Impact of cross-protective vaccines on epidemiological and evolutionary dynamics of influenza.
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ABSTRACT:
SUBMITTER: Arinaminpathy N
PROVIDER: S-EPMC3286944 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In this review, we analyze the epidemiological and ecological features of influenza B, one of the most common and severe respiratory infections. The review presents various strategies for cross-protective influenza B vaccine development, including recombinant viruses, virus-like particles, and recombinant proteins. We provide an overview of viral proteins as cross-protective vaccine targets, along with other updated broadly protective vaccine strategies. The importance of developing such vaccines lies not only in influenza B prevention, but also in the very attractive prospect of eradicating the influenza B virus in the human population.
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Project description:Influenza vaccines with broad cross-protection are urgently needed. The highly conserved ectodomain of the influenza matrix protein 2 (M2e) can be a promising candidate if its low immunogenicity was overcome. In this study, we generated protein nanoclusters self-assembled from conformation-stabilized M2e tetramers (tM2e) to improve its immunogenicity. The resulting nanoclusters showed an average hydrodynamic diameter of 227 nm. Vaccination with the nanoclusters by an intranasal route elicited high levels of serum antigen-specific IgG in mice (approximately 100-fold higher than that obtained with soluble tM2e), as well as antigen-specific T cell and mucosal antibody responses. The immunity conferred complete protection against lethal challenge with homo- as well as heterosubtypic viruses. These results demonstrate that nanoclusters assembled from conformation-stabilized M2e are promising as a potential universal influenza A vaccine. Self-assembly into nanoclusters represents a novel approach for increasing the immunogenicity of vaccine antigens.From the clinical editorIn order to develop more effective influenza vaccination, the highly conserved ectodomain of M2e could be a promising candidate. Unfortunately, it is a weak antigen for vaccination purposes. In this study, self-assembled protein nanoclusters of tM2e were generated and tested. The nanoclusters demonstrated superior vaccination properties, with complete protection against lethal challenge in the studied rodent model, raising hope for the introduction of similar vaccines to challenge human influenza outbreaks.
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Project description:Epidemiological and evolutionary dynamics of influenza B Victoria and Yamagata lineages remained poorly understood in the tropical Southeast Asia region, despite causing seasonal outbreaks worldwide. From 2012-2014, nasopharyngeal swab samples collected from outpatients experiencing acute upper respiratory tract infection symptoms in Kuala Lumpur, Malaysia, were screened for influenza viruses using a multiplex RT-PCR assay. Among 2,010/3,935 (51.1%) patients infected with at least one respiratory virus, 287 (14.3%) and 183 (9.1%) samples were tested positive for influenza A and B viruses, respectively. Influenza-positive cases correlate significantly with meteorological factors-total amount of rainfall, relative humidity, number of rain days, ground temperature and particulate matter (PM10). Phylogenetic reconstruction of haemagglutinin (HA) gene from 168 influenza B viruses grouped them into Yamagata Clade 3 (65, 38.7%), Yamagata Clade 2 (48, 28.6%) and Victoria Clade 1 (55, 32.7%). With neuraminidase (NA) phylogeny, 30 intra-clade (29 within Yamagata Clade 3, 1 within Victoria Clade 1) and 1 inter-clade (Yamagata Clade 2-HA/Yamagata Clade 3-NA) reassortants were identified. Study of virus temporal dynamics revealed a lineage shift from Victoria to Yamagata (2012-2013), and a clade shift from Yamagata Clade 2 to Clade 3 (2013-2014). Yamagata Clade 3 predominating in 2014 consisted of intra-clade reassortants that were closely related to a recent WHO vaccine candidate strain (B/Phuket/3073/2013), with the reassortment event occurred approximately 2 years ago based on Bayesian molecular clock estimation. Malaysian Victoria Clade 1 viruses carried H274Y substitution in the active site of neuraminidase, which confers resistance to oseltamivir. Statistical analyses on clinical and demographic data showed Yamagata-infected patients were older and more likely to experience headache while Victoria-infected patients were more likely to experience nasal congestion and sore throat. This study describes the evolution of influenza B viruses in Malaysia and highlights the importance of continuous surveillance for better vaccination policy in this region.
