RESUMEN
Influenza viruses infect 5-30% of the world's population annually, resulting in millions of incidents of hospitalization and thousands of mortalities worldwide every year. Although annual vaccination has significantly reduced hospitalization rates in vulnerable populations, the current vaccines are estimated to offer a wide range of protection from 10 to 60% annually. Such incomplete immunity may be related to both poor antigenic coverage of circulating strains, as well as to the insufficient induction of protective immunity. Beyond the role of hemagglutinin (HA) and neuraminidase (NA), vaccine-induced Abs have the capacity to induce a broader array of Ab effector functions, including Ab-dependent cellular cytotoxicity, that has been implicated in universal immunity against influenza viruses. However, whether different vaccine platforms can induce functional humoral immunity in a distinct manner remains incompletely defined. In this study, we compared vaccine-induced humoral immune responses induced by two seasonal influenza vaccines in Homo sapiens, the i.m. inactivated vaccine (IIV/Fluzone) and the live attenuated mucosal vaccine (LAIV/FluMist). Whereas the inactivated influenza vaccine induced superior Ab titers and FcγR binding capacity to diverse HA and NA Ags, the live attenuated influenza mucosal vaccine induced a more robust functional humoral immune response against both the HA and NA domains. Multivariate Ab analysis further highlighted the significantly different overall functional humoral immune profiles induced by the two vaccines, marked by differences in IgG titers, FcR binding, and both NK cell-recruiting and opsonophagocytic Ab functions. These results highlight the striking differences in Ab Fc-effector profiles induced systemically by two distinct influenza vaccine platforms.
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Vacunas contra la Influenza , Gripe Humana , Orthomyxoviridae , Humanos , Inmunidad Humoral , Estaciones del Año , Vacunación , Hemaglutininas , Vacunas Atenuadas , Vacunas de Productos Inactivados , Anticuerpos AntiviralesRESUMEN
The long-term effects of host factors on vaccine-elicited immune responses have not been well studied, and the interactions of host factors with annual influenza vaccinations are yet to be explored. We analyzed data from a cohort of 386 individuals who received the standard-dose influenza vaccine and enrolled in ≥2 seasons from 2016 to 2020. Our analyses indicated disparate vaccine-elicited immune responses between males and females in adults when they were repeatedly vaccinated for at least 2 seasons. Notably, we found interactive effects between age and body mass index (BMI) on overall immune responses, and between sex at birth and BMI in adults.
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Vacunas contra la Influenza , Gripe Humana , Masculino , Adulto , Femenino , Recién Nacido , Humanos , Gripe Humana/prevención & control , Inmunidad Humoral , Estudios de Seguimiento , Anticuerpos Antivirales , Vacunación , Pruebas de Inhibición de HemaglutinaciónRESUMEN
The seasonal influenza vaccine is only effective in half of the vaccinated population. To identify determinants of vaccine efficacy, we used data from > 1,300 vaccination events to predict the response to vaccination measured as seroconversion as well as hemagglutination inhibition (HAI) titer levels one year after. We evaluated the predictive capabilities of age, body mass index (BMI), sex, race, comorbidities, vaccination history, and baseline HAI titers, as well as vaccination month and vaccine dose in multiple linear regression models. The models predicted the categorical response for > 75% of the cases in all subsets with one exception. Prior vaccination, baseline titer level, and age were the major determinants of seroconversion, all of which had negative effects. Further, we identified a gender effect in older participants and an effect of vaccination month. BMI had a surprisingly small effect, likely due to its correlation with age. Comorbidities, vaccine dose, and race had negligible effects. Our models can generate a new seroconversion score that is corrected for the impact of these factors which can facilitate future biomarker identification.
