RESUMEN
Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic disease affecting camels and humans. The live attenuated vaccine represents a candidate human vaccine because it can induce strong immune responses in immunized hosts. The attenuated vaccine strain of the highly pathogenic virus can also be used to produce a cell-based vaccine in the BSL2 GMP facility. In this study, we evaluated the reversion potential of pathogenicity to pathogenic wild-type virus to ensure the safety of the live attenuated vaccine strain. We passaged our previously developed cold-adapted live attenuated MERS-CoV vaccine strain at 22 °C (EMC2012-CA22°C) in Vero cells at 37 °C as often as 15 times to determine the potential of pathogenicity reversion in hDPP4 (human dipeptidyl peptidase 4)-transgenic mice, K18-hDPP4. The serial passage of EMC2012-CA22°C in Vero cells at 37 °C up to 15 times did not result in pathogenicity reversion to wild-type MERS-CoV. In K18-hDPP4 mice infected with this virus, no weight loss or mortality was observed, and no virus was detected in tissues such as the lung, kidney, brain, and nasal turbinate. In addition, mice immunized with this virus produced a robust neutralizing antibody response and were fully protected from lethal challenge with wild-type MERS-CoV. The cold-adapted attenuated MERS-CoV vaccine strain (EMC2012-CA22°C) was not reverted to wild-type pathogenic virus after 15 passages in Vero cells at 37 °C.
Asunto(s)
Frío , Coronavirus del Síndrome Respiratorio de Oriente Medio , Vacunas Atenuadas , Vacunas Virales , Animales , Chlorocebus aethiops , Células Vero , Coronavirus del Síndrome Respiratorio de Oriente Medio/genética , Coronavirus del Síndrome Respiratorio de Oriente Medio/inmunología , Vacunas Atenuadas/inmunología , Ratones , Vacunas Virales/inmunología , Vacunas Virales/genética , Infecciones por Coronavirus/prevención & control , Infecciones por Coronavirus/virología , Infecciones por Coronavirus/inmunología , Ratones Transgénicos , Humanos , Anticuerpos Antivirales/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/sangre , Pase Seriado , Dipeptidil Peptidasa 4/genética , FemeninoRESUMEN
Rotavirus (RV) vaccines have demonstrated substantial effectiveness in reducing the healthcare burden caused by gastroenteritis (RVGE) worldwide. This study aims to understand the differential impact of RV vaccination in reducing RVGE burden in children under 7 years old in China. A Markov Model was used to investigate the health impact of introducing two different RV vaccines into the Chinese population. The analysis was conducted for RV5, a live pentavalent human-bovine reassortant vaccine, and Lanzhou Lamb RV (LLR), a live-attenuated monovalent RV vaccine, separately, by comparing the strategy of each vaccine to no vaccination within a Chinese birth cohort, including 100,000 children modeled until 7 years of age. The vaccination scenario assumed a vaccination coverage of 2.5%, 2.5%, 90% and 5% for doses one, two, three and no vaccine, respectively, for both vaccines. Strategies with RV5, LLR, and no vaccination were associated with 9,895, 49,069, and 64,746 symptomatic RV infections, respectively. RV5 and LLR were associated with an 85% and 24% reduction in the total symptomatic RV infections, respectively, suggesting that the health benefits of RV5 are at least three-fold greater than those associated with the LLR. Further, strategies with RV5 and LLR resulted in an estimated 206 and 59-year increase in quality-adjusted life years (QALYs), respectively. Sensitivity and scenario analyses supported the robustness of the base-case findings. Use of RV vaccine is expected to improve RV-associated health outcomes and its adoption will help alleviate the burden of RVGE in China. RV5 use will result in significantly better health outcomes.
Asunto(s)
Gastroenteritis , Infecciones por Rotavirus , Vacunas contra Rotavirus , Vacunación , Humanos , Vacunas contra Rotavirus/administración & dosificación , Vacunas contra Rotavirus/inmunología , Infecciones por Rotavirus/prevención & control , China/epidemiología , Lactante , Preescolar , Vacunación/estadística & datos numéricos , Niño , Gastroenteritis/prevención & control , Gastroenteritis/virología , Gastroenteritis/epidemiología , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/inmunología , Cobertura de Vacunación/estadística & datos numéricos , Cadenas de Markov , Recién Nacido , Masculino , Rotavirus/inmunología , FemeninoRESUMEN
Largemouth bass ranavirus (LMBV) causes disease outbreaks and high mortality at all stages of largemouth bass farming. Therefore, live vaccine development is critical for largemouth bass prevention against LMBV by immersion immunization. Herein, an attenuated LMBV strain with good immunogenicity, designated as LMBV-2007136, was screened from the natural LMBV strains bank through challenge assay and immersion immunization experiment. After determing the safe concentration range of LMBV-2007136, the minimum immunizing dose of immersion immunization was verified. When largemouth bass were vaccinated by immersion at the lowest concentration of 102.0 TCID50/mL, all of fish were survival post virulent LMBV challenge, and the relative percent survival (RPS) was 100 %. And the immune gene expression levels of IL-10, IL-12, IFN-γ, and IgM in the spleen and kidney post-vaccination were significantly up-regulated compared to the control group, but TNF-α expression showed no significant changes. The safety and efficacy of LMBV-2007136 at passages P8, P13, and P18 were futher assessed, and no death of largemouth bass was observed within 21 days post-immunization and RPS of three vaccination groups was 100 %, suggesting that the safety and efficacy of the attenuated strain at different passages was stable. Furthermore, in the virulence reversion test, the attenuated strain was propagated through 5 times in largemouth bass by intraperitoneal injection and no abnormality and mortality were observed, further proving the attenuated vaccine candidate LMBV-2007136 was safe. These results proved that LMBV-2007136 could be a promising candidate for a live vaccine to protect largemouth bass from LMBV disease.
