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Development of next-generation influenza virus vaccines is crucial to improve protection against circulating and emerging viruses. Current vaccine formulations have to be updated annually due to mutations in seasonal strains and do not offer protection against strains with pandemic potential. Computationally optimized broadly reactive antigen (COBRA) methodology has been utilized by our group to generate broadly reactive immunogens for individual influenza subtypes, which elicit protective immune responses against a broad range of strains over numerous seasons. Octavalent mixtures of COBRA hemagglutinin (HA) (H1, H2, H3, H5, H7, and influenza B virus) plus neuraminidase (NA) (N1 and N2) recombinant proteins mixed with c-di-AMP adjuvant were administered intranasally to naive or pre-immune ferrets in prime-boost fashion. Four weeks after final vaccination, collected sera were analyzed for breadth of antibody response, and the animals were challenged with seasonal or pre-pandemic strains. The octavalent COBRA vaccine elicited antibodies that recognized a broad panel of strains representing different subtypes, and these vaccinated animals were protected against influenza virus challenges. Overall, this study demonstrated that the mixture of eight COBRA HA/NA proteins mixed with an intranasal adjuvant is a promising candidate for a universal influenza vaccine. IMPORTANCE: Influenza is a respiratory virus which infects around a billion people globally every year, with millions experiencing severe illness. Commercial vaccine efficacy varies year to year and can be low due to mismatch of circulating virus strains. Thus, the formulation of current vaccines has to be adapted accordingly every year. The development of a broadly reactive influenza vaccine would lessen the global economic and public health burden caused by the different types of influenza viruses. The significance of our research is producing a promising universal vaccine candidate which provides protection against a wider range of virus strains over a wider range of time.
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Understanding the molecular mechanisms underpinning diverse vaccination responses is critical for developing efficient vaccines. Molecular subtyping can offer insights into heterogeneous nature of responses and aid in vaccine design. We analyzed multi-omic data from 62 haemagglutinin seasonal influenza vaccine recipients (2019-2020), including transcriptomics, proteomics, glycomics, and metabolomics data collected pre-vaccination. We performed a subtyping analysis on the integrated data revealing five subtypes with distinct molecular signatures. These subtypes differed in the expression of pre-existing adaptive or innate immunity signatures, which were linked to significant variation in baseline immunoglobulin A (IgA) and hemagglutination inhibition (HAI) titer levels. It is worth noting that these differences persisted through day 28 post-vaccination, indicating the effect of initial immune state on vaccination response. These findings highlight the significance of interpersonal variation in baseline immune status as a crucial factor in determining the effectiveness of seasonal vaccines. Ultimately, incorporating molecular profiling could enable personalized vaccine optimization.
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Anticuerpos Antivirales , Vacunas contra la Influenza , Gripe Humana , Multiómica , Vacunación , Humanos , Inmunidad Adaptativa/inmunología , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/sangre , Formación de Anticuerpos/inmunología , Pruebas de Inhibición de Hemaglutinación , Inmunidad Innata/inmunología , Inmunoglobulina A/inmunología , Inmunoglobulina A/sangre , Vacunas contra la Influenza/administración & dosificación , Vacunas contra la Influenza/inmunología , Gripe Humana/inmunología , Gripe Humana/prevención & control , Proteómica/métodos , Estaciones del AñoRESUMEN
BACKGROUND: The effect of vaccination on the epigenome remains poorly characterized. In previous research, we identified an association between seroprotection against influenza and DNA methylation at sites associated with the RIG-1 signaling pathway, which recognizes viral double-stranded RNA and leads to a type I interferon response. However, these studies did not fully account for confounding factors including age, gender, and BMI, along with changes in cell-type composition. RESULTS: Here, we studied the influenza vaccine response in a longitudinal cohort vaccinated over two consecutive years (2019-2020 and 2020-2021), using peripheral blood mononuclear cells and a targeted DNA methylation approach. To address the effects of multiple factors on the epigenome, we designed a multivariate multiple regression model that included seroprotection levels as quantified by the hemagglutination-inhibition (HAI) assay test. CONCLUSIONS: Our findings indicate that 179 methylation sites can be combined as potential signatures to predict seroprotection. These sites were not only enriched for genes involved in the regulation of the RIG-I signaling pathway, as found previously, but also enriched for other genes associated with innate immunity to viruses and the transcription factor binding sites of BRD4, which is known to impact T cell memory. We propose a model to suggest that the RIG-I pathway and BRD4 could potentially be modulated to improve immunization strategies.
