RESUMEN
BACKGROUND: Rabbit hemorrhagic disease (RHD) is an acute infectious disease that damages the rabbit industry by producing significant mortality rates in young and adult rabbits. RHD is better controlled by vaccination. OBJECTIVE: The current study's goal was to prepare and evaluate the immuno-enhancing effect of montanide ISA70 and aluminum hydroxide (Al(OH)3) gel incorporated within the inactivated RHDV2 vaccine and assess the vaccine's protective efficacy against the homologous and heterologous local RHDV2 strains in rabbits. METHODS: Inactivated RHDV vaccines were prepared using Montanide ISA70 oil or Al(OH)3 gel adjuvants and submitted to sterility, safety, and potency tests. 200 rabbits were equally divided into 4 groups: G1 (control), G2 (vaccinated with gel-incorporated vaccine), G3 (vaccinated with montanide-incorporated vaccine), and G4 (vaccinated with gel- and montanide-incorporated vaccines). Individual blood samples were collected from one week to six months from all groups. The vaccine's potency was measured by the HI test and protection percentage post challenge. RESULTS: Data revealed slightly increasing HI titer means reaching the 1st peak at 4 weeks post-vaccination (7.33, 7.67, and 7.33 log2 in the 2nd, 3rd, and 4th groups, respectively), then slightly decreasing and peaked again, giving 9.33 log2 for the2nd group at 3 months post-vaccination (MPV), 10.67 log2 for 3rd the group, and 10.33 log2 for the 4th group at 5 months post-vaccination. Titer gradually decreased but remained protective. The protection rate ranged from 80-100% and 80-90% for homologous and heterologous local RHDV2 vaccines, respectively, within 3 weeks and 6 months post-challenge. The montanide oil RHDV2 vaccine induced better protection than the aluminum gel RHDV2 vaccine. CONCLUSION: The results demonstrated evidence of cross-protection between RHDV2 strains. The oil emulsion vaccine induced higher and longer-lasting antibody titers than those obtained with the RHDV2 aluminum gel vaccine.
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Hidróxido de Aluminio , Infecciones por Caliciviridae , Virus de la Enfermedad Hemorrágica del Conejo , Vacunas Virales , Animales , Conejos , Hidróxido de Aluminio/farmacología , Hidróxido de Aluminio/administración & dosificación , Virus de la Enfermedad Hemorrágica del Conejo/inmunología , Vacunas Virales/inmunología , Infecciones por Caliciviridae/veterinaria , Infecciones por Caliciviridae/prevención & control , Geles , Adyuvantes Inmunológicos/farmacología , Adyuvantes Inmunológicos/administración & dosificación , Vacunas de Productos Inactivados/inmunología , Ácidos Oléicos/farmacología , Ácidos Oléicos/administración & dosificaciónRESUMEN
Bacterial septicemia represents a significant disease affecting cultured grass carp culture, with the primary etiological agent identified as the Gram-negative bacterium Aeromonas veronii. In response to an outbreak of septicemia in Guangzhou, we developed a formaldehyde-inactivated vaccine against an A. veronii strain designated AV-GZ21-2. This strain exhibited high pathogenicity in experimental infections across at all developmental stages of grass carp. Mortality rates for grass carp weighing 15 ± 5 g ranged from 16 % to 92 % at exposure temperatures of 19 °C-34 °C, respectively. The median lethal dose (LD50) for grass carp groups weighing 15 ± 5 g, 60 ± 10 g, 150 ± 30 g and 500 ± 50 g were determined to be 1.43, 2.52, 4.65 and 7.12 × 107(CFU/mL), respectively. We investigated the inactivated vaccine in conbination with aluminum hydroxide gel (AV-AHG), Montanide ISA201VG (AV-201VG), and white oil (AV-WO) adjuvants. This study aimed to optimize inactivation conditions and identify the adjuvant that elicits the most robust immune response. The AV-GZ21-2 inactivated bacterial solution (AV),when combined with various adjuvants, was capable of inducing a strong specific immune response in grass carp. The relative percent survival (RPS) following a lethal challenge with AV-GZ21-2 were 94 % for AV-AHG, 88 % for AV-201VG, 84 % for AV-WO and 78 % for AV alone. The minimum immunization dose of the AV-AHG vaccine was determined to be 6.0 × 107 CFU per fish, providing immunity for a duration of six months with an immune protection level exceeding 75 %. Furthermore, the AV-AHG vaccine demonstrated significant protective efficacy against various epidemic isolates of A. veronii. Consequently, we developed an inactivated vaccine targeting a highly pathogenic strain of A. veronii, incorporating an aluminum hydroxide gel adjuvant, which resulted in high immune protection and a duration of immunity exceeding six months. These findings suggest that the AV-AHG vaccine holds substantial potential for industrial application.
