Universal Vaccines and Vaccine Platforms to Protect against Influenza Viruses in Humans and Agriculture.
TL;DR: Current vaccines to protect humans and animals against influenza are discussed, highlighting challenges faced to effective and uniform novel vaccination strategies and approaches.
Abstract: Influenza virus infections pose a significant threat to public health due to annual seasonal epidemics and occasional pandemics. Influenza is also associated with significant economic losses in animal production. The most effective way to prevent influenza infections is through vaccination. Current vaccine programs rely heavily on the vaccine's ability to stimulate neutralizing antibody responses to the hemagglutinin (HA) protein. One of the biggest challenges to an effective vaccination program lies on the fact that influenza viruses are ever-changing, leading to antigenic drift that results in escape from earlier immune responses. Efforts toward overcoming these challenges aim at improving the strength and/or breadth of the immune response. Novel vaccine technologies, the so-called universal vaccines, focus on stimulating better cross-protection against many or all influenza strains. However, vaccine platforms or manufacturing technologies being tested to improve vaccine efficacy are heterogeneous between different species and/or either tailored for epidemic or pandemic influenza. Here, we discuss current vaccines to protect humans and animals against influenza, highlighting challenges faced to effective and uniform novel vaccination strategies and approaches.
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TL;DR: The Working Group on University Responses to Federal Initiatives on Sexual Assault formed in June formed in order to address federal measures as well as to continue changes already in progress, according to Associate Vice Provost Matthew Taylor.
Abstract: Dean of Undergraduates John Hutchinson, the General Council and President David Leebron assembled the Working Group on University Responses to Federal Initiatives on Sexual Assault in June, according to Associate Vice Provost Matthew Taylor. The group formed in order to address federal measures as well as to continue changes already in progress. The federal government began releasing guidelines on how universities and colleges should address sexual assault beginning in April 2014. The White House task force report, Not Alone, features certain recommendations regarding training, prevention and adjudication of sexual assault. “The working group is looking at Rice’s policies, processes and communications about sexual violence and sexual harassment, in light of what the government is either recommending or requiring to make sure that we have a clear sense of the areas in which,” Taylor said. “We either exceed the recommendations or there are things that we need to do to meet the recommendations.” The working group consists of both undergraduate and graduate representatives, as well as leadership from the Student Wellbeing Office, Student Judicial Programs, the Rice University Police Department, the Rice Counseling Center, Athletics and Graduate and Post-Doctoral Studies, among others. There are approximately an equal number of males and females in the group. “I wouldn’t say [we have had] findings yet,” Taylor said. “We have tried to educate ourselves on the government’s recommendations.” According to Taylor, the working group focused on immediate shortterm issues for the summer. Many of the federal recommendations were already being met by Rice, and several aspects were already undergoing changes before the formation of the working group. Before the working group was formed, Associate Dean of Undergraduates Donald Ostdiek had already decided to hire a Title IX Resource Navigator, who will help students navigate the investigation if they choose to come forward and report a sexual assault. The main efforts of the working group are directed towards meeting federal guidelines that state that universities should designate employees to whom students can report sexual assault in confidence. Taylor said although Rice already has designated individuals, the policy’s language did not clearly outline whether those individuals are Title IX officers, responsible employees or non-disclosing employees. He said the new language encourages individuals to report cases. “The Title IX officers, in most cases, don’t have to report a student’s name, but we make it equally fair that, in some cases, the university would have to take action based on the law,” Taylor said. “Some of the people that we know students are most likely to go to for advice after a sexual assault are college masters, resident [associates] and college coordinators. We make it clear that they are responsible employees [who are] required to notify one of the Title IX