Asunto(s)
Lubina , Infecciones por Virus ADN , Enfermedades de los Peces , Ranavirus , Vacunas Atenuadas , Vacunas Virales , Animales , Lubina/inmunología , Ranavirus/inmunología , Enfermedades de los Peces/prevención & control , Enfermedades de los Peces/inmunología , Enfermedades de los Peces/virología , Infecciones por Virus ADN/veterinaria , Infecciones por Virus ADN/prevención & control , Infecciones por Virus ADN/inmunología , Vacunas Virales/inmunología , Vacunas Virales/administración & dosificación , Vacunas Atenuadas/inmunología , Vacunas Atenuadas/administración & dosificación , Inmunización/veterinaria , Inmersión , Vacunación/veterinariaRESUMEN
Aeromonas veronii is an opportunistic pathogen that poses great threat to aquaculture and human health, so there is an urgent need for green and efficient methods to deal with its infection. In this study, single and double gene deletion strains (AV-ΔaroA, AV-Δppk1 and AV-ΔaroA/ppk1) that can be stably inherited were constructed. Pathogenicity test showed that the toxicity of AV-ΔaroA and AV-ΔaroA/ppk1 was significantly lower compared to wild-type A. veronii. Biological characterization analysis revealed that the decrease in pathogenicity might be due to the declined growth, motility, biofilm formation abilities and the expression of virulence-related genes in mutants. Subsequently, we evaluated the efficacy of AV-ΔaroA/ppk1 as a live attenuated vaccine (LAV). Safety assessment experiments showed that AV-ΔaroA/ppk1 injected at a concentration of 3 × 107 CFU/mL was safe for C. carassius. The relative percentage survival of AV-ΔaroA/ppk1 was 67.85 %, significantly higher than that of the inactivated A. veronii, which had an RPS of 54.84 %. This improved protective effect was mainly attributed to the increased levels of A. veronii specific IgM antibody, enhanced alkaline phosphatase, lysozyme and superoxide dismutase activities, as well as higher expression levels of several immune related genes. Together, these findings deepen our understanding of the functional roles of aroA and ppk1 in A. veronii pathogenicity, provide a good candidate of LAV for A. veronii.
Asunto(s)
Aeromonas veronii , Vacunas Bacterianas , Enfermedades de los Peces , Infecciones por Bacterias Gramnegativas , Vacunas Atenuadas , Aeromonas veronii/patogenicidad , Aeromonas veronii/fisiología , Aeromonas veronii/inmunología , Vacunas Atenuadas/inmunología , Vacunas Bacterianas/inmunología , Infecciones por Bacterias Gramnegativas/veterinaria , Infecciones por Bacterias Gramnegativas/inmunología , Infecciones por Bacterias Gramnegativas/prevención & control , Enfermedades de los Peces/prevención & control , Enfermedades de los Peces/inmunología , Enfermedades de los Peces/microbiología , Animales , Virulencia , Proteínas Bacterianas/genética , Proteínas Bacterianas/inmunología , Carpas/inmunología , Eliminación de GenRESUMEN
Vasovagal syncope, or fainting, can be triggered by various stimuli, including medical procedures. Syncope after vaccination has been reported, most commonly among adolescents, and can result in injuries. Using the Vaccine Adverse Event Reporting System (VAERS), we reviewed and summarized reports of syncope after live attenuated influenza vaccine, intranasal (LAIV) administered as the sole vaccine (i.e., no concomitant injections). From June 17, 2003 (date of LAIV licensure in the US) through May 31, 2024, VAERS received 50 reports of syncope after LAIV. Nearly half (23; 46 %) pertained to individuals 10-19 years of age. While the vast majority of reports (35; 70 %) did not describe any injuries, 15 people (30 %) were injured, most commonly by falling and hitting their head or face. Twenty-two people (44 %) required evaluation in the emergency department or doctor's office, including an individual who lost consciousness while he was driving home from the vaccination appointment. He did not report any injuries, but the car was severely damaged. Nearly three-quarters of people (37; 74 %) developed syncope within 15 min after vaccination, but fewer than half of reports (24; 48 %) stated that the patient had waited in the observation area for at 15 min. Based on approximately 111.9 million doses of LAIV distributed in the US during the same time period, the reporting rate is approximately 0.4 per million doses, suggesting that syncope following LAIV is rare. The information summarized here may enable clinicians, patients, and caregivers to make a more informed decision regarding preventing injuries that may occur following LAIV-related syncope.