Asunto(s)
Adyuvantes Inmunológicos , Aeromonas veronii , Vacunas Bacterianas , Carpas , Enfermedades de los Peces , Infecciones por Bacterias Gramnegativas , Vacunas de Productos Inactivados , Animales , Carpas/microbiología , Vacunas Bacterianas/inmunología , Vacunas Bacterianas/administración & dosificación , Vacunas de Productos Inactivados/inmunología , Vacunas de Productos Inactivados/administración & dosificación , Aeromonas veronii/inmunología , Enfermedades de los Peces/prevención & control , Enfermedades de los Peces/microbiología , Enfermedades de los Peces/inmunología , Infecciones por Bacterias Gramnegativas/prevención & control , Infecciones por Bacterias Gramnegativas/veterinaria , Infecciones por Bacterias Gramnegativas/inmunología , Virulencia , Adyuvantes Inmunológicos/administración & dosificación , Dosificación Letal Mediana , Temperatura , China/epidemiología , Hidróxido de Aluminio/administración & dosificaciónRESUMEN
We compared the immunogenicity of recombinant S. pneumoniae pneumolysin (rPly) when administered with and without Al(OH)3 adjuvant, and evaluated the protective properties of recombinant protein in the active defense experiment. It was shown that double immunization with rPly+Al(OH)3 increases the levels of IgG antibodies in comparison with the control (p<0.01), while triple immunization results in a more significant increase in IgG antibody levels (p<0.001). Double immunization with rPly without Al(OH)3 does not induce a significant increase in antibody levels in comparison with the control, while triple immunization results in a slight but significant increase in antibody levels (p<0.05). The active defense test proved the protective activity of rPly against S. pneumoniae serotype 3 at intranasal infection.
Asunto(s)
Anticuerpos Antibacterianos , Proteínas Bacterianas , Inmunoglobulina G , Proteínas Recombinantes , Streptococcus pneumoniae , Estreptolisinas , Estreptolisinas/inmunología , Estreptolisinas/genética , Proteínas Bacterianas/inmunología , Proteínas Bacterianas/genética , Streptococcus pneumoniae/inmunología , Streptococcus pneumoniae/genética , Animales , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/genética , Anticuerpos Antibacterianos/inmunología , Anticuerpos Antibacterianos/sangre , Inmunoglobulina G/inmunología , Inmunoglobulina G/sangre , Ratones , Infecciones Neumocócicas/inmunología , Infecciones Neumocócicas/prevención & control , Infecciones Neumocócicas/microbiología , Adyuvantes Inmunológicos , Hidróxido de Aluminio/inmunología , Hidróxido de Aluminio/administración & dosificación , Vacunas Neumococicas/inmunología , Vacunas Neumococicas/administración & dosificación , FemeninoRESUMEN
BACKGROUND: The achievement of optimal vaccine efficacy is contingent upon the collaborative interactions between T and B cells in adaptive immunity. Although multiple immunization strategies have been proposed, there is a notable scarcity of comprehensive investigations pertaining to enhance immune effects through immune strategy adjustments for individual vaccine. METHODS: The hierarchically structured aluminum hydroxide microgel-stabilized Pickering emulsion (ASPE) was prepared by ultrasonic method. This study explored the influence of the immune strategy of ASPE to immune responses, including antigen exposure pattern, adjuvants and antigen dosage, and administration interval. RESULTS: The findings revealed that external antigen adsorption facilitated increased exposure of antigen epitopes, leading to elevated IgG titers and secretion of cytokines such as interferon-gamma (IFN-γ) or interleukin-4 (IL-4). Additionally, even a low dose (1 µg/dose) of antigens of ASPE boosted sufficient neutralizing antibody levels and memory T cells compared to high-dose antigens, which consistent with the adjuvant dosage effect. Furthermore, maintaining a 4-week immunization interval yielded optimal levels of antigen-specific IgG titers in both short-term and long-term scenarios, as compared to intervals of 2, 3, and 5 weeks. A consistent trend was observed in the proliferation of memory B cells, reaching a superior level at the 4-week interval, which could enhance protection against viral re-infection. CONCLUSION: Tailoring immunization strategies for specific vaccines has emerged as powerful driver in maximizing vaccine efficacy and eliciting robust immune responses, thereby presenting cutting-edge approaches to enhanced vaccination.