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Vacunas contra la Influenza , Gripe Humana , Anciano , Anticuerpos Antivirales , Pruebas de Inhibición de Hemaglutinación , Humanos , Gripe Humana/prevención & control , VacunaciónRESUMEN
Current seasonal influenza vaccines are limited in that they need to be reformulated every year in order to account for the constant mutation of the virus. Hemagglutinin (HA) immunogens have been developed using a computationally optimized broadly reactive antigen (COBRA) methodology, which are able to elicit an antibody response that neutralizes antigenically distinct influenza strains; however, subunit proteins are not immunogenic enough on their own to generate a substantial immune response. Due to this, different delivery strategies and adjuvants can be used to improve immunogenicity. Recently, we reported a new coordination polymer composed of the dipeptide carnosine and zinc (ZnCar) that is able to deliver protein antigens along with CpG to generate a potent immune response. In the present work, ZnCar was used to deliver the COBRA HA immunogen Y2 and the adjuvant CpG. We incorporated Y2 into ZnCar using two different methods to assess which would be the most immunogenic. Mice vaccinated with Y2 and CpG complexed with ZnCar showed an improved humoral and cellular response when compared to mice vaccinated with soluble Y2 and CpG. Further, we demonstrate in vitro that when Y2 and CpG are coordinated with ZnCar, they are protected from degradation at 40 °C for 3 months or 24 °C for 6 months. Overall, ZnCar shows promise as a delivery vehicle for subunit vaccines, given its superior immunogenicity and in vitro storage stability.
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Carnosina , Vacunas contra la Influenza , Gripe Humana , Animales , Ratones , Humanos , Adyuvantes Inmunológicos , Adyuvantes Farmacéuticos , PolímerosRESUMEN
A key to improving vaccine design and vaccination strategy is to understand the mechanism behind the variation of vaccine response with host factors. Glycosylation, a critical modulator of immunity, has no clear role in determining vaccine responses. To gain insight into the association between glycosylation and vaccine-induced antibody levels, we profiled the pre- and postvaccination serum protein glycomes of 160 Caucasian adults receiving the FLUZONE influenza vaccine during the 2019-2020 influenza season using lectin microarray technology. We found that prevaccination levels of Lewis A antigen (Lea) are significantly higher in nonresponders than responders. Glycoproteomic analysis showed that Lea-bearing proteins are enriched in complement activation pathways, suggesting a potential role of glycosylation in tuning the activities of complement proteins, which may be implicated in mounting vaccine responses. In addition, we observed a postvaccination increase in sialyl Lewis X antigen (sLex) and a decrease in high mannose glycans among high responders, which were not observed in nonresponders. These data suggest that the immune system may actively modulate glycosylation as part of its effort to establish effective protection postvaccination.
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Vacunas contra la Influenza , Gripe Humana , Anticuerpos Antivirales , Glicosilación , Humanos , Gripe Humana/prevención & control , Manosa/metabolismo , Polisacáridos/metabolismo , Proteínas/metabolismoRESUMEN
OBJECTIVE: The purpose of this study was to explore how both ongoing emotional distress and the experience of a targeted rejection over the past 6 months are associated with adolescents' antibody response to influenza virus vaccination. We predicted that experiencing a targeted rejection would amplify the hypothesized negative association between emotional distress and antibody response after vaccination. METHODS: Adolescent participants (N = 148) completed two study visits (mean [standard deviation] days between visits = 27.4 [1.8]). At the first visit, they provided blood samples, were administered the seasonal (2018-2019) quadrivalent influenza vaccine (Fluzone, Sanofi Pasteur), completed questionnaires, and participated in a semistructured interview. At the second visit, they provided another blood sample. Hemagglutination-inhibition assays were conducted to determine prevaccination and postvaccination antibody titers. Targeted rejection experiences were coded from adolescents' interviews. RESULTS: The emotional distress by targeted rejection interaction predicted antibody response to the two A strains and the composite of all vaccine strains (b values = -0.451 to -0.843, p values < .05), but not the two B strains. Results suggested that, among adolescents who experienced a targeted rejection over the past 6 months, emotional distress was negatively associated with vaccine response (however, this finding did not reach statistical significance). Conversely, among adolescents who did not experience a targeted rejection, emotional distress was positively associated with vaccine response (b = 0.173, p = .032). CONCLUSIONS: The current study highlights the importance of evaluating both acute life events and ongoing distress as they relate to adaptive immune functioning in adolescence.