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Metilación de ADN , Inmunidad Innata , Vacunas contra la Influenza , Gripe Humana , Humanos , Metilación de ADN/genética , Metilación de ADN/efectos de los fármacos , Vacunas contra la Influenza/inmunología , Vacunas contra la Influenza/administración & dosificación , Inmunidad Innata/genética , Femenino , Masculino , Gripe Humana/prevención & control , Gripe Humana/inmunología , Gripe Humana/genética , Persona de Mediana Edad , Adulto , Transducción de Señal , Linfocitos T/inmunología , Estudios Longitudinales , Epigénesis Genética , Vacunación , Proteína 58 DEAD Box/genética , Proteína 58 DEAD Box/inmunología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismoRESUMEN
Influenza seasons occur annually, building immune history for individuals, but the influence of this history on subsequent influenza vaccine protection remains unclear. We extracted data from an animal trial to study its potential impact. The trial involved 80 ferrets, each receiving either one type of infection or a placebo before vaccination. We quantified the vaccine protection by evaluating hemagglutination inhibition (HAI) antibody titer responses. We tested whether hosts with different infection histories exhibited similar level of responses when receiving the same vaccine for all homologous and heterologous outcomes. We observed that different pre-existing immunities were generally beneficial to vaccine induced responses, but varied in magnitude. Without pre-immunity, post-vaccination HAI titers after the 1st dose of the vaccine were less likely to be above 1:40, and a booster shot was needed. Our study suggests that pre-existing immunity may strengthen and extend the homologous and heterologous vaccine responses.
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Anticuerpos Antivirales , Hurones , Pruebas de Inhibición de Hemaglutinación , Vacunas contra la Influenza , Infecciones por Orthomyxoviridae , Animales , Hurones/inmunología , Vacunas contra la Influenza/inmunología , Vacunas contra la Influenza/administración & dosificación , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/prevención & control , Formación de Anticuerpos/inmunología , Vacunación , Masculino , FemeninoRESUMEN
Influenza remains a worldwide public health threat. Although seasonal influenza vaccines are currently the best means of preventing severe disease, the standard-of-care vaccines require frequent updating due to antigenic drift and can have low efficacy, particularly in vulnerable populations. Here, we demonstrate that a single administration of a recombinant adenovirus-associated virus (rAAV) vector expressing a computationally optimized broadly reactive antigen (COBRA)-derived influenza H1 hemagglutinin (HA) induces strongly neutralizing and broadly protective antibodies in naïve mice and ferrets with pre-existing influenza immunity. Following a lethal viral challenge, the rAAV-COBRA vaccine allowed for significantly reduced viral loads in the upper and lower respiratory tracts and complete protection from morbidity and mortality that lasted for at least 5 months post-vaccination. We observed no signs of antibody waning during this study. CpG motif enrichment of the antigen can act as an internal adjuvant to further enhance the immune responses to allow for lower vaccine dosages with the induction of unique interferon-producing CD4+ and CD8+ T cells specific to HA head and stem peptide sequences. Our studies highlight the utility of rAAV as an effective platform to improve seasonal influenza vaccines. IMPORTANCE: Developing an improved seasonal influenza vaccine remains an ambitious goal of researchers and clinicians alike. With influenza routinely causing severe epidemics with the potential to rise to pandemic levels, it is critical to create an effective, broadly protective, and durable vaccine to improve public health worldwide. As a potential solution, we created a rAAV viral vector expressing a COBRA-optimized influenza hemagglutinin antigen with modestly enriched CpG motifs to evoke a robust and long-lasting immune response after a single intramuscular dose without needing boosts or adjuvants. Importantly, the rAAV vaccine boosted antibody breadth to future strains in ferrets with pre-existing influenza immunity. Together, our data support further investigation into the utility of viral vectors as a potential avenue to improve our seasonal influenza vaccines.