coordinators if they are alerted by a student to a case of sexual assault or sexual violence.” Director of the Center for Student Wellbeing Kate Noonan and Wellbeing Advisor Saralyn Hernandez also contributed to the working group. Hernandez and Noonan said the Wellbeing Advisors are committed to providing trauma-informed support to students who have experienced sexual misconduct. “For survivors who prefer offcampus resources, Rice contracts with the Houston Area Women’s Center, [which] can provide support to Rice students outside the hedges,” Noonan and Hernandez said. Currently, new students undergo training during Orientation Week through Project Sexual Assault-Free Environment, presented by the Houston Area Women’s Resource Center and the Student Wellbeing Office. Although the working group did not have any influence on this year’s presentation of Project SAFE, the presentation already met federal recommendations by focusing on bystander prevention. The presentation discussed non-disclosing and responsible employees, although it did not talk about consequences for potential perpetrators. Colin Losey, a Martel College sophomore who transferred from the University of Chicago, said although he thought the presentation itself was satisfactory, he did not feel that all of the options for victims of sexual assault were covered, especially the option to report to police outside the university. “I’m a transfer student from a university that was recently hit with a major Title IX investigation, and a lot of what has come out from that is that the university’s adjudication process was used in a way to keep things internal,” Losey said. “Given what has happened at other college campuses across the country, students should be clear that this is criminal behavior, and they can press criminal charges.You don’t need to contact Rice first, and Rice need not be involved.” However, Taylor said offering Project SAFE only during O-Week is unsatisfactory and that there must Honor Council removes undergraduates from graduate cases, violates constitution
384 citations
TL;DR: Approaches to improve vaccine efficacy which harness new insights from influenza antigen structure and human immunity are discussed, highlighting major targets, vaccines in development and ongoing challenges.
Abstract: Seasonal influenza vaccines lack efficacy against drifted or pandemic influenza strains. Developing improved vaccines that elicit broader immunity remains a public health priority. Immune responses to current vaccines focus on the haemagglutinin head domain, whereas next-generation vaccines target less variable virus structures, including the haemagglutinin stem. Strategies employed to improve vaccine efficacy involve using structure-based design and nanoparticle display to optimize the antigenicity and immunogenicity of target antigens; increasing the antigen dose; using novel adjuvants; stimulating cellular immunity; and targeting other viral proteins, including neuraminidase, matrix protein 2 or nucleoprotein. Improved understanding of influenza antigen structure and immunobiology is advancing novel vaccine candidates into human trials. Current seasonal influenza vaccines lack efficacy against drifted or pandemic virus strains, and the development of novel vaccines that elicit broader immunity represents a public health priority. Here, Nabel and colleagues discuss approaches to improve vaccine efficacy which harness new insights from influenza antigen structure and human immunity, highlighting major targets, vaccines in development and ongoing challenges.
149 citations
TL;DR: An overview of current vaccine options is provided and efforts directed toward the development of next-generation vaccines are described, including closer monitoring of viral evolution.
Abstract: Although antiviral drugs and vaccines have reduced the economic and healthcare burdens of influenza, influenza epidemics continue to take a toll. Over the past decade, research on influenza viruses has revealed a potential path to improvement. The clues have come from accumulated discoveries from basic and clinical studies. Now, virus surveillance allows researchers to monitor influenza virus epidemic trends and to accumulate virus sequences in public databases, which leads to better selection of candidate viruses for vaccines and early detection of drug-resistant viruses. Here we provide an overview of current vaccine options and describe efforts directed toward the development of next-generation vaccines. Finally, we propose a plan for the development of an optimal influenza vaccine.
102 citations
TL;DR: The pathophysiology associated with the 1918 virus and its predilection for the young and healthy, the rise of influenza therapeutic research following the pandemic, and the level of preparedness for future pandemics are discussed are discussed.