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Vacunas contra la Influenza , Gripe Humana , Distrés Psicológico , Adolescente , Anticuerpos Antivirales , Formación de Anticuerpos , Humanos , Subtipo H3N2 del Virus de la Influenza A , Gripe Humana/prevención & control , VacunaciónRESUMEN
Most preclinical animal studies test influenza vaccines in immunologically naive animal models, even though the results of vaccination may not accurately reflect the effectiveness of vaccine candidates in humans that have preexisting immunity to influenza. In this study, novel, broadly reactive influenza vaccine candidates were assessed in preimmune ferrets. These animals were infected with different H1N1 isolates before being vaccinated or infected with another influenza virus. Previously, our group has described the design and characterization of computationally optimized broadly reactive hemagglutinin (HA) antigens (COBRA) for H1N1 isolates. Vaccinating ferrets with virus-like particle (VLP) vaccines expressing COBRA HA proteins elicited antibodies with hemagglutination inhibition (HAI) activity against more H1N1 viruses in the panel than VLP vaccines expressing wild-type HA proteins. Specifically, ferrets infected with the 1986 virus and vaccinated with a single dose of the COBRA HA VLP vaccines elicited antibodies with HAI activity against 11 to 14 of the 15 H1N1 viruses isolated between 1934 and 2013. A subset of ferrets was infected with influenza viruses expressing the COBRA HA antigens. These COBRA preimmune ferrets had superior breadth of HAI activity after vaccination with COBRA HA VLP vaccines than COBRA preimmune ferrets vaccinated with VLP vaccines expressing wild-type HA proteins. Overall, priming naive ferrets with COBRA HA based viruses or using COBRA HA based vaccines to boost preexisting antibodies induced by wild-type H1N1 viruses, COBRA HA antigens elicited sera with the broadest HAI reactivity against multiple antigenic H1N1 viral variants. This is the first report demonstrating the effectiveness of a broadly reactive or universal influenza vaccine in a preimmune ferret model.IMPORTANCE Currently, many groups are testing influenza vaccine candidates to meet the challenge of developing a vaccine that elicits broadly reactive and long-lasting protective immune responses. The goal of these vaccines is to stimulate immune responses that react against most, if not all, circulating influenza strains, over a long period of time in all populations of people. Commonly, these experimental vaccines are tested in naive animal models that do not have anti-influenza immune responses; however, humans have preexisting immunity to influenza viral antigens, particularly antibodies to the HA and NA glycoproteins. Therefore, this study investigated how preexisting antibodies to historical influenza viruses influenced HAI-specific antibodies and protective efficacy using a broadly protective vaccine candidate.
Asunto(s)
Anticuerpos Antivirales/biosíntesis , Subtipo H1N1 del Virus de la Influenza A/inmunología , Vacunas contra la Influenza/inmunología , Gripe Humana/inmunología , Animales , Anticuerpos Antivirales/inmunología , Antígenos Virales/inmunología , Hurones , Pruebas de Inhibición de Hemaglutinación , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Humanos , Subtipo H1N1 del Virus de la Influenza A/clasificación , Vacunas contra la Influenza/administración & dosificación , Gripe Humana/prevención & control , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/prevención & control , Infecciones por Orthomyxoviridae/virología , Vacunas de Partículas Similares a Virus/administración & dosificación , Vacunas de Partículas Similares a Virus/inmunologíaRESUMEN
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
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.
Asunto(s)
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
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
Influenza virus outbreaks are a major burden worldwide each year. Current vaccination strategies are inadequate due to antigenic drift/shift of the virus and the elicitation of low immune responses. The use of computationally optimized broadly reactive antigen (COBRA) hemagglutinin (HA) immunogens subvert the constantly mutating viruses; however, they are poorly immunogenic on their own. To increase the immunogenicity of subunit vaccines such as this, adjuvants can be delivered with the vaccine. For example, agonists of the stimulator of interferon genes (STING) have proven efficacy as vaccine adjuvants. However, their use in high-risk populations most vulnerable to influenza virus infection has not been closely examined. Here, we utilize a vaccine platform consisting of acetalated dextran microparticles loaded with COBRA HA and the STING agonist cyclic GMP-AMP. We examine the immunogenicity of this platform in mouse models of obesity, aging, and chemotherapy-induced immunosuppression. Further, we examine vaccine efficacy in collaborative cross mice, a genetically diverse population that mimics human genetic heterogeneity. Overall, this vaccine platform had variable efficacy in these populations supporting work to better tailor adjuvants to specific populations.