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Inmunidad Adaptativa , Anticuerpos Antivirales , Dependovirus , Hurones , Glicoproteínas Hemaglutininas del Virus de la Influenza , Vacunas contra la Influenza , Infecciones por Orthomyxoviridae , Animales , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Glicoproteínas Hemaglutininas del Virus de la Influenza/genética , Vacunas contra la Influenza/inmunología , Vacunas contra la Influenza/administración & dosificación , Ratones , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/sangre , Infecciones por Orthomyxoviridae/prevención & control , Infecciones por Orthomyxoviridae/inmunología , Dependovirus/genética , Dependovirus/inmunología , Anticuerpos Neutralizantes/inmunología , Humanos , Femenino , Vectores Genéticos , Ratones Endogámicos BALB C , Vacunación , Gripe Humana/prevención & control , Gripe Humana/inmunología , Linfocitos T CD8-positivos/inmunologíaRESUMEN
The hemagglutinin (HA) and neuraminidase (NA) surface proteins are the primary and secondary immune targets for most influenza vaccines. In this study, H2, H5, H7, N1, and N2 antigens designed by the computationally optimized broadly reactive antigen (COBRA) methodology were incorporated into an adjuvant-formulated vaccine to assess the protective efficacy and immune response against A/Hong Kong/125/2017 H7N9 virus challenge in pre-immune mice. The elicited antibodies bound to H2, H5, H7, N1, and N2 wild-type antigens; cH6/1 antigens; and cH7/3 antigens, with hemagglutinin inhibition (HAI) activity against broad panels of the H2Nx, H5Nx, and H7Nx influenza strains. Mice vaccinated with the pentavalent COBRA HA/NA vaccine showed little to no weight loss, no clinical signs of diseases, and were protected from mortality when challenged with the lethal H7N9 virus. Virus titers in the lungs of vaccinated mice were lower and cleared more rapidly than in mock-vaccinated mice. Some vaccinated mice showed no detectable lung injury or inflammation. Antibody-secreting cells were significantly increased in COBRA-vaccinated mice, with higher total Ig and H7-specific ASC. Thus, the combination of H2, H5, H7, N1, and N2 COBRA antigens presents a potential for the formulation of a universal influenza virus vaccine.
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Influenza exposures early in life are believed to shape future susceptibility to influenza infections by imprinting immunological biases that affect cross-reactivity to future influenza viruses. However, direct serological evidence linked to susceptibility is limited. Here we analysed haemagglutination-inhibition titres in 1,451 cross-sectional samples collected between 1992 and 2020, from individuals born between 1917 and 2008, against influenza B virus (IBV) isolates from 1940 to 2021. We included testing of 'future' isolates that circulated after sample collection. We show that immunological biases are conferred by early life IBV infection and result in lineage-specific cross-reactivity of a birth cohort towards future IBV isolates. This translates into differential estimates of susceptibility between birth cohorts towards the B/Yamagata and B/Victoria lineages, predicting lineage-specific birth-cohort distributions of observed medically attended IBV infections. Our data suggest that immunological measurements of imprinting could be important in modelling and predicting virus epidemiology.
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Anticuerpos Antivirales , Reacciones Cruzadas , Virus de la Influenza B , Gripe Humana , Humanos , Virus de la Influenza B/inmunología , Reacciones Cruzadas/inmunología , Gripe Humana/inmunología , Gripe Humana/virología , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Estudios Transversales , Femenino , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Masculino , Pruebas de Inhibición de Hemaglutinación , Cohorte de Nacimiento , Adulto , Persona de Mediana Edad , Susceptibilidad a Enfermedades/inmunologíaRESUMEN
In humans, seasonal influenza viruses cause epidemics. Avian influenza viruses are of particular concern because they can infect multiple species and lead to unpredictable and severe disease. Therefore, there is an urgent need for a universal influenza vaccine that provides protection against all influenza strains. The cyclic GMP-AMP (cGAMP) is a promising adjuvant for subunit vaccines, which promotes type I interferons' production through the stimulator of interferon genes (STING) pathway. The encapsulation of cGAMP in acetalated dextran (Ace-DEX) microparticles (MPs) enhances its intracellular delivery. In this study, the Computationally Optimized Broadly Reactive Antigen (COBRA) methodology was used to generate H1, H3, and H5 vaccine candidates. Monovalent and multivalent COBRA HA vaccines formulated with cGAMP Ace-DEX MPs were evaluated in mice for protective antibody responses. cGAMP MPs adjuvanted COBRA HA vaccines elicited robust antigen-specific antibodies following vaccination. Compared with COBRA HA vaccine groups with no adjuvant or blank MPs, the cGAMP MPs enhanced HAI activity elicited by COBRA HA vaccines. The HAI activity was not significantly different between cGAMP MPs adjuvanted monovalent or multivalent COBRA HA vaccines. The cGAMP MPs adjuvanted COBRA vaccine groups had higher antigen-specific IgG2a-binding titers than the COBRA vaccine groups with no adjuvant or blank MPs. The COBRA vaccines formulated with cGAMP MPs mitigated diseases caused by influenza viral challenge and decreased pulmonary viral titers in mice. Therefore, the formulation of COBRA vaccines plus cGAMP MPs is a promising universal influenza vaccine that elicits protective immune responses against human seasonal and pre-pandemic strains. IMPORTANCE: Influenza viruses cause severe respiratory disease, particularly in the very young and the elderly. Next-generation influenza vaccines are needed to protect against new influenza variants. This report used a promising adjuvant, cyclic GMP-AMP (cGAMP), to enhance the elicited antibodies by an improved influenza hemagglutinin candidate and protect against influenza virus infection. Overall, adding adjuvants to influenza vaccines is an effective method to improve vaccines.