Abstract: In the spring of 1918, the “War to End All Wars”, which would ultimately claim more than 37 million lives, had entered into its final year and would change the global political and economic landscape forever. At the same time, a new global threat was emerging and would become one of the most devastating global health crises in recorded history. The 1918 H1N1 pandemic virus spread across Europe, North America, and Asia over a 12-month period resulting in an estimated 500 million infections and 50–100 million deaths worldwide, of which ~ 50% of these occurred within the fall of 1918 (Emerg Infect Dis 12:15-22, 2006, Bull Hist Med 76:105-115, 2002). However, the molecular factors that contributed to the emergence of, and subsequent public health catastrophe associated with, the 1918 pandemic virus remained largely unknown until 2005, when the characterization of the reconstructed pandemic virus was announced heralding a new era of advanced molecular investigations (Science 310:77-80, 2005). In the century following the emergence of the 1918 pandemic virus we have landed on the Moon, developed the electronic computer (and a global internet), and have eradicated smallpox. In contrast, we have a largely remedial knowledge and understanding of one of the greatest scourges in recorded history. Here, we reflect on the 1918 influenza pandemic, including its emergence and subsequent rapid global spread. In addition, we discuss the pathophysiology associated with the 1918 virus and its predilection for the young and healthy, the rise of influenza therapeutic research following the pandemic, and, finally, our level of preparedness for future pandemics.
91 citations
TL;DR: The development of a novel or improved universal influenza vaccines may be greatly facilitated by new technologies including virus-like particles, T-cell-inducing peptides and recombinant proteins, synthetic viruses, broadly neutralizing antibodies, and nucleic acid-based vaccines.
Abstract: Despite advancements in immunotherapeutic approaches, influenza continues to cause severe illness, particularly among immunocompromised individuals, young children, and elderly adults. Vaccination is the most effective way to reduce rates of morbidity and mortality caused by influenza viruses. Frequent genetic shift and drift among influenza-virus strains with the resultant disparity between circulating and vaccine virus strains limits the effectiveness of the available conventional influenza vaccines. One approach to overcome this limitation is to develop a universal influenza vaccine that could provide protection against all subtypes of influenza viruses. Moreover, the development of a novel or improved universal influenza vaccines may be greatly facilitated by new technologies including virus-like particles, T-cell-inducing peptides and recombinant proteins, synthetic viruses, broadly neutralizing antibodies, and nucleic acid-based vaccines. This review discusses recent scientific advances in the development of next-generation universal influenza vaccines.
83 citations
Cites background from "Universal Vaccines and Vaccine Plat..."
...Therefore, a combination of antibody and CTLinducing strategies may be required for an effective universal influenza vaccine development (133)....
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...As published reports suggested that the majority of T cellbased vaccines focus on conserved T-cell epitopes in NP and M proteins and are helpful in reducing disease progression and mortality against heterologous virus infections (133, 134)....
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...Ongoing clinical trials based on coadministration of seasonal influenza vaccine with MVA-NP + M1 (viral vectored vaccine based on modified vaccinia virus Ankara expressing influenza NP and M1 proteins) and prime-boost strategies induced both T-cells and antibody responses (133, 135, 136)....
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References
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TL;DR: In this paper, it was shown that signalling through CD40 can replace CD4+ T-helper cells in priming of helper-dependent CD8+ CTL responses.
Abstract: Although in vivo priming of CD8+ cytotoxic T lymphocytes (CTLs) generally requires the participation of CD4+ T-helper lymphocytes, the nature of the 'help' provided to CTLs is unknown. One widely held view is that help for CTLs is mediated by cytokines produced by T-helper cells activated in proximity to the CTL precursor at the surface of an antigen-presenting cell (APC). An alternative theory is that, rather than being directly supplied to the CTL by the helper cell, help is delivered through activation of the APC, which can then prime the CTL directly. CD40 and its ligand, CD40L, may activate the APC to allow CTL priming. CD40L is expressed on the surface of activated CD4+ T-helper cells and is involved in their activation and in the development of their effector functions. Ligation of CD40 on the surface of APCs such as dendritic cells, macrophages and B cells greatly increases their antigen-presentation and co-stimulatory capacity. Here we report that signalling through CD40 can replace CD4+ T-helper cells in priming of helper-dependent CD8+ CTL responses. Blockade of CD40L inhibits CTL priming; this inhibition is overcome by signalling through CD40. CD40-CD40L interactions are therefore vital in the delivery of T-cell help for CTL priming.