Asunto(s)
Sistemas de Registro de Reacción Adversa a Medicamentos , Vacunas contra la Influenza , Síncope , Vacunas Atenuadas , Humanos , Vacunas contra la Influenza/efectos adversos , Vacunas contra la Influenza/administración & dosificación , Adolescente , Vacunas Atenuadas/efectos adversos , Vacunas Atenuadas/administración & dosificación , Adulto Joven , Adulto , Masculino , Femenino , Sistemas de Registro de Reacción Adversa a Medicamentos/estadística & datos numéricos , Niño , Síncope/etiología , Síncope/epidemiología , Persona de Mediana Edad , Gripe Humana/prevención & control , Gripe Humana/complicaciones , Estados Unidos/epidemiología , Anciano , Vacunación/efectos adversos , Administración IntranasalRESUMEN
BACKGROUND: Toxoplasma gondii is an intracellular opportunistic pathogenic protozoan that poses serious threats, particularly in immunocompromised individuals. In the absence of a robust prophylactic measure, the mitigation and management of toxoplasmosis present formidable challenges to public health. We recently found that GRA72 plays an important role in parasitophorous vacuole (PV) morphology, growth and virulence of T. gondii. However, whether gra72-deficient strain can be used as a vaccine remains unknown. METHODS: We first examined the attenuated virulence of gra72 gene knockout strain (PruΔgra72) and the parasite load in organs of the infected mice. Subsequently, we evaluated the immune-protective effects of the PruΔgra72 vaccination against challenge with various types of T. gondii tachyzoites and Pru cysts. Furthermore, levels of antibodies and cytokines induced by PruΔgra72 vaccination were examined. Statistical analysis was conducted by Student's t-test or Mantel-Cox log-rank test based on data obtained from three independent experiments with GraphPad Prism 8.0. RESULTS: We found that PruΔgra72 strain exhibited a significantly attenuated virulence even at the highest dose of 5 × 107 tachyzoites in Kunming mice model. The significant decrease of brain cyst burden and parasite load in the organs of the PruΔgra72-infected mice suggested its potentiality as a live-attenuated vaccine. Hence, we explored the protective immunity of PruΔgra72 vaccination against toxoplasmosis. Results showed that vaccination with 5 × 106 PruΔgra72 tachyzoites triggered a strong and sustained Th1-biased immune response, marked by significantly increased levels of anti-T. gondii IgG antibodies, and significantly higher levels of Th1 type cytokines (IL-2, IL-12 and IFN-γ) compared to that of Th2 type (IL-4 and IL-10). Vaccination with 5 × 106 PruΔgra72 tachyzoites in mice conferred long-term protection against T. gondii infection by less virulent tachyzoites (ToxoDB#9 PYS and Pru strains) and Pru cysts, provided partial protection against acute infection by high virulent Type I RH tachyzoites and significantly decreased brain cyst burden of chronically infected mice. CONCLUSIONS: The avirulent PruΔgra72 induced strong protective immunity against acute and chronic T. gondii infection and is a promising candidate for developing a safe and effective live-attenuated vaccine against T. gondii infection.
Asunto(s)
Anticuerpos Antiprotozoarios , Proteínas Protozoarias , Vacunas Antiprotozoos , Toxoplasma , Toxoplasmosis Animal , Vacunas Atenuadas , Animales , Toxoplasma/inmunología , Toxoplasma/genética , Ratones , Vacunas Antiprotozoos/inmunología , Vacunas Antiprotozoos/administración & dosificación , Vacunas Atenuadas/inmunología , Vacunas Atenuadas/administración & dosificación , Proteínas Protozoarias/inmunología , Proteínas Protozoarias/genética , Anticuerpos Antiprotozoarios/sangre , Femenino , Toxoplasmosis Animal/prevención & control , Toxoplasmosis Animal/inmunología , Citocinas/metabolismo , Virulencia , Carga de Parásitos , Modelos Animales de Enfermedad , Enfermedad Crónica , Toxoplasmosis/prevención & control , Toxoplasmosis/inmunología , Toxoplasmosis/parasitologíaRESUMEN
African swine fever (ASF) is a highly contagious and severe hemorrhagic transboundary swine viral disease with up to a 100% mortality rate, which leads to a tremendous socio-economic loss worldwide. The lack of safe and efficacious ASF vaccines is the greatest challenge in the prevention and control of ASF. In this study, we generated a safe and effective live-attenuated virus (LAV) vaccine candidate VNUA-ASFV-LAVL3 by serially passaging a virulent genotype II strain (VNUA-ASFV-L2) in an immortalized porcine alveolar macrophage cell line (3D4/21, 50 passages). VNUA-ASFV-LAVL3 lost its hemadsorption ability but maintained comparable growth kinetics in 3D4/21 cells to that of the parental strain. Notably, it exhibited significant attenuation of virulence in pigs across different doses (103, 104, and 105 TCID50). All vaccinated pigs remained healthy with no clinical signs of African swine fever virus (ASFV) infection throughout the 28-day observation period of immunization. VNUA-ASFV-LAVL3 was efficiently cleared from the blood at 14-17 days post-infection, even at the highest dose (105 TCID50). Importantly, the attenuation observed in vivo did not compromise the ability of VNUA-ASFV-LAVL3 to induce protective immunity. Vaccination with VNUA-ASFV-LAVL3 elicited robust humoral and cellular immune responses in pigs, achieving 100% protection against a lethal wild-type ASFV (genotype II) challenge at all tested doses (103, 104, and 105 TCID50). Furthermore, a single vaccination (104 TCID50) provided protection for up to 2 months. These findings suggest that VNUA-ASFV-LAVL3 can be utilized as a promising safe and efficacious LAV candidate against the contemporary pandemic genotype II ASFV.