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Project description:Influenza A viruses exhibit complex epidemiological patterns in a number of mammalian and avian hosts. Understanding transmission of these viruses necessitates taking into account their evolution, which represents a challenge for developing mathematical models. This is because the phrasing of multi-strain systems in terms of traditional compartmental ODE models either requires simplifying assumptions to be made that overlook important evolutionary processes, or leads to complex dynamical systems that are too cumbersome to analyse.Here, we develop an Individual-Based Model (IBM) in order to address simultaneously the ecology, epidemiology and evolution of strain-polymorphic pathogens, using Influenza A viruses as an illustrative example.We carry out careful validation of our IBM against comparable mathematical models to demonstrate the robustness of our algorithm and the sound basis for this novel framework. We discuss how this new approach can give critical insights in the study of influenza evolution.
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Project description:Sequential infection with antigenically distinct influenza viruses induces cross-protective immune responses against heterologous virus strains in animal models. Here we investigated whether sequential immunization with antigenically distinct influenza vaccines can also provide cross-protection. To this end, we compared immune responses and protective potential against challenge with A(H1N1)pdm09 in mice infected sequentially with seasonal A(H1N1) virus followed by A(H3N2) virus or immunized sequentially with whole inactivated virus (WIV) or subunit (SU) vaccine derived from these viruses. Sequential infection provided solid cross-protection against A(H1N1)pdm09 infection while sequential vaccination with WIV, though not capable of preventing weight loss upon infection completely, protected the mice from reaching the humane endpoint. In contrast, sequential SU vaccination did not prevent rapid and extensive weight loss. Protection correlated with levels of cross-reactive but non-neutralizing antibodies of the IgG2a subclass, general increase of memory T cells and induction of influenza-specific CD4+ and CD8+ T cells. Adoptive serum transfer experiments revealed that despite lacking neutralizing activity, serum antibodies induced by sequential infection protected mice from weight loss and vigorous virus growth in the lungs upon A(H1N1)pdm09 virus challenge. Antibodies induced by WIV vaccination alleviated symptoms but could not control virus growth in the lung. Depletion of T cells prior to challenge revealed that CD8+ T cells, but not CD4+ T cells, contributed to cross-protection. These results imply that sequential immunization with WIV but not SU derived from antigenically distinct viruses could alleviate the severity of infection caused by a pandemic and may improve protection to unpredictable seasonal infection.
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Project description:As in past pandemics, co-circulating pathogens may play a role in the epidemiology of coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In particular, experimental evidence indicates that influenza infection can up-regulate the expression of ACE2-the receptor of SARS-CoV-2 in human cells-and facilitate SARS-CoV-2 infection. Here we hypothesized that influenza impacted the epidemiology of SARS-CoV-2 during the early 2020 epidemic of COVID-19 in Europe. To test this hypothesis, we developed a population-based model of SARS-CoV-2 transmission and of COVID-19 mortality, which simultaneously incorporated the impact of non-pharmaceutical control measures and of influenza on the epidemiological dynamics of SARS-CoV-2. Using statistical inference methods based on iterated filtering, we confronted this model with mortality incidence data in four European countries (Belgium, Italy, Norway, and Spain) to systematically test a range of assumptions about the impact of influenza. We found consistent evidence for a 1.8-3.4-fold (uncertainty range across countries: 1.1 to 5.0) average population-level increase in SARS-CoV-2 transmission associated with influenza during the period of co-circulation. These estimates remained robust to a variety of alternative assumptions regarding the epidemiological traits of SARS-CoV-2 and the modeled impact of control measures. Although further confirmatory evidence is required, our results suggest that influenza could facilitate the spread and hamper effective control of SARS-CoV-2. More generally, they highlight the possible role of co-circulating pathogens in the epidemiology of COVID-19.
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Project description:The efficacy of influenza vaccines, currently at 44%, is limited by the rapid antigenic evolution of the virus and a manufacturing process that can lead to vaccine mismatch. The National Institute of Allergy and Infectious Diseases (NIAID) recently identified the development of a universal influenza vaccine with an efficacy of at least 75% as a high scientific priority. The US Congress approved $130 million funding for the 2019 fiscal year to support the development of a universal vaccine, and another $1 billion over 5 y has been proposed in the Flu Vaccine Act. Using a model of influenza transmission, we evaluated the population-level impacts of universal influenza vaccines distributed according to empirical age-specific coverage at multiple scales in the United States. We estimate that replacing just 10% of typical seasonal vaccines with 75% efficacious universal vaccines would avert ∼5.3 million cases, 81,000 hospitalizations, and 6,300 influenza-related deaths per year. This would prevent over $1.1 billion in direct health care costs compared to a typical season, based on average data from the 2010-11 to 2018-19 seasons. A complete replacement of seasonal vaccines with universal vaccines is projected to prevent 17 million cases, 251,000 hospitalizations, 19,500 deaths, and $3.5 billion in direct health care costs. States with high per-hospitalization medical expenses along with a large proportion of elderly residents are expected to receive the maximum economic benefit. Replacing even a fraction of seasonal vaccines with universal vaccines justifies the substantial cost of vaccine development.