RESUMEN
Influenza B viruses (IBV) can cause severe disease and death much like influenza A viruses (IAV), with a disproportionate number of infections in children. Despite moving to a quadrivalent vaccine to include strains from both the B/Victoria and B/Yamagata lineages, vaccine effectiveness rates continue to be variable and low in many past seasons. To develop more effective influenza B virus vaccines, three novel IBV hemagglutinin (HA) vaccines were designed using a computationally optimized broadly reactive antigen (COBRA) methodology. These IBV HA proteins were expressed on the surface of a virus-like particle (VLP) and used to vaccinate ferrets that were pre-immune to historical B/Victoria or B/Yamagata lineage viruses. Ferrets vaccinated with B-COBRA HA vaccines had neutralizing antibodies with high titer HAI titer against all influenza B viruses regardless of pre-immunization history. Conversely, VLPs expressing wild-type IBV HA antigens preferentially boosted titers against viruses from the same lineage and there was little-to-no seroprotective antibodies detected in ferrets with mismatched IBV pre-immune infections. Overall, a single IBV HA developed using the COBRA methodology elicited protective broadly-reactive antibodies against current and future drifted IBVs from both lineages.
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Vacunas contra la Influenza , Gripe Humana , Infecciones por Orthomyxoviridae , Niño , Animales , Humanos , Virus de la Influenza B , Hemaglutininas , Anticuerpos Neutralizantes , Hurones , Anticuerpos Antivirales , Glicoproteínas Hemaglutininas del Virus de la Influenza , Antígenos ViralesRESUMEN
Influenza represents a major and ongoing public health hazard. Current collaborative efforts are aimed toward creating a universal flu vaccine with the goals of both improving responses to vaccination and increasing the breadth of protection against multiple strains and clades from a single vaccine. As an intermediate step toward these goals, the current work is focused on evaluating the systemic host response to vaccination in both normal and high-risk populations, such as the obese and geriatric populations, which have been linked to poor responses to vaccination. We therefore employed a metabolomics approach using a time-course (n = 5 time points) of the response to human vaccination against influenza from the time before vaccination (pre) to 90 days following vaccination. We analyzed the urinary profiles of a cohort of subjects (n = 179) designed to evenly sample across age, sex, BMI, and other demographic factors, stratifying their responses to vaccination as "High", "Low", or "None" based on the seroconversion measured by hemagglutination inhibition assay (HAI) from plasma samples at day 28 post-vaccination. Overall, we putatively identified 15,903 distinct, named, small-molecule structures (4473 at 10% FDR) among the 895 samples analyzed, with the aim of identifying metabolite correlates of the vaccine response, as well as prognostic and diagnostic markers from the periods before and after vaccination, respectively. Notably, we found that the metabolic profiles could unbiasedly separate the high-risk High-responders from the high-risk None-responders (obese/geriatric) within 3 days post-vaccination. The purine metabolites Guanine and Hypoxanthine were negatively associated with high seroconversion (p = 0.0032, p < 0.0001, respectively), while Acetyl-Leucine and 5-Aminovaleric acid were positively associated. Further changes in Cystine, Glutamic acid, Kynurenine and other metabolites implicated early oxidative stress (3 days) after vaccination as a hallmark of the High-responders. Ongoing efforts are aimed toward validating these putative markers using a ferret model of influenza infection, as well as an independent cohort of human seasonal vaccination and human challenge studies with live virus.