Asunto(s)
Virus de la Fiebre Porcina Africana , Fiebre Porcina Africana , Genotipo , Vacunas Atenuadas , Vacunas Virales , Animales , Virus de la Fiebre Porcina Africana/genética , Virus de la Fiebre Porcina Africana/inmunología , Vacunas Atenuadas/inmunología , Vacunas Atenuadas/genética , Vacunas Atenuadas/administración & dosificación , Porcinos , Fiebre Porcina Africana/prevención & control , Fiebre Porcina Africana/inmunología , Fiebre Porcina Africana/virología , Vacunas Virales/inmunología , Vacunas Virales/genética , Vacunas Virales/administración & dosificación , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Línea Celular , Virulencia , Vacunación/veterinariaRESUMEN
Severe fever with thrombocytopenia syndrome (SFTS) is a newly identified tick-borne viral hemorrhagic fever caused by Dabie Banda virus (DBV). The virus was first discovered in eastern China in 2009 and is now considered an infectious disease with a mortality rate ranging from 6.3% to 30%. The best strategy for controlling SFTS is to develop effective vaccines. However, no approved vaccines are currently available to prevent this disease, despite the number of extensive and in-depth studies conducted on DBV in the past few years. This review focuses on the structure of DBV and the induced host immune responses which are the fundamental factors in vaccine development, and thoroughly summarizes the current research progress on DBV vaccines. The developing DBV vaccines include protein subunit vaccines, live attenuated vaccines, recombinant virus vector vaccines, and DNA vaccines. At present, almost all candidate vaccines for DBV are in the laboratory development or preclinical stages. There remain challenges in successfully developing clinically approved DBV vaccines.
Asunto(s)
Vacunas Virales , Humanos , Vacunas Virales/inmunología , Animales , Vacunas Atenuadas/inmunología , Desarrollo de Vacunas , Síndrome de Trombocitopenia Febril Grave/prevención & control , Síndrome de Trombocitopenia Febril Grave/inmunología , Phlebovirus/inmunología , Phlebovirus/genética , Vacunas de ADN/inmunología , Vacunas de Subunidad/inmunologíaRESUMEN
BACKGROUND: Kenya introduced a monovalent rotavirus vaccine administered orally at 6 and 10 weeks of age into her National Immunization Program in July 2014. The study evaluated the long-term impact of the vaccine on hospitalization for all-cause and rotavirus-specific acute gastroenteritis (AGE) and strain epidemiology in Kenya. METHODS: Data on all-cause and rotavirus-specific AGE and strain distribution were derived from an eleven-year hospital-based surveillance of AGE among children aged <5 years at Kiambu County Teaching and Referral Hospital (KCTRH) in Central Kenya between 2009 and 2020. Fecal samples were screened for group A rotavirus using ELISA and genotyped using multiplex semi-nested RT-PCR. Trends in all-cause and rotavirus-related AGE and strain distribution were compared between the pre-vaccine (July 2009-June 2014), early post-vaccine (July 2014-June 2016) and late post-vaccine (February 2019-October 2020) periods. RESULTS: Rotavirus-specific AGE was detected at 27.5% (429/1546, 95% CI: 25.5-30.1%) in the pre-vaccine period; 13.8% (91/658, 95% CI: 11.3-16.6%) in the early post-vaccine period (July 2014-June 2016); and 12.0% (229/1916, 95% CI: 10.6-13.5%) in the late post-vaccine period (February 2019-October 2020). This amounted to a decline of 49.8% (95% CI: 34.6%-63.7%) in rotavirus-specific AGE in the early post-vaccine period and 53.4% (95% CI: 41.5-70.3%) in the late post-vaccine period when compared to the pre-vaccine period. All-cause AGE hospitalizations declined by 40.2% (95% CI: 30.8%-50.2%) and 75.3% (95% CI: 65.9-83.1%) in the early post-vaccine and late post-vaccine periods, respectively, when compared to the pre-vaccine period. G3P [8] was the predominant strain in the late post-vaccine period, replacing G1P[8] which had predominated in the pre-vaccine and early post-vaccine periods. Additionally, we detected considerable proportions of uncommon strains G3P[6] (4.8%) and G12P[6] (3.5%) in the post-vaccine era. CONCLUSION: Rotavirus vaccination has resulted in a significant decline in all-cause and rotavirus-specific AGE, and thus, provides strong evidence for public health policy makers in Kenya to support the sustained use of the rotavirus vaccine in routine immunization. However, the shift in strain dominance and age distribution of rotavirus AGE in the post-vaccine era underscores the need for continued surveillance to assess any possible vaccine-induced selective pressure that could diminish the vaccine effectiveness over time.