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Adyuvantes Inmunológicos , Emulsiones , Inmunoglobulina G , Animales , Ratones , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Femenino , Eficacia de las Vacunas , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/sangre , Compuestos de Alumbre/administración & dosificación , Ratones Endogámicos BALB C , Linfocitos B/inmunología , Interferón gamma/inmunología , Interleucina-4/inmunología , Adyuvantes de Vacunas/administración & dosificación , Hidróxido de Aluminio/inmunología , Hidróxido de Aluminio/administración & dosificación , Linfocitos T/inmunología , Células T de Memoria/inmunología , Citocinas/inmunologíaRESUMEN
The development of high-purity antigens promotes the urgent need of novel adjuvant with the capability to trigger high levels of immune response. Polyinosinic-polycytidylic (Poly(I:C)) is a synthetic double-stranded RNA (dsRNA) that can engage Toll-like receptor 3 (TLR3) to initiate immune responses. However, the Poly(I:C)-induced toxicity and inefficient delivery prevent its applications. In our study, combination adjuvants are formulated by aluminum oxyhydroxide nanorods (AlOOH NRs) and Poly(I:C), named Al-Poly(I:C), and the covalent interaction between the two components is further demonstrated. Al-Poly(I:C) mediates enhanced humoral and cellular immune responses in three antigen models, i.e., HBsAg virus-like particles (VLPs), human papilloma virus (HPV) VLPs and varicella-zoster virus (VZV) glycoprotein E (gE). Further mechanistic studies demonstrate that the dose and molecular weight (MW) of Poly(I:C) determine the physicochemical properties and adjuvanticity of the Al-Poly(I:C) combination adjuvants. Al-Poly(I:C) with higher Poly(I:C) dose promotes antigen-bearing dendritic cells (DCs) recruitment and B cells proliferation in lymph nodes. Al-Poly(I:C) formulated with higher MW Poly(I:C) induces higher activation of helper T cells, B cells, and CTLs. This study demonstrates that Al-Poly(I:C) potentiates the humoral and cellular responses in vaccine formulations. It offers insights for adjuvant design to meet the formulation requirements in both prophylactic and therapeutic vaccines.
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Adyuvantes Inmunológicos , Poli I-C , Poli I-C/administración & dosificación , Poli I-C/farmacología , Animales , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/farmacología , Adyuvantes Inmunológicos/química , Femenino , Ratones Endogámicos C57BL , Hidróxido de Aluminio/administración & dosificación , Hidróxido de Aluminio/química , Nanotubos/química , Inmunidad Humoral/efectos de los fármacos , Antígenos de Superficie de la Hepatitis B/inmunología , Antígenos de Superficie de la Hepatitis B/administración & dosificación , Humanos , Ratones , Inmunidad Celular/efectos de los fármacos , Ratones Endogámicos BALB C , Vacunas/administración & dosificación , Vacunas/inmunología , Óxido de AluminioRESUMEN
Whole virus-based inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide have been critical to the COVID-19 pandemic response. Although these vaccines are protective against homologous coronavirus infection, the emergence of novel variants and the presence of large zoonotic reservoirs harboring novel heterologous coronaviruses provide significant opportunities for vaccine breakthrough, which raises the risk of adverse outcomes like vaccine-associated enhanced respiratory disease. Here, we use a female mouse model of coronavirus disease to evaluate inactivated vaccine performance against either homologous challenge with SARS-CoV-2 or heterologous challenge with a bat-derived coronavirus that represents a potential emerging disease threat. We show that inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide can cause enhanced respiratory disease during heterologous infection, while use of an alternative adjuvant does not drive disease and promotes heterologous viral clearance. In this work, we highlight the impact of adjuvant selection on inactivated vaccine safety and efficacy against heterologous coronavirus infection.