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Vacunas contra la Influenza , Gripe Humana , Humanos , Animales , Anciano , Anticuerpos Antivirales , Hurones , Vacunación , Pruebas de Inhibición de Hemaglutinación , MetabolomaRESUMEN
Influenza is a global health concern with millions of infections occurring yearly. Seasonal flu vaccines are one way to combat this virus; however, they are poorly protective against influenza as the virus is constantly mutating, particularly at the immunodominant hemagglutinin (HA) head group. A more broadly acting approach involves Computationally Optimized Broadly Reactive Antigen (COBRA). COBRA HA generates a broad immune response that is capable of protecting against mutating strains. Unfortunately, protein-based vaccines are often weekly immunogenic, so to help boost the immune response, we employed the use of acetalated dextran (Ace-DEX) microparticles (MPs) two ways: one to conjugate COBRA HA to the surface and a second to encapsulate cGAMP. To conjugate the COBRA HA to the surface of the Ace-DEX MPs, a poly(L-lactide)-polyethylene glycol co-polymer with a vinyl sulfone terminal group (PLLA-PEG-VS) was used. MPs encapsulating the STING agonist cGAMP were co-delivered with the antigen to form a broadly active influenza vaccine. This vaccine approach was evaluated in vivo with a prime-boost-boost vaccination schedule and illustrated generation of a humoral and cellular response that could protect against a lethal challenge of A/California/07/2009 in BALB/c mice.
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Vacunas contra la Influenza , Infecciones por Orthomyxoviridae , Animales , Humanos , Ratones , Dextranos , Gripe Humana/prevención & control , Sulfonas , Ratones Endogámicos BALB C , Infecciones por Orthomyxoviridae/prevención & control , Vacunas de SubunidadRESUMEN
Currently licensed vaccine adjuvants offer limited mucosal immunity, which is needed to better combat respiratory infections such as influenza. Mast cells (MCs) are emerging as a target for a new class of mucosal vaccine adjuvants. Here, we developed and characterized a nanoparticulate adjuvant composed of an MC activator [mastoparan-7 (M7)] and a TLR ligand (CpG). This novel nanoparticle (NP) adjuvant was co-formulated with a computationally optimized broadly reactive antigen (COBRA) for hemagglutinin (HA), which is broadly reactive against influenza strains. M7 was combined at different ratios with CpG and tested for in vitro immune responses and cytotoxicity. We observed significantly higher cytokine production in dendritic cells and MCs with the lowest cytotoxicity at a charge-neutralizing ratio of nitrogen/phosphate = 1 for M7 and CpG. This combination formed spherical NPs approximately 200 nm in diameter with self-assembling capacity. Mice were vaccinated intranasally with COBRA HA and M7-CpG NPs in a prime-boost-boost schedule. Vaccinated mice had significantly higher antigen-specific antibody responses (IgG and IgA) in serum and mucosa compared with controls. Splenocytes from vaccinated mice had significantly increased cytokine production upon antigen recall and the presence of central and effector memory T cells in draining lymph nodes. Finally, co-immunization with NPs and COBRA HA induced influenza H3N2-specific HA inhibition antibody titers across multiple strains and partially protected mice from a challenge against an H3N2 virus. These results illustrate that the M7-CpG NP adjuvant combination can induce a protective immune response with a broadly reactive influenza antigen via mucosal vaccination.
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Vacunas contra la Influenza , Gripe Humana , Infecciones por Orthomyxoviridae , Animales , Ratones , Humanos , Adyuvantes de Vacunas , Subtipo H3N2 del Virus de la Influenza A , Anticuerpos Antivirales , Adyuvantes Inmunológicos , Vacunación , Adyuvantes Farmacéuticos , Hemaglutininas , CitocinasRESUMEN
Influenza virus poses an ongoing human health threat with pandemic potential. Due to mutations in circulating strains, formulating effective vaccines remains a challenge. The use of computationally optimized broadly reactive antigen (COBRA) hemagglutinin (HA) proteins is a promising vaccine strategy to protect against a wide range of current and future influenza viruses. Though effective in preclinical studies, the mechanistic basis driving the broad reactivity of COBRA proteins remains to be elucidated. Here, we report the crystal structure of the COBRA HA termed P1 and identify antigenic and glycosylation properties that contribute to its immunogenicity. We further report the cryo-EM structure of the P1-elicited broadly neutralizing antibody 1F8 bound to COBRA P1, revealing 1F8 to recognize an atypical receptor binding site epitope via an unexpected mode of binding.