Asunto(s)
Gastroenteritis , Programas de Inmunización , Análisis de Series de Tiempo Interrumpido , Infecciones por Rotavirus , Vacunas contra Rotavirus , Rotavirus , Vacunación , Humanos , Vacunas contra Rotavirus/administración & dosificación , Vacunas contra Rotavirus/inmunología , Infecciones por Rotavirus/prevención & control , Infecciones por Rotavirus/epidemiología , Gastroenteritis/epidemiología , Gastroenteritis/virología , Gastroenteritis/prevención & control , Kenia/epidemiología , Preescolar , Rotavirus/inmunología , Rotavirus/genética , Lactante , Vacunación/estadística & datos numéricos , Hospitalización/estadística & datos numéricos , Femenino , Heces/virología , Masculino , Genotipo , Vacunas Atenuadas/inmunología , Vacunas Atenuadas/administración & dosificaciónRESUMEN
Modified Vaccinia Ankara Bavarian Nordic (MVA-BN) as a smallpox and mpox vaccine has been approved in its liquid-frozen (LF) formulation in the US, Canada, and EU. A freeze-dried (FD) formulation may offer additional benefits, such as a longer shelf life and reduced dependence on cold chain storage and transport. In a phase 2 clinical trial, 651 vaccinia-naïve participants were vaccinated with two doses of MVA-BN LF or FD, 4 weeks apart. The objectives were to compare MVA-BN FD with LF in terms of vaccine-induced immune responses, safety, and reactogenicity. Non-inferiority of the immune response was assessed by the 95% CI of the geometric mean ratios. Both formulations induced robust vaccinia-specific humoral and cellular immune responses. At peak humoral responses (Week 6), geometric means of total antibody titers were 1096 (95% CI 1013, 1186) from the FD group and 877 (95% CI 804, 956) from the LF group, achieving the primary endpoint of non-inferiority of MVA-BN FD compared to MVA-BN LF. At peak cellular responses (Week 2), geometric means of T cell spot forming units were 449 (95% CI 341, 590) from the FD group and 316 (95% CI 234, 427) from the LF group. Both formulations of MVA-BN were well tolerated, with similar unsolicited AEs and solicited systemic reactions in both groups but slightly more local reactions in the FD group. No vaccine-related serious adverse events (SAEs) or vaccine-related AE of special interest were reported. The FD formulation of MVA-BN was shown to be equivalent to MVA-BN LF.
Asunto(s)
Anticuerpos Antivirales , Liofilización , Vacuna contra Viruela , Humanos , Vacuna contra Viruela/inmunología , Vacuna contra Viruela/efectos adversos , Vacuna contra Viruela/administración & dosificación , Femenino , Masculino , Adulto , Adulto Joven , Anticuerpos Antivirales/sangre , Persona de Mediana Edad , Vacunas de ADN/inmunología , Vacunas de ADN/administración & dosificación , Vacunas de ADN/efectos adversos , Inmunidad Humoral , Inmunidad Celular , Adolescente , Viruela/prevención & control , Viruela/inmunología , Congelación , Vacunas AtenuadasRESUMEN
Live attenuated vaccines (LAVs) whose virulence would be controlled at the tissue level could be a crucial tool to effectively fight intracellular bacterial pathogens, because they would optimize the induction of protective immune memory while avoiding the long-term persistence of vaccine strains in the host. Rational development of these new LAVs implies developing an exhaustive map of the bacterial virulence genes according to the host organs implicated. We report here the use of transposon sequencing to compare the bacterial genes involved in the multiplication of Brucella melitensis, a major causative agent of brucellosis, in the lungs and spleens of C57BL/6 infected mice. We found 257 and 135 genes predicted to be essential for B. melitensis multiplication in the spleen and lung, respectively, with 87 genes common to both organs. We selected genes whose deletion is predicted to produce moderate or severe attenuation in the spleen, the main known reservoir of Brucella, and compared deletion mutants for these genes for their ability to protect mice against challenge with a virulent strain of B. melitensis. The protective efficacy of a deletion mutant for the plsC gene, implicated in phospholipid biosynthesis, is similar to that of the reference Rev.1 vaccine but with a shorter persistence in the spleen. Our results demonstrate that B. melitensis faces different selective pressures depending on the organ and underscore the effectiveness of functional genome mapping for the design of new safer LAV candidates.
Asunto(s)
Vacuna contra la Brucelosis , Brucella melitensis , Brucelosis , Ratones Endogámicos C57BL , Bazo , Animales , Brucella melitensis/inmunología , Brucella melitensis/genética , Brucella melitensis/patogenicidad , Brucelosis/prevención & control , Brucelosis/inmunología , Brucelosis/microbiología , Ratones , Bazo/microbiología , Bazo/inmunología , Vacuna contra la Brucelosis/inmunología , Vacuna contra la Brucelosis/genética , Vacunas Atenuadas/inmunología , Virulencia , Femenino , Genoma Bacteriano , Pulmón/microbiología , Pulmón/inmunologíaRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) continues its significant health and economic impact globally. Despite the success of spike-protein vaccines in preventing severe disease, long-lasting protection against emerging variants and the prevention of breakthrough infections and transmission remain elusive. We generate an intranasal live-attenuated SARS-CoV-2 vaccine, CDO-7N-1, using codon deoptimization. CDO-7N-1 shows highly attenuated replication and minimal or no lung pathology in vivo over multiple passages. It induces robust mucosal and systemic neutralizing antibody and T-cell subset responses, in mice (female K18-hACE2 and male HFH4-hACE2 mice), hamsters, and macaques triggered by a single immunization. Mice and hamsters vaccinated with CDO-7N-1 are protected from challenge with wild-type (WT) SARS-CoV-2 and other variants of concern. Serum from vaccinated animals neutralizes WT SARS-CoV-2, variants of concern (beta and delta), variants of interest (omicron XBB.1.5) and SARS-CoV-1. Antibody responses are sustained and enhanced by repeated immunization or infection with WT SARS-CoV-2. Immunity against all SARS-CoV-2 proteins by CDO-7N-1 should improve efficacy against future SARS-CoV-2 variants.