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Adyuvantes Inmunológicos , Anticuerpos Antivirales , Glicoproteínas Hemaglutininas del Virus de la Influenza , Vacunas contra la Influenza , Nucleótidos Cíclicos , Infecciones por Orthomyxoviridae , Animales , Femenino , Humanos , Ratones , Adyuvantes Inmunológicos/administración & dosificación , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Vacunas contra la Influenza/inmunología , Vacunas contra la Influenza/administración & dosificación , Ratones Endogámicos BALB C , Nucleótidos Cíclicos/inmunología , Nucleótidos Cíclicos/administración & dosificación , Infecciones por Orthomyxoviridae/prevención & control , Infecciones por Orthomyxoviridae/inmunologíaRESUMEN
Influenza outbreaks are a major burden worldwide annually. While seasonal vaccines do provide protection against infection, they are limited in that they need to be updated every year to account for the constantly mutating virus. Recently, lipid nanoparticles (LNPs) encapsulating mRNA have seen major success as a vaccine platform for SARS-CoV-2. Herein, we applied LNPs to deliver an mRNA encoding a computationally optimized broadly active (COBRA) influenza immunogen. These COBRA mRNA LNPs induced a broadly active neutralizing antibody response and protection after lethal influenza challenge. To further increase the immunogenicity of the COBRA mRNA LNPs, we combined them with acetalated dextran microparticles encapsulating a STING agonist. Contrary to recent findings, the STING agonist decreased the immunogenicity of the COBRA mRNA LNPs which was likely due to a decrease in mRNA translation as shown in vitro. Overall, this work aids in future selection of adjuvants to use with mRNA LNP vaccines.
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Vacunas contra la Influenza , Nanovacunas , Nucleótidos Cíclicos , Animales , Femenino , Ratones , Adyuvantes Inmunológicos/administración & dosificación , Anticuerpos Neutralizantes/inmunología , Dextranos/química , Dextranos/administración & dosificación , Inmunogenicidad Vacunal , Vacunas contra la Influenza/administración & dosificación , Vacunas contra la Influenza/inmunología , Lípidos/química , Lípidos/administración & dosificación , Liposomas , Ratones Endogámicos BALB C , Vacunas de ARNm , Nanopartículas/administración & dosificación , Nanopartículas/química , Nanovacunas/administración & dosificación , Nanovacunas/química , Nucleótidos Cíclicos/administración & dosificación , Infecciones por Orthomyxoviridae/prevención & control , Infecciones por Orthomyxoviridae/inmunología , Polímeros/química , Polímeros/administración & dosificación , ARN Mensajero/administración & dosificación , ARN Mensajero/inmunologíaRESUMEN
Background: The effect of vaccination on the epigenome remains poorly characterized. In previous research, we identified an association between seroprotection against influenza and DNA methylation at sites associated with the RIG-1 signaling pathway, which recognizes viral double-stranded RNA and leads to a type I interferon response. However, these studies did not fully account for confounding factors including age, gender, and BMI, along with changes in cell type composition. Results: Here, we studied the influenza vaccine response in a longitudinal cohort vaccinated over two consecutive years (2019-2020 and 2020-2021), using peripheral blood mononuclear cells and a targeted DNA methylation approach. To address the effects of multiple factors on the epigenome, we designed a multivariate multiple regression model that included seroprotection levels as quantified by the hemagglutination-inhibition (HAI) assay test. Conclusions: Our findings indicate that 179 methylation sites can be combined as potential signatures to predict seroprotection. These sites were not only enriched for genes involved in the regulation of the RIG-I signaling pathway, as found previously, but also enriched for other genes associated with innate immunity to viruses and the transcription factor binding sites of BRD4, which is known to impact T cell memory. We propose a model to suggest that the RIG-I pathway and BRD4 could potentially be modulated to improve immunization strategies.
