediated immunity.
•Inactivated vaccines induce protective antibodies against antigenically matching strains.•There is an unmet need for ‘one fits all’ influenza vaccines.•These should induce antibody and T cell ...responses to conserved epitopes.•Potential vaccine targets are HA stalk, NA, M2e and internal proteins.
Currently used inactivated influenza vaccines aim at the induction of virus-neutralizing antibodies directed to the variable head domain of the viral hemagglutinin. Although these vaccines are effective against antigenically matching virus strains, they offer little protection against antigenically distinct drift variants or potentially pandemic viruses of alternative subtypes. In the last decades, the threat of novel influenza pandemics has sparked research efforts to develop vaccines that induce more broadly protective immunity. Here, we discuss the immune responses induced by conventional ‘tailor-made’ inactivated and live influenza vaccines and novel ‘one fits all’ candidate vaccines able to induce cross-reactive virus-specific antibody and T cell responses and to afford protection to a wider range of influenza viruses.
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