2,676 citations
"Universal Vaccines and Vaccine Plat..." refers background in this paper
...CD4+ T cells are predominantly helper cells, and offer co-stimulatory signals for the priming of B cells (Alam et al., 2014) and CD8+ T cells (Schoenberger et al., 1998) after....
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TL;DR: It is shown that the new swine-origin influenza A (H1N1) virus emerged in Mexico and the United States was derived from several viruses circulating in swine, and that the initial transmission to humans occurred several months before recognition of the outbreak.
Abstract: In March and early April 2009, a new swine-origin influenza A (H1N1) virus (S-OIV) emerged in Mexico and the United States. During the first few weeks of surveillance, the virus spread worldwide to 30 countries (as of May 11) by human-to-human transmission, causing the World Health Organization to raise its pandemic alert to level 5 of 6. This virus has the potential to develop into the first influenza pandemic of the twenty-first century. Here we use evolutionary analysis to estimate the timescale of the origins and the early development of the S-OIV epidemic. We show that it was derived from several viruses circulating in swine, and that the initial transmission to humans occurred several months before recognition of the outbreak. A phylogenetic estimate of the gaps in genetic surveillance indicates a long period of unsampled ancestry before the S-OIV outbreak, suggesting that the reassortment of swine lineages may have occurred years before emergence in humans, and that the multiple genetic ancestry of S-OIV is not indicative of an artificial origin. Furthermore, the unsampled history of the epidemic means that the nature and location of the genetically closest swine viruses reveal little about the immediate origin of the epidemic, despite the fact that we included a panel of closely related and previously unpublished swine influenza isolates. Our results highlight the need for systematic surveillance of influenza in swine, and provide evidence that the mixing of new genetic elements in swine can result in the emergence of viruses with pandemic potential in humans.
2,023 citations
"Universal Vaccines and Vaccine Plat..." refers background in this paper
...The 2009 H1N1 pandemic was a result of a swine-origin IAV with a unique combination of gene segments that had not been detected in pigs before, and quickly became globally widespread (Smith et al., 2009)....
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TL;DR: An eight-plasmid DNA transfection system for the rescue of infectious influenza A virus from cloned cDNA facilitates the design and recovery of both recombinant and reassortant influenza A viruses, and may also be applicable to the recovery of other RNA viruses entirely from cloning cDNA.
Abstract: We have developed an eight-plasmid DNA transfection system for the rescue of infectious influenza A virus from cloned cDNA. In this plasmid-based expression system, viral cDNA is inserted between the RNA polymerase I (pol I) promoter and terminator sequences. This entire pol I transcription unit is flanked by an RNA polymerase II (pol II) promoter and a polyadenylation site. The orientation of the two transcription units allows the synthesis of negative-sense viral RNA and positive-sense mRNA from one viral cDNA template. This pol I–pol II system starts with the initiation of transcription of the two cellular RNA polymerase enzymes from their own promoters, presumably in different compartments of the nucleus. The interaction of all molecules derived from the cellular and viral transcription and translation machinery results in the generation of infectious influenza A virus. The utility of this system is proved by the recovery of the two influenza A viruses: A/WSN/33 (H1N1) and A/Teal/HK/W312/97 (H6N1). Seventy-two hours after the transfection of eight expression plasmids into cocultured 293T and MDCK cells, the virus yield in the supernatant of the transfected cells was between 2 × 105 and 2 × 107 infectious viruses per milliliter. We also used this eight-plasmid system for the generation of single and quadruple reassortant viruses between A/Teal/HK/W312/97 (H6N1) and A/WSN/33 (H1N1). Because the pol I–pol II system facilitates the design and recovery of both recombinant and reassortant influenza A viruses, it may also be applicable to the recovery of other RNA viruses entirely from cloned cDNA.