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Hidróxido de Aluminio , Vacunas contra la COVID-19 , COVID-19 , SARS-CoV-2 , Vacunas de Productos Inactivados , Animales , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Femenino , COVID-19/prevención & control , COVID-19/inmunología , COVID-19/virología , Ratones , Vacunas de Productos Inactivados/inmunología , SARS-CoV-2/inmunología , Hidróxido de Aluminio/administración & dosificación , Modelos Animales de Enfermedad , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes de Vacunas , Anticuerpos Antivirales/inmunología , Ratones Endogámicos BALB C , Humanos , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/inmunologíaRESUMEN
COVID-19, caused by SARS-CoV-2, and meningococcal disease, caused by Neisseria meningitidis, are relevant infectious diseases, preventable through vaccination. Outer membrane vesicles (OMVs), released from Gram-negative bacteria, such as N. meningitidis, present adjuvant characteristics and may confer protection against meningococcal disease. Here, we evaluated in mice the humoral and cellular immune response to different doses of receptor binding domain (RBD) of SARS-CoV-2 adjuvanted by N. meningitidis C:2a:P1.5 OMVs and aluminum hydroxide, as a combined preparation for these pathogens. The immunization induced IgG antibodies of high avidity for RBD and OMVs, besides IgG that recognized the Omicron BA.2 variant of SARS-CoV-2 with intermediary avidity. Cellular immunity showed IFN-γ and IL-4 secretion in response to RBD and OMV stimuli, demonstrating immunologic memory and a mixed Th1/Th2 response. Offspring presented transferred IgG of similar levels and avidity as their mothers. Humoral immunity did not point to the superiority of any RBD dose, but the group immunized with a lower antigenic dose (0.5 µg) had the better cellular response. Overall, OMVs enhanced RBD immunogenicity and conferred an immune response directed to N. meningitidis too.
Asunto(s)
Anticuerpos Antivirales , COVID-19 , Inmunoglobulina G , Neisseria meningitidis , SARS-CoV-2 , Animales , Ratones , Inmunoglobulina G/sangre , Neisseria meningitidis/inmunología , Femenino , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , COVID-19/prevención & control , COVID-19/inmunología , SARS-CoV-2/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Inmunidad Celular , Inmunidad Humoral , Ratones Endogámicos BALB C , Infecciones Meningocócicas/prevención & control , Infecciones Meningocócicas/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Adyuvantes de Vacunas/administración & dosificación , Hidróxido de Aluminio/administración & dosificación , Hidróxido de Aluminio/inmunología , Inmunización/métodos , Afinidad de Anticuerpos , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunología , Vacunas Meningococicas/inmunología , Vacunas Meningococicas/administración & dosificación , Memoria Inmunológica , Células TH1/inmunologíaRESUMEN
Malaria remains a global health challenge, necessitating the development of effective vaccines. The RTS,S vaccination prevents Plasmodium falciparum (Pf) malaria but is ineffective against Plasmodium vivax (Pv) disease. Herein, we evaluated the murine immunogenicity of a recombinant PvCSP incorporating prevalent polymorphisms, adjuvanted with Alhydrogel or Poly I:C. Both formulations induced prolonged IgG responses, with IgG1 dominance by the Alhydrogel group and high titers of all IgG isotypes by the Poly I:C counterpart. Poly I:C-adjuvanted vaccination increased splenic plasma cells, terminally-differentiated memory cells (MBCs), and precursors relative to the Alhydrogel-combined immunization. Splenic B-cells from Poly I:C-vaccinated mice revealed an antibody-secreting cell- and MBC-differentiating gene expression profile. Biological processes such as antibody folding and secretion were highlighted by the Poly I:C-adjuvanted vaccination. These findings underscore the potential of Poly I:C to strengthen immune responses against Pv malaria.