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Highly pathogenic avian influenza (HPAI) viruses remain a major threat to both the poultry industry and human public health, and these viruses continue to spread worldwide. In this study, mice were vaccinated with COBRA H2, H5, and H7 hemagglutinin (HA) and two neuraminidase (NA) proteins, N1 and N2. Vaccinated mice were fully protected against lethal challenge with H5N6 influenza virus. Sera collected after vaccination showed cross-reactive IgG antibodies against a panel of wild-type H2, H5, and H7 HA proteins, and N1 and N2 NA proteins. Mice with pre-existing immunity to H1N1 and H3N2 influenza viruses that were subsequently vaccinated with COBRA HA/NA vaccines had enhanced anti-HA stem antibodies compared to vaccinated mice without pre-existing immunity. In addition, sera collected after vaccination had hemagglutinin inhibitory activity against a panel of H2Nx, H5Nx, and H7Nx influenza viruses. These protective antibodies were maintained up for up to 4 months after vaccination.
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Anticuerpos Antivirales , Glicoproteínas Hemaglutininas del Virus de la Influenza , Vacunas contra la Influenza , Neuraminidasa , Infecciones por Orthomyxoviridae , Animales , Vacunas contra la Influenza/inmunología , Vacunas contra la Influenza/administración & dosificación , Neuraminidasa/inmunología , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Infecciones por Orthomyxoviridae/prevención & control , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/virología , Ratones , Ratones Endogámicos BALB C , Femenino , Vacunación , Virus de la Influenza A/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Reacciones Cruzadas , Humanos , Proteínas Virales/inmunología , Proteínas Virales/genéticaRESUMEN
Adjuvants enhance, prolong, and modulate immune responses by vaccine antigens to maximize protective immunity and enable more effective immunization in the young and elderly. Most adjuvants are formulated with injectable vaccines. However, an intranasal route of vaccination may induce mucosal and systemic immune responses for enhancing protective immunity in individuals and be easier to administer compared to injectable vaccines. In this study, a next generation of broadly-reactive influenza hemagglutinin (HA) vaccines were developed using the Computationally Optimized Broadly Reactive Antigen (COBRA) methodology. These HA vaccines were formulated with Mastoparan 7 (M7-NH2) mast cell degranulating peptide adjuvant and administered intranasally to determine vaccine-induced seroconversion of antibodies against a panel of influenza viruses and protection following infection with H1N1 and H3N2 viruses in mice. Mice vaccinated intranasally with M7-NH2-adjuvanted COBRA HA vaccines had high HAIs against a panel of H1N1 and H3N2 influenza viruses and were protected against both morbidity and mortality, with reduced viral lung titers, following challenge with an H1N1 influenza virus. Additionally, M7-NH2 adjuvanted COBRA HA vaccines induced Th2 skewed immune responses with robust IgG and isotype antibodies in the serum and mucosal lung lavages. Overall, this intranasally delivered M7-NH2 -adjuvanted COBRA HA vaccine provides effective protection against drifted H1N1 and H3N2 viruses.