Asunto(s)
Administración Intranasal , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacunas contra la COVID-19 , COVID-19 , SARS-CoV-2 , Vacunas Atenuadas , Animales , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , SARS-CoV-2/inmunología , SARS-CoV-2/genética , COVID-19/prevención & control , COVID-19/inmunología , COVID-19/virología , Vacunas Atenuadas/inmunología , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/genética , Ratones , Anticuerpos Neutralizantes/inmunología , Femenino , Anticuerpos Antivirales/inmunología , Masculino , Humanos , Cricetinae , Codón , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/genética , Linfocitos T/inmunología , Chlorocebus aethiopsRESUMEN
Rift Valley fever (RVF) is an important zoonotic viral disease affecting several species of domestic and wild ruminants, causing major economic losses and dozens of human deaths in various geographical areas of Africa, where it is endemic. Although it is not present in Europe, there is a risk of its introduction and spread linked to globalisation and climate change. At present, the only measure that could help to prevent the disease is vaccination of flocks in areas at risk of RVF. Available live attenuated vaccines are an effective means of controlling the disease, but their use is often questioned due to residual virulence, particularly in susceptible hosts such as pregnant sheep. On the other hand, no vaccine is currently licensed for use in humans. The development of safe and effective vaccines is therefore a major area of research. In previous studies, we selected under selective mutagenic pressure a highly attenuated RVFV 56/74 virus variant called 40Fp8. This virus showed an extremely attenuated phenotype in both wild-type and immunodeficient A129 (IFNARKO) mice, yet was still able to induce protective immunity after a single inoculation, thus supporting its use as a safe, live attenuated vaccine. To further investigate its safety, in this work we have analysed the attenuation level of 40Fp8 in immunosuppressed mice (A129) when administered by the intranasal route, and compared it with other attenuated RVF viruses that are the basis of vaccines in use or in development. Our results show that 40Fp8 has a much higher attenuated level than these other viruses and confirm its potential as a candidate for safe RVF vaccine development.
Asunto(s)
Administración Intranasal , Fiebre del Valle del Rift , Virus de la Fiebre del Valle del Rift , Vacunas Atenuadas , Vacunas Virales , Animales , Fiebre del Valle del Rift/prevención & control , Fiebre del Valle del Rift/inmunología , Vacunas Atenuadas/inmunología , Vacunas Atenuadas/administración & dosificación , Virus de la Fiebre del Valle del Rift/inmunología , Ratones , Vacunas Virales/inmunología , Vacunas Virales/administración & dosificación , Femenino , Vacunación/métodos , Anticuerpos Antivirales/sangreAsunto(s)
Vacunas contra la COVID-19 , COVID-19 , SARS-CoV-2 , Vacunas Atenuadas , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Humanos , COVID-19/prevención & control , COVID-19/inmunología , COVID-19/epidemiología , SARS-CoV-2/inmunología , SARS-CoV-2/genética , Vacunas Atenuadas/inmunología , Vacunas Atenuadas/administración & dosificaciónRESUMEN
This study assesses different IBV vaccination regimens in broiler chickens using commercially available live attenuated GI-23 (Egyptian-VAR2) and GI-1 (H120) vaccines. Vaccines were administered at 1, 14 days of age, or both. The ciliostasis test, following wild-type VAR2 challenge at 28 days of age, indicated that classic H120+VAR2 at one day old followed by the VAR2 vaccine at 14 days of age provided the highest level of protection (89.58%). Similarly, administering VAR2 at 1 day of age and classic H120 at 14 days of age demonstrated substantial protection (85.42%). Conversely, administering only classic H120 and VAR2 at one day old resulted in the lowest protection level (54.17%). Tracheal virus shedding quantification and assessment of trachea and kidney degenerative changes were significantly lower in vaccinated groups compared to the unvaccinated-challenged group. In conclusion, a carefully planned vaccination regimen based on homologous vaccination offers the most effective clinical protection in broiler chickens.