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Adyuvantes de Vacunas , Hidróxido de Aluminio , Inmunogenicidad Vacunal , Vacunas contra la Malaria , Malaria Vivax , Plasmodium vivax , Poli I-C , Proteínas Protozoarias , Poli I-C/administración & dosificación , Plasmodium vivax/inmunología , Inmunidad Humoral , Inmunidad Celular , Proteínas Protozoarias/inmunología , Vacunas contra la Malaria/química , Vacunas contra la Malaria/inmunología , Hidróxido de Aluminio/administración & dosificación , Inmunoglobulina G/sangre , Masculino , Animales , Células Plasmáticas/inmunología , Femenino , Ratones Endogámicos C57BL , Proteínas Recombinantes/inmunología , Vacunación , Adyuvantes de Vacunas/administración & dosificación , Malaria Vivax/prevención & controlRESUMEN
BACKGROUND: The stalling global progress in malaria control highlights the need for novel tools for malaria elimination, including transmission-blocking vaccines. Transmission-blocking vaccines aim to induce human antibodies that block parasite development in the mosquito and mosquitoes becoming infectious. The Pfs48/45 protein is a leading Plasmodium falciparum transmission-blocking vaccine candidate. The R0.6C fusion protein, consisting of Pfs48/45 domain 3 (6C) and the N-terminal region of P. falciparum glutamate-rich protein (R0), has previously been produced in Lactococcus lactis and elicited functional antibodies in rodents. Here, we assess the safety and transmission-reducing efficacy of R0.6C adsorbed to aluminium hydroxide with and without Matrix-M™ adjuvant in humans. METHODS: In this first-in-human, open-label clinical trial, malaria-naïve adults, aged 18-55 years, were recruited at the Radboudumc in Nijmegen, the Netherlands. Participants received four intramuscular vaccinations on days 0, 28, 56 and 168 with either 30 µg or 100 µg of R0.6C and were randomised for the allocation of one of the two different adjuvant combinations: aluminium hydroxide alone, or aluminium hydroxide combined with Matrix-M1™ adjuvant. Adverse events were recorded from inclusion until 84 days after the fourth vaccination. Anti-R0.6C and anti-6C IgG titres were measured by enzyme-linked immunosorbent assay. Transmission-reducing activity of participants' serum and purified vaccine-specific immunoglobulin G was assessed by standard membrane feeding assays using laboratory-reared Anopheles stephensi mosquitoes and cultured P. falciparum gametocytes. RESULTS: Thirty-one participants completed four vaccinations and were included in the analysis. Administration of all doses was safe and well-tolerated, with one related grade 3 adverse event (transient fever) and no serious adverse events occurring. Anti-R0.6C and anti-6C IgG titres were similar between the 30 and 100 µg R0.6C arms, but higher in Matrix-M1™ arms. Neat participant sera did not induce significant transmission-reducing activity in mosquito feeding experiments, but concentrated vaccine-specific IgGs purified from sera collected two weeks after the fourth vaccination achieved up to 99% transmission-reducing activity. CONCLUSIONS: R0.6C/aluminium hydroxide with or without Matrix-M1™ is safe, immunogenic and induces functional Pfs48/45-specific transmission-blocking antibodies, albeit at insufficient serum concentrations to result in transmission reduction by neat serum. Future work should focus on identifying alternative vaccine formulations or regimens that enhance functional antibody responses. TRIAL REGISTRATION: The trial is registered with ClinicalTrials.gov under identifier NCT04862416.