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Adyuvantes Inmunológicos , Administración Intranasal , Anticuerpos Antivirales , Glicoproteínas Hemaglutininas del Virus de la Influenza , Subtipo H1N1 del Virus de la Influenza A , Subtipo H3N2 del Virus de la Influenza A , Vacunas contra la Influenza , Infecciones por Orthomyxoviridae , Vacunas contra la Influenza/inmunología , Vacunas contra la Influenza/administración & dosificación , Animales , Ratones , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Subtipo H1N1 del Virus de la Influenza A/inmunología , Subtipo H3N2 del Virus de la Influenza A/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Anticuerpos Antivirales/inmunología , Infecciones por Orthomyxoviridae/prevención & control , Infecciones por Orthomyxoviridae/inmunología , Femenino , Ratones Endogámicos BALB C , Péptidos y Proteínas de Señalización Intercelular/inmunología , Adyuvantes de Vacunas/administración & dosificaciónRESUMEN
Participants between the ages of 10-86 years old were vaccinated with split-inactivated influenza vaccine (Fluzone®) in six consecutive influenza seasons from 2016-2017 to 2021-2022. Vaccine effectiveness varies from season to season as a result of both host immune responses as well as evolutionary changes in the influenza virus surface glycoproteins that provide challenges to vaccine manufacturers to produce more effective annual vaccines. Next generation influenza vaccines are in development and may provide protective immune responses against a broader number of influenza viruses and reduce the need for annual vaccination. An improved understanding how current influenza vaccines are influenced by human host immune responses in people of different ages and co-morbidities is necessary for designing the next-generation of 'universal' or broadly-protective influenza vaccines. Overall, pre-existing immune responses to previous influenza virus exposures, either by past infections or vaccinations, is a critical factor influencing host responses to seasonal influenza vaccination. Participants vaccinated in consecutive seasons had reduced serum hemagglutination-inhibition (HAI) activity against strains included in the vaccine compared to participants that had not been vaccinated in the preceding 1-2 years prior to entering this study. The magnitude and breadth of these antibody responses were also modulated by the age of the participant. Elderly participants over 65 years of age, in general, had lower pre-existing HAI titers each season prior to vaccination with lower post-vaccination titers compared to children or young adults under the age of 35. The administration of higher doses (HD) of the split-inactivated vaccine enhanced the antibody titers in the elderly. This report showcases 6 consecutive years of antibody HAI activity in human subjects receiving seasonal split-inactivated influenza vaccine.
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Anticuerpos Antivirales , Vacunas contra la Influenza , Gripe Humana , Estaciones del Año , Vacunas de Productos Inactivados , Humanos , Vacunas contra la Influenza/inmunología , Vacunas contra la Influenza/administración & dosificación , Adulto , Anciano , Persona de Mediana Edad , Adolescente , Niño , Anciano de 80 o más Años , Masculino , Gripe Humana/prevención & control , Gripe Humana/inmunología , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/sangre , Femenino , Adulto Joven , Vacunas de Productos Inactivados/inmunología , Vacunación , Pruebas de Inhibición de Hemaglutinación , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Estudios LongitudinalesRESUMEN
The influenza viruses cause seasonal respiratory illness that affect millions of people globally every year. Prophylactic vaccines are the recommended method to prevent the breakout of influenza epidemics. One of the current commercial influenza vaccines consists of inactivated viruses that are selected months prior to the start of a new influenza season. In many seasons, the vaccine effectiveness (VE) of these vaccines can be relatively low. Therefore, there is an urgent need to develop an improved, more universal influenza vaccine (UIV) that can provide broad protection against various drifted strains in all age groups. To meet this need, the computationally optimized broadly reactive antigen (COBRA) methodology was developed to design a hemagglutinin (HA) molecule as a new influenza vaccine. In this study, COBRA HA-based inactivated influenza viruses (IIV) expressing the COBRA HA from H1 or H3 influenza viruses were developed and characterized for the elicitation of immediate and long-term protective immunity in both immunologically naïve or influenza pre-immune animal models. These results were compared to animals vaccinated with IIV vaccines expressing wild-type H1 or H3 HA proteins (WT-IIV). The COBRA-IIV elicited long-lasting broadly reactive antibodies that had hemagglutination-inhibition (HAI) activity against drifted influenza variants.
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Anticuerpos Antivirales , Glicoproteínas Hemaglutininas del Virus de la Influenza , Vacunas contra la Influenza , Infecciones por Orthomyxoviridae , Vacunas de Productos Inactivados , Vacunas contra la Influenza/inmunología , Vacunas contra la Influenza/administración & dosificación , Animales , Vacunas de Productos Inactivados/inmunología , Vacunas de Productos Inactivados/administración & dosificación , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Infecciones por Orthomyxoviridae/prevención & control , Infecciones por Orthomyxoviridae/inmunología , Ratones , Femenino , Ratones Endogámicos BALB C , Humanos , Gripe Humana/prevención & control , Gripe Humana/inmunología , Eficacia de las Vacunas , Pruebas de Inhibición de HemaglutinaciónRESUMEN
Influenza causes significant morbidity and mortality. As an alternative approach to current seasonal vaccines, the computationally optimized broadly reactive antigen (COBRA) platform has been previously applied to hemagglutinin (HA). This approach integrates wild-type HA sequences into a single immunogen to expand the breadth of accessible antibody epitopes. Adding to previous studies of H1, H3, and H5 COBRA HAs, we define the structural features of another H1 subtype COBRA, X6, that incorporates HA sequences from before and after the 2009 H1N1 influenza pandemic. We determined structures of this antigen alone and in complex with COBRA-specific as well as broadly reactive and functional antibodies, analyzing its antigenicity. We found that X6 possesses features representing both historic and recent H1 HA strains, enabling binding to both head- and stem-reactive antibodies. Overall, these data confirm the integrity of broadly reactive antibody epitopes of X6 and contribute to design efforts for a next-generation vaccine.