1,522 citations
TL;DR: A new reverse-genetics system that allows one to efficiently generate influenza A viruses entirely from cloned cDNAs is described, which should be useful in viral mutagenesis studies and in the production of vaccines and gene therapy vectors.
Abstract: We describe a new reverse-genetics system that allows one to efficiently generate influenza A viruses entirely from cloned cDNAs. Human embryonic kidney cells (293T) were transfected with eight plasmids, each encoding a viral RNA of the A/WSN/33 (H1N1) or A/PR/8/34 (H1N1) virus, flanked by the human RNA polymerase I promoter and the mouse RNA polymerase I terminator—together with plasmids encoding viral nucleoprotein and the PB2, PB1, and PA viral polymerases. This strategy yielded >1 × 103 plaque-forming units (pfu) of virus per ml of supernatant at 48 hr posttransfection. The addition of plasmids expressing all of the remaining viral structural proteins led to a substantial increase in virus production, 3 × 104–5 × 107 pfu/ml. We also used reverse genetics to generate a reassortant virus containing the PB1 gene of the A/PR/8/34 virus, with all other genes representing A/WSN/33. Additional viruses produced by this method had mutations in the PA gene or possessed a foreign epitope in the head of the neuraminidase protein. This efficient system, which does not require helper virus infection, should be useful in viral mutagenesis studies and in the production of vaccines and gene therapy vectors.
1,325 citations
"Universal Vaccines and Vaccine Plat..." refers background in this paper
...Goodman et al. (2011) showed increased CD4+ and CD8+ T cell response in mice by using a prime/ boost regimen with DNA and MVA-vectors containing human T cell epitopes for M1, NS1, PB1, and PA proteins or conserved regions of H5N1 HA and NA on an NP backbone, which led to reduced viral replication and delayed mortality after challenge with H1N1 viruses....
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...Some antigen formulations, such as peptides and DNA vaccines need adjuvants to improve Frontiers in Microbiology | www.frontiersin.org 9 February 2018 | Volume 9 | Article 123 immunogenicity....
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...DNA vaccines against influenza are often based on expression of the HA protein, but the humoral immunogenicity is considered suboptimal in humans and large animals when compared to the traditional vaccine approaches....
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...Others have used the priming regimen to increase DNA vaccine immunogenicity....
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...In a recent study, by using the NK cell agonist α-Galactosylceramide as an adjuvant in mice, there was a significant increase in the IgG titers and IFN-γ levels compared with mice receiving the DNA vaccine alone (Fotouhi et al., 2017)....
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TL;DR: TheCR6261 epitope identified here should accelerate the design and implementation of improved vaccines that can elicit CR6261-like antibodies, as well as antibody-based therapies for the treatment of influenza.
Abstract: Influenza virus presents an important and persistent threat to public health worldwide, and current vaccines provide immunity to viral isolates similar to the vaccine strain. High-affinity antibodies against a conserved epitope could provide immunity to the diverse influenza subtypes and protection against future pandemic viruses. Cocrystal structures were determined at 2.2 and 2.7 angstrom resolutions for broadly neutralizing human antibody CR6261 Fab in complexes with the major surface antigen (hemagglutinin, HA) from viruses responsible for the 1918 H1N1 influenza pandemic and a recent lethal case of H5N1 avian influenza. In contrast to other structurally characterized influenza antibodies, CR6261 recognizes a highly conserved helical region in the membrane-proximal stem of HA1 and HA2. The antibody neutralizes the virus by blocking conformational rearrangements associated with membrane fusion. The CR6261 epitope identified here should accelerate the design and implementation of improved vaccines that can elicit CR6261-like antibodies, as well as antibody-based therapies for the treatment of influenza.
1,325 citations