Asunto(s)
Vacunas contra la Malaria , Malaria Falciparum , Glicoproteínas de Membrana , Plasmodium falciparum , Proteínas Protozoarias , Adolescente , Adulto , Animales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Adyuvantes Inmunológicos/administración & dosificación , Hidróxido de Aluminio/administración & dosificación , Anticuerpos Antiprotozoarios , Vacunas contra la Malaria/inmunología , Vacunas contra la Malaria/administración & dosificación , Malaria Falciparum/prevención & control , Malaria Falciparum/transmisión , Malaria Falciparum/inmunología , Países Bajos , Plasmodium falciparum/inmunología , Proteínas Protozoarias/inmunologíaRESUMEN
Foot-and-mouth disease (FMD) has a high prevalence in cloven-hoofed animals. It is also highly contagious and remains a serious threat to livestock worldwide. Despite the widespread vaccination program in Iran, outbreaks of FMD continue to occur. Vaccination is one of the most effective methods of preventing FMD. The vaccines used in Iran are of the inactivated type and contain several serotypes. Since inactivated vaccines without adjuvants do not induce a high and durable antibody response, it is necessary to use adjuvants. Montanide ISA 206 VG is a mineral oil-based adjuvant that produces a water-in-oil-in-water (w:o:w) emulsion in vaccine preparations. However, a large number of manufacturers in Iran and around the world still use alum adjuvant (with or without saponin) to produce the FMD vaccine. This study used Montanide ISA 206 and alum adjuvants to administer the O2010 serotype of the FMD virus to goats. A total of six goats were divided randomly into three groups. Vaccines were administered subcutaneously twice, at a one-month interval. Blood sampling was done at different times, and the micro-neutralization method was used to measure the neutralizing antibody titer in each serum. Seven days after the second vaccination, the alum group's antibody titer was higher but not statistically significant. However, from the 28th day after the second injection until the end of the study, the Montanide ISA 206 group's antibody titer was significantly higher than that of the alum group. Six months after the second injection, the antibody titer in the ISA 206 group remained at the peak level, while in the alum group, it decreased and reached the minimum protective level. Nine months after the second injection, the antibody titer remained at its peak level in the ISA 206 group, whereas it dropped significantly in the alum group. Based on the findings, ISA 206 VG is capable of generating long-term humoral immunity in goats against the FMD serotype O2010 and could replace aluminum hydroxide adjuvants in FMD vaccine preparations.
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Adyuvantes Inmunológicos , Hidróxido de Aluminio , Anticuerpos Neutralizantes , Virus de la Fiebre Aftosa , Fiebre Aftosa , Enfermedades de las Cabras , Cabras , Vacunas Virales , Animales , Hidróxido de Aluminio/administración & dosificación , Hidróxido de Aluminio/farmacología , Virus de la Fiebre Aftosa/inmunología , Enfermedades de las Cabras/prevención & control , Fiebre Aftosa/prevención & control , Fiebre Aftosa/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/farmacología , Vacunas Virales/inmunología , Vacunas Virales/administración & dosificación , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Irán , Ácidos Oléicos/administración & dosificación , Manitol/análogos & derivados , Manitol/administración & dosificaciónRESUMEN
Aluminum-containing adjuvants are extensively used in inactive human and animal vaccines owing to their favorable immunostimulatory and safe properties. Nonetheless, there is controversy over the effects of different aluminum salts as an adjuvant for the bovine parainfluenza virus type 3 (BPIV3) vaccine. In order to find a suitable adjuvant, we studied the effects of two adjuvants (i.e., aluminum hydroxide [Al(OH)3] and aluminum potassium sulfate [AlPO4]) on the production of neutralizing antibodies (NAbs) for an experimental BPIV3 vaccine. The animals under study (Guinea pigs) were randomly assigned to five groups of experimental vaccines containing Al(OH)3 (AH), AlPO4 (AP), Al(OH)3-AlPO4 mixture (MIX), commercial vaccine (COM), and control (NS). The treatment groups were immunized with two doses of vaccine 21 days apart (on days 0 and 21), and the control group received normal saline under the same conditions. The animals were monitored for 42 days, and blood samples were then taken. The results indicated that all vaccines were able to induce the production of NAbs at levels higher than the minimum protective titer (0.6). An increase in titer was observed throughout the monitoring period. Moreover, an increase in both the level and mean titer of NAbs obtained from the vaccine containing Al(OH)3 adjuvant was significantly higher than in the other studied groups (P≤0.005). The comparison of NAbs titer in other groups did not display a significant difference. Considering the speed of rising and the optimal titer of NAbs production in the experimental vaccine, the Al(OH)3 adjuvant is a suitable candidate for preparing a vaccine against BPIV3 for immunization.