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Anticuerpos Antivirales , Glicoproteínas Hemaglutininas del Virus de la Influenza , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Glicoproteínas Hemaglutininas del Virus de la Influenza/química , Humanos , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/química , Modelos Moleculares , Antígenos Virales/inmunología , Antígenos Virales/química , Antígenos Virales/genética , Epítopos/inmunología , Epítopos/química , Vacunas contra la Influenza/inmunología , Vacunas contra la Influenza/química , Subtipo H1N1 del Virus de la Influenza A/inmunología , Subtipo H1N1 del Virus de la Influenza A/química , Gripe Humana/inmunología , Gripe Humana/virología , Cristalografía por Rayos X , Unión ProteicaRESUMEN
OBJECTIVE: Psychological distress has been associated with dampened antibody production following vaccination. Questions remain, however, about whether psychological distress influences vaccine response uniformly across the lifespan, and whether changes in distress result in changes in antibody production across the same period. METHODS: Participants (N = 148; Mage = 32.2 years, SD = 19.7, range = 12-80 years) took part in consecutive vaccine studies during the 2017-2018 and 2018-2019 influenza seasons. Each influenza season, they reported on their depressive symptoms, provided blood samples, and received the standard influenza vaccine. Participants then provided a second blood sample one month later. Antibody titers were examined pre- and post-vaccination. RESULTS: Analyses examined both within-season and across-season effects of depressive symptoms, age, and their interaction on vaccine response. Within-season analyses revealed that age predicted antibody response during both seasons (2017-2018 and 2018-2019). Neither depressive symptoms nor the interaction with age were associated with antibody response to vaccination within either season. Across the two seasons, age significantly moderated the association between change in depressive symptoms and change in antibody production. For people who were 48 or older, increases in depressive symptoms across the two seasons were associated with a less robust response to the vaccine in the second season relative to the first season. For people younger than 48, changes in depressive symptoms were not significantly related to changes in antibody production. CONCLUSIONS: These findings highlight the important role of mental health for older adults' vaccine response, which could have clinical relevance for protection against disease.
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Anticuerpos Antivirales , Formación de Anticuerpos , Depresión , Vacunas contra la Influenza , Gripe Humana , Vacunación , Humanos , Vacunas contra la Influenza/inmunología , Vacunas contra la Influenza/administración & dosificación , Adolescente , Adulto , Depresión/inmunología , Masculino , Femenino , Adulto Joven , Persona de Mediana Edad , Gripe Humana/prevención & control , Gripe Humana/inmunología , Anciano , Anciano de 80 o más Años , Anticuerpos Antivirales/sangre , Vacunación/psicología , Formación de Anticuerpos/inmunología , Niño , Estaciones del AñoRESUMEN
Adjuvants enhance immune responses stimulated by vaccines. To date, many seasonal influenza vaccines are not formulated with an adjuvant. In the present study, the adjuvant Advax-SM™ was combined with next generation, broadly reactive influenza hemagglutinin (HA) vaccines that were designed using a computationally optimized broadly reactive antigen (COBRA) methodology. Advax-SM™ is a novel adjuvant comprising inulin polysaccharide and CpG55.2, a TLR9 agonist. COBRA HA vaccines were combined with Advax-SM™ or a comparator squalene emulsion (SE) adjuvant and administered to mice intramuscularly. Mice vaccinated with Advax-SM™ adjuvanted COBRA HA vaccines had increased serum levels of anti-influenza IgG and IgA, high hemagglutination inhibition activity against a panel of H1N1 and H3N2 influenza viruses, and increased anti-influenza antibody secreting cells isolated from spleens. COBRA HA plus Advax-SM™ immunized mice were protected against both morbidity and mortality following viral challenge and, at postmortem, had no detectable lung viral titers or lung inflammation. Overall, the Advax-SM™-adjuvanted COBRA HA formulation provided effective protection against drifted H1N1 and H3N2 influenza viruses.