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Pollos , Infecciones por Coronavirus , Virus de la Bronquitis Infecciosa , Enfermedades de las Aves de Corral , Vacunas Atenuadas , Vacunas Virales , Animales , Virus de la Bronquitis Infecciosa/inmunología , Virus de la Bronquitis Infecciosa/genética , Pollos/virología , Enfermedades de las Aves de Corral/prevención & control , Enfermedades de las Aves de Corral/virología , Enfermedades de las Aves de Corral/inmunología , Infecciones por Coronavirus/veterinaria , Infecciones por Coronavirus/prevención & control , Infecciones por Coronavirus/virología , Infecciones por Coronavirus/inmunología , Vacunas Virales/inmunología , Vacunas Virales/administración & dosificación , Vacunas Atenuadas/inmunología , Vacunas Atenuadas/administración & dosificación , Vacunación/veterinaria , Esparcimiento de Virus , Tráquea/virología , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Eficacia de las VacunasRESUMEN
Pseudomonas plecoglossicida is one of most important pathogenic bacterial species in large yellow croaker and several other commercially valuable fish species. In our previous study, a GacS deficient mutant (ΔgacS) was constructed and its virulence showed substantially attenuated. In present study, the safety, immunogenicity and protective effect of the ΔgacS were evaluated in large yellow croaker as a live-attenuated vaccine candidate. It was shown that the ΔgacS strain exhibited good safety to large yellow croaker and there was no mortality or clinical symptoms observed in all fish that infected by ΔgacS strain with the doses range from 2 × 105ï½107 CFU per fish via intraperitoneal injection (IP) or immersion (IM), and almost all bacteria were cleaned up in the spleen of the fish at 14-day post infection. Specific antibodies could be detected at 7-day and 14-day post infection by direct agglutination method, and the valences of antibodies and bactericidal activities of the serum were significant increased with vaccination doses and vaccination time. Moreover, the expressions of some molecules and cytokines involved in specific immune responses were detected in the ΔgacS strain immunization group and control group. After challenged by the wild-type (WT) strain XSDHY-P, the relative percentage survival (RPS) showed highly correlated with the immunized dosage regardless of vaccination methods. It showed that the RPS of the IP groups were 39.47 %, 57.89 %, 71.05 % with the immune dosage in a descending order, respectively, and the RPS of the IM groups were 26.31 %, 36.84 %, 76.31 % with the immune dosage in a descending order, respectively. In summary, the ΔgacS strain exhibited safety and good protective effect to large yellow croaker and was a potential live vaccine candidate.
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Enfermedades de los Peces , Perciformes , Infecciones por Pseudomonas , Pseudomonas , Vacunas Atenuadas , Animales , Enfermedades de los Peces/inmunología , Enfermedades de los Peces/prevención & control , Perciformes/inmunología , Vacunas Atenuadas/inmunología , Vacunas Atenuadas/administración & dosificación , Infecciones por Pseudomonas/veterinaria , Infecciones por Pseudomonas/prevención & control , Infecciones por Pseudomonas/inmunología , Pseudomonas/inmunología , Vacunas Bacterianas/inmunología , Vacunas Bacterianas/administración & dosificación , Vacunas contra la Infección por Pseudomonas/inmunología , Vacunas contra la Infección por Pseudomonas/genética , Inmunogenicidad VacunalRESUMEN
BACKGROUND: MTBVAC is a live attenuated tuberculosis vaccine, currently undergoing phase III evaluation for tuberculosis prevention. In previous preclinical studies, we found that local pulmonary administration of MTBVAC via the intranasal route had a strong therapeutic effect against asthma. This effect correlated with the abrogation of allergen-specific Th2 response in the lungs. METHODS: Using different mouse models of asthma, we investigated the effect of MTBVAC administered by intravenous (IV) route and its potential as immunotherapeutic agent to induce desensitisation of allergen-specific responses at a systemic level. We explored the effects of this process in the efficacy against airway hyperresponsiveness (AHR) induced by exposure to different allergens. FINDINGS: IV MTBVAC was highly efficient at reducing AHR induced by different allergens. Additionally, IV MTBVAC was found to be well-tolerated, being progressively eliminated from the different organs analysed. From a mechanistic standpoint, we observed that MTBVAC intravenous, but not intranasal, impaired allergen-specific Th2 response in both lungs and spleen. This reduction at a systemic level correlated with long-term therapeutic protection against allergen exposure. Our results also revealed differential immunological mechanisms governing systemic and local pulmonary allergen desensitisation processes. Notably, in a cohort of patients with asthma sensitive to house dust mite (HDM), in vitro incubation of peripheral blood mononuclear cells (PBMCs) with MTBVAC prevented allergen-specific production of Th2 cytokines IL-4 and IL-5. INTERPRETATION: Altogether, our results suggest that intravenous MTBVAC could be a plausible allergen desensitising approach for treatment of asthma, and could provide long-term protection against allergen exposure. FUNDING: MCIN/AEI/10.13039/501100011033 [grants number RTI2018-097625-B-I00 and PID2022-138624OB-I00]; Consorcio Centro de Investigación Biomédica en Red- (Groups CB06/06/0020 and CB06/06/0013), Instituto de Salud Carlos III.