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Adyuvantes Inmunológicos , Hidróxido de Aluminio , Anticuerpos Neutralizantes , Virus de la Parainfluenza 3 Bovina , Animales , Adyuvantes Inmunológicos/farmacología , Adyuvantes Inmunológicos/administración & dosificación , Hidróxido de Aluminio/farmacología , Hidróxido de Aluminio/administración & dosificación , Anticuerpos Neutralizantes/sangre , Cobayas , Virus de la Parainfluenza 3 Bovina/inmunología , Vacunas Virales/inmunología , Vacunas Virales/administración & dosificación , Vacunas Virales/farmacología , Anticuerpos Antivirales/sangre , Distribución Aleatoria , Compuestos de Aluminio/farmacología , Compuestos de Aluminio/administración & dosificación , FemeninoRESUMEN
Asthma is characterized by airway remodeling. Glucocorticoid induced transcript 1 (GLCCI1) was reported to be associated with the development of asthma, while its exact mechanism is still not clear. In our study, ovalbumin (OVA) combined with aluminum hydroxide were used to establish asthmatic mouse model. ELISA assay was fulfilled to ensure the concentration of inflammatory factors in both bronchoalveolar lavage fluid and serum. The pathological changes and collagen deposition in lung tissues were analyzed using H&E staining and Masson staining, respectively. The expression of proteins was measured using western blot, and the expression of GLCCI1 mRNA was ensured by qRT-PCR. Here, we demonstrated that OVA-induced inflammation, lung structural remodeling and collagen deposition in asthmatic mice was notably improved by hydroprednisone treatment or GLCCI1 overexpressing. The expression of GLCCI1 was decreased, while IL-13, periostin and TGF-ß1 were increased in the lung tissue of asthmatic mice. Importantly, upregulation of GLCCI1 suppressed the expression of IL-13, periostin and TGF-ß1, phosphorylation of Smad2 and Smad3, and extracellular matrix (ECM) deposition-related proteins expression. IL-13-induced upregulation of periostin and TGF-ß1 expression, phosphorylation of Smad2 and Smad3, and ECM deposition in airway epithelial cells (AECs) was repressed by GLCCI1 increasing. Furthermore, our results showed that overexpression of GLCCI1 repressed the effect of IL-13 on AECs via inhibiting periostin expression. Overall, our data revealed that GLCCI1 limited the airway remodeling in mice with asthma through inhibiting IL-13/periostin/TGF-ß1 signaling pathway. Our data provided a novel target for asthma treatment.
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Remodelación de las Vías Aéreas (Respiratorias)/inmunología , Asma/inmunología , Pulmón/patología , Receptores de Glucocorticoides/metabolismo , Hidróxido de Aluminio/administración & dosificación , Hidróxido de Aluminio/toxicidad , Animales , Asma/inducido químicamente , Asma/tratamiento farmacológico , Asma/patología , Moléculas de Adhesión Celular/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Interleucina-13/metabolismo , Pulmón/efectos de los fármacos , Pulmón/inmunología , Ratones , Ovalbúmina/administración & dosificación , Ovalbúmina/inmunología , Prednisona/administración & dosificación , Receptores de Glucocorticoides/agonistas , Transducción de Señal/inmunología , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
The COVID-19 pandemic presents an unprecedented challenge to global public health. Rapid development and deployment of safe and effective vaccines are imperative to control the pandemic. In the current study, we applied our adjuvanted stable prefusion SARS-CoV-2 spike (S-2P)-based vaccine, MVC-COV1901, to hamster models to demonstrate immunogenicity and protection from virus challenge. Golden Syrian hamsters immunized intramuscularly with two injections of 1 µg or 5 µg of S-2P adjuvanted with CpG 1018 and aluminum hydroxide (alum) were challenged intranasally with SARS-CoV-2. Prior to virus challenge, the vaccine induced high levels of neutralizing antibodies with 10,000-fold higher IgG level and an average of 50-fold higher pseudovirus neutralizing titers in either dose groups than vehicle or adjuvant control groups. Six days after infection, vaccinated hamsters did not display any weight loss associated with infection and had significantly reduced lung pathology and most importantly, lung viral load levels were reduced to lower than detection limit compared to unvaccinated animals. Vaccination with either 1 µg or 5 µg of adjuvanted S-2P produced comparable immunogenicity and protection from infection. This study builds upon our previous results to support the clinical development of MVC-COV1901 as a safe, highly immunogenic, and protective COVID-19 vaccine.