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Subtipo H1N1 del Virus de la Influenza A , Vacunas contra la Influenza , Infecciones por Orthomyxoviridae , Humanos , Hemaglutininas , Subtipo H1N1 del Virus de la Influenza A/genética , Anticuerpos Antivirales , Glicoproteínas Hemaglutininas del Virus de la Influenza/química , Glicoproteínas Hemaglutininas del Virus de la Influenza/genéticaRESUMEN
Novel cell-based assays were developed to assess antibody-dependence cellular cytotoxicity (ADCC) antibodies against both vaccine and a representative circulation strain HA and NA proteins for the 2014-15 influenza season. The four assays using target cells stably expressing one of the four proteins worked well. In pre- and post-vaccine sera from 70 participants in a pre-season vaccine trial, we found ADCC antibodies and a rise in ADCC antibody titer against target cells expressing the 4 proteins but a much higher titer for the vaccine than the circulating HA in both pre-and post-vaccine sera. These differences in HA ADCC antibodies were not reflected in differences in HA binding antibodies. Our observations suggested that relatively minor changes on the subtype HA can result in large differences in ADCC activity.
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Subtipo H1N1 del Virus de la Influenza A , Vacunas contra la Influenza , Gripe Humana , Anticuerpos Antivirales , Citotoxicidad Celular Dependiente de Anticuerpos , Reacciones Cruzadas , Glicoproteínas Hemaglutininas del Virus de la Influenza , Humanos , Gripe Humana/prevención & control , VacunaciónRESUMEN
The development of a safe and effective vaccine is a key requirement to overcoming the COVID-19 pandemic. Recombinant proteins represent the most reliable and safe vaccine approach but generally require a suitable adjuvant for robust and durable immunity. We used the SARS-CoV-2 genomic sequence and in silico structural modelling to design a recombinant spike protein vaccine (Covax-19™). A synthetic gene encoding the spike extracellular domain (ECD) was inserted into a baculovirus backbone to express the protein in insect cell cultures. The spike ECD was formulated with Advax-SM adjuvant and first tested for immunogenicity in C57BL/6 and BALB/c mice. Covax-19 vaccine induced high spike protein binding antibody levels that neutralised the original lineage B.1.319 virus from which the vaccine spike protein was derived, as well as the variant B.1.1.7 lineage virus. Covax-19 vaccine also induced a high frequency of spike-specific CD4 + and CD8 + memory T-cells with a dominant Th1 phenotype associated with the ability to kill spike-labelled target cells in vivo. Ferrets immunised with Covax-19 vaccine intramuscularly twice 2 weeks apart made spike receptor binding domain (RBD) IgG and were protected against an intranasal challenge with SARS-CoV-2 virus given two weeks after the last immunisation. Notably, ferrets that received the two higher doses of Covax-19 vaccine had no detectable virus in their lungs or in nasal washes at day 3 post-challenge, suggesting that in addition to lung protection, Covax-19 vaccine may have the potential to reduce virus transmission. This data supports advancement of Covax-19 vaccine into human clinical trials.
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COVID-19 , Glicoproteína de la Espiga del Coronavirus , Animales , Anticuerpos Antivirales , Hurones , Humanos , Inmunización , Inulina/análogos & derivados , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Pandemias , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/genéticaRESUMEN
Pre-existing immunity to influenza is dependent on a number of factors and can vary greatly within and across influenza subtypes. In this study, volunteers (aged 18-85 years) were vaccinated with split, inactivated FluzoneTM in four consecutive influenza seasons from 2013 to 2016. The impact of repeat vaccination on breadth and durability of functional antibodies was assessed for total IgG and IgA anti-hemagglutinin (HA) binding antibodies and hemagglutination-inhibition (HAI) activity against both influenza B lineages. Many subjects were able to maintain high seroprotective titers to the vaccine strains in subsequent years, which resulted in low vaccine-induced seroconversion rates. This was especially evident in younger subjects who typically had higher titers and maintained these titers into the following season. In contrast, the HAI titers in elderly subjects were generally lower and more likely to decline prior to the start of the next influenza season. Immunological recall or 'back-boosting' to antigenically related viruses was associated with seroconversion. Overall, influenza vaccination in both younger and older people elicited broadly reactive immune responses within a lineage, as well as cross-reactive immune responses between lineages. This study exemplified the impact that age and influenza exposure history have on determining an individual's ability to respond to future influenza infections.