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Project description:Seasonal influenza vaccines are often ineffective because they elicit strain-specific antibody responses to mutation-prone sites on the hemagglutinin (HA) head. Vaccines that provide long-lasting immunity to conserved epitopes are needed. Recently, we reported a nanoparticle-based vaccine platform produced by solid-phase peptide synthesis (SPPS) for targeting linear and helical protein-based epitopes. Here, we illustrate its potential for building broadly protective influenza vaccines. Targeting known epitopes in the HA stem, neuraminidase (NA) active site, and M2 ectodomain (M2e) conferred 50-75% survival against 5LD50 influenza B and H1N1 challenge; combining stem and M2e antigens increased survival to 90%. Additionally, protein sequence and structural information were employed in tandem to identify alternative epitopes that stimulate greater protection; we report three novel HA and NA sites that are highly conserved in type B viruses. One new target in the HA stem stimulated 100% survival, highlighting the value of this simple epitope discovery strategy. A candidate influenza B vaccine targeting two adjacent HA stem sites led to >104-fold reduction in pulmonary viral load. These studies describe a compelling platform for building vaccines that target conserved influenza epitopes.
| S-EPMC8158873 | biostudies-literature
Project description:BackgroundThe rapid spread of the 2009 H1N1 pandemic influenza virus (pH1N1) highlighted problems associated with relying on strain-matched vaccines. A lengthy process of strain identification, manufacture, and testing is required for current strain-matched vaccines and delays vaccine availability. Vaccines inducing immunity to conserved viral proteins could be manufactured and tested in advance and provide cross-protection against novel influenza viruses until strain-matched vaccines became available. Here we test two prototype vaccines for cross-protection against the recent pandemic virus.Methodology/principal findingsBALB/c and C57BL/6 mice were intranasally immunized with a single dose of cold-adapted (ca) influenza viruses from 1977 or recombinant adenoviruses (rAd) expressing 1934 nucleoprotein (NP) and consensus matrix 2 (M2) (NP+M2-rAd). Antibodies against the M2 ectodomain (M2e) were seen in NP+M2-rAd immunized BALB/c but not C57BL/6 mice, and cross-reacted with pH1N1 M2e. The ca-immunized mice did not develop antibodies against M2e. Despite sequence differences between vaccine and challenge virus NP and M2e epitopes, extensive cross-reactivity of lung T cells with pH1N1 peptides was detected following immunization. Both ca and NP+M2-rAd immunization protected BALB/c and C57BL/6 mice against challenge with a mouse-adapted pH1N1 virus.Conclusion/significanceCross-protective vaccines such as NP+M2-rAd and ca virus are effective against pH1N1 challenge within 3 weeks of immunization. Protection was not dependent on recognition of the highly variable external viral proteins and could be achieved with a single vaccine dose. The rAd vaccine was superior to the ca vaccine by certain measures, justifying continued investigation of this experimental vaccine even though ca vaccine is already available. This study highlights the potential for cross-protective vaccines as a public health option early in an influenza pandemic.
| S-EPMC3137593 | biostudies-literature
Project description:Influenza virus is a respiratory pathogen that can cause disease in humans, with symptoms ranging from mild to life-threatening. The vast majority of influenza virus infections in humans are observed during seasonal epidemics and occasional pandemics. Given the substantial public health burden associated with influenza virus infection, yearly vaccination is recommended for protection against seasonal influenza viruses. Despite vigilant surveillance for new variants and careful selection of seasonal vaccine strains, the efficacy of seasonal vaccines can vary widely from year to year. This often results in lowered protection within the population, regardless of vaccination status. In order to broaden the protection afforded by seasonal influenza vaccines, the National Institute of Allergy and Infectious Diseases (NIAID) has deemed the development of a universal influenza virus vaccine to be a priority in influenza virus vaccine research. This universal vaccine would provide protection against all influenza virus strains, eliminating the need for the yearly reformulations of seasonal influenza vaccines. In addition to universal influenza vaccine efforts, substantial progress has been made in developing novel influenza virus therapeutics that utilize broadly neutralizing antibodies to provide protection against influenza virus infection and to mitigate disease outcomes during infection. In this review, we discuss various approaches toward the goal of improving influenza virus vaccine efficacy through a universal influenza virus vaccine. We also address the novel methods of discovery and utilization of broadly neutralizing antibodies to improve influenza disease outcomes.
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