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Administración Intravenosa , Alérgenos , Asma , Desensibilización Inmunológica , Modelos Animales de Enfermedad , Vacunas contra la Tuberculosis , Animales , Asma/inmunología , Asma/prevención & control , Ratones , Alérgenos/inmunología , Alérgenos/administración & dosificación , Humanos , Desensibilización Inmunológica/métodos , Femenino , Vacunas contra la Tuberculosis/inmunología , Vacunas contra la Tuberculosis/administración & dosificación , Pulmón/inmunología , Pulmón/patología , Células Th2/inmunología , Vacunas Atenuadas/inmunología , Vacunas Atenuadas/administración & dosificación , Citocinas/metabolismo , Ratones Endogámicos BALB CRESUMEN
BACKGROUND: Salmonella entericaserovar Choleraesuis (S.C) is a swine enteric pathogen causing paratyphoid fever, enterocolitis, and septicemia in piglets. S. C is mainly transmitted through the fecal-oral route. Vaccination is an effective strategy for preventing and controlling Salmonella infection. RESULTS: Herein, we used CRISPR-Cas9 technology to knockout the virulence regulatory genes, rpoS, and slyA of S. C and constructed the ∆rpoS, ∆slyA, and ∆rpoS ∆slyA strains. The phenotypic characteristics of the mutant strains remained unchanged compared with the parental wild-type strain. In vivo study, unlike the wild-type strain, the ∆slyA and ∆rpoS ∆slyA strains alleviated splenomegaly, colon atrophy, and lower bacterial loads in the spleen, liver, ileum, and colon. These mutant strains survived in Peyer's patches (PPs) and mesenteric lymph nodes (MLN) for up to 15 days post-infection. Furthermore, the immunization of the ∆rpoS ∆slyA strain induced robust humoral and cellular immune responses. CONCLUSIONS: Consequently, vaccination with ∆rpoS ∆slyA conferred a high percentage of protection against lethal invasive Salmonella, specifically S. C, in mice. This study provided novel insights into the development of live-attenuated vaccines against the infection of S. C.
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Salmonelosis Animal , Vacunas contra la Salmonella , Vacunas Atenuadas , Animales , Vacunas Atenuadas/inmunología , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/genética , Vacunas contra la Salmonella/inmunología , Vacunas contra la Salmonella/administración & dosificación , Vacunas contra la Salmonella/genética , Ratones , Salmonelosis Animal/prevención & control , Salmonelosis Animal/inmunología , Salmonelosis Animal/microbiología , Femenino , Ratones Endogámicos BALB C , Mutación , Virulencia/genética , Salmonella enterica/inmunología , Salmonella enterica/genética , Salmonella enterica/patogenicidad , Sistemas CRISPR-Cas , Porcinos , Inmunidad Humoral , Inmunidad CelularRESUMEN
Malaria vaccination approaches using live Plasmodium parasites are currently explored, with either attenuated mosquito-derived sporozoites or attenuated blood-stage parasites. Both approaches would profit from the availability of attenuated and avirulent parasites with a reduced blood-stage multiplication rate. Here we screened gene-deletion mutants of the rodent parasite P. berghei and the human parasite P. falciparum for slow growth. Furthermore, we tested the P. berghei mutants for avirulence and resolving blood-stage infections, while preserving sporozoite formation and liver infection. Targeting 51 genes yielded 18 P. berghei gene-deletion mutants with several mutants causing mild infections. Infections with the two most attenuated mutants either by blood stages or by sporozoites were cleared by the immune response. Immunization of mice led to protection from disease after challenge with wild-type sporozoites. Two of six generated P. falciparum gene-deletion mutants showed a slow growth rate. Slow-growing, avirulent P. falciparum mutants will constitute valuable tools to inform on the induction of immune responses and will aid in developing new as well as safeguarding existing attenuated parasite vaccines.
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Vacunas contra la Malaria , Malaria , Plasmodium berghei , Plasmodium falciparum , Esporozoítos , Vacunas Atenuadas , Animales , Vacunas contra la Malaria/inmunología , Vacunas contra la Malaria/administración & dosificación , Esporozoítos/inmunología , Plasmodium berghei/inmunología , Plasmodium berghei/genética , Plasmodium falciparum/inmunología , Plasmodium falciparum/genética , Plasmodium falciparum/crecimiento & desarrollo , Vacunas Atenuadas/inmunología , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/genética , Malaria/prevención & control , Malaria/parasitología , Malaria/inmunología , Ratones , Vacunación/métodos , Humanos , Eliminación de Gen , FemeninoRESUMEN
Live-attenuated influenza vaccines (LAIV) offer advantages over the commonly used inactivated split influenza vaccines. However, finding the optimal balance between sufficient attenuation and immunogenicity has remained a challenge. We recently developed an alternative LAIV based on the 2009 pandemic H1N1 virus with a truncated NS1 protein and lacking PA-X protein expression (NS1(1-126)-ΔPAX). This virus showed a blunted replication and elicited a strong innate immune response. In the present study, we evaluated the efficacy of this vaccine candidate in the porcine animal model as a pertinent in vivo system. Immunization of pigs via the nasal route with the novel NS1(1-126)-ΔPAX LAIV did not cause disease and elicited a strong mucosal immune response that completely blocked replication of the homologous challenge virus in the respiratory tract. However, we observed prolonged shedding of our vaccine candidate from the upper respiratory tract. To improve LAIV safety, we developed a novel prime/boost vaccination strategy combining primary intramuscular immunization with a haemagglutinin-encoding propagation-defective vesicular stomatitis virus (VSV) replicon, followed by a secondary immunization with the NS1(1-126)-ΔPAX LAIV via the nasal route. This two-step immunization procedure significantly reduced LAIV shedding, increased the production of specific serum IgG, neutralizing antibodies, and Th1 memory cells, and resulted in sterilizing immunity against homologous virus challenge. In conclusion, our novel intramuscular prime/intranasal boost regimen interferes with virus shedding and transmission, a feature that will help combat influenza epidemics and pandemics.