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Adyuvantes Inmunológicos/administración & dosificación , Hidróxido de Aluminio/administración & dosificación , COVID-19/prevención & control , Oligodesoxirribonucleótidos/administración & dosificación , Glicoproteína de la Espiga del Coronavirus/inmunología , Hidróxido de Aluminio/inmunología , Animales , Anticuerpos Neutralizantes/metabolismo , COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Vacunas contra la COVID-19/inmunología , Línea Celular , Cricetinae , Femenino , Humanos , Inmunización , Inyecciones Intramusculares , Oligodesoxirribonucleótidos/inmunología , SARS-CoV-2/inmunología , SARS-CoV-2/fisiología , Carga Viral/efectos de los fármacosAsunto(s)
Composición de Medicamentos/ética , Vacunas contra Papillomavirus/efectos adversos , Sociedades Científicas/ética , Vacunas Combinadas/efectos adversos , Hidróxido de Aluminio/administración & dosificación , Hidróxido de Aluminio/efectos adversos , Ensayos Clínicos como Asunto/ética , Composición de Medicamentos/estadística & datos numéricos , Humanos , Periodismo Médico/normas , Vacunas contra Papillomavirus/administración & dosificación , Vacunas contra Papillomavirus/inmunología , Fosfatos/administración & dosificación , Fosfatos/efectos adversos , Placebos/administración & dosificación , Seguridad , Vacunas Combinadas/administración & dosificación , Vacunas Combinadas/inmunologíaAsunto(s)
Hidróxido de Aluminio/efectos adversos , Composición de Medicamentos/métodos , Vacunas contra Papillomavirus/efectos adversos , Fosfatos/efectos adversos , Placebos/normas , Vacunas Combinadas/efectos adversos , Hidróxido de Aluminio/administración & dosificación , Ensayos Clínicos como Asunto/ética , Ensayos Clínicos como Asunto/normas , Humanos , Vacunas contra Papillomavirus/administración & dosificación , Vacunas contra Papillomavirus/inmunología , Fosfatos/administración & dosificación , Placebos/administración & dosificación , Sociedades Científicas/normas , Vacunas Combinadas/administración & dosificación , Vacunas Combinadas/inmunologíaRESUMEN
BACKGROUNDVaccines that block human-to-mosquito Plasmodium transmission are needed for malaria eradication, and clinical trials have targeted zygote antigen Pfs25 for decades. We reported that a Pfs25 protein-protein conjugate vaccine formulated in alum adjuvant induced serum functional activity in both US and Malian adults. However, antibody levels declined rapidly, and transmission-reducing activity required 4 vaccine doses. Functional immunogenicity and durability must be improved before advancing transmission-blocking vaccines further in clinical development. We hypothesized that the prefertilization protein Pfs230 alone or in combination with Pfs25 would improve functional activity.METHODSTransmission-blocking vaccine candidates based on gamete antigen Pfs230 or Pfs25 were conjugated with Exoprotein A, formulated in Alhydrogel, and administered to mice, rhesus macaques, and humans. Antibody levels were measured by ELISA and transmission-reducing activity was assessed by the standard membrane feeding assay.RESULTSPfs25-EPA/Alhydrogel and Pfs230D1-EPA/Alhydrogel induced similar serum functional activity in mice, but Pfs230D1-EPA induced significantly greater activity in rhesus monkeys that was enhanced by complement. In US adults, 2 vaccine doses induced complement-dependent activity in 4 of 5 Pfs230D1-EPA/Alhydrogel recipients but no significant activity in 5 Pfs25-EPA recipients, and combination with Pfs25-EPA did not increase activity over Pfs230D1-EPA alone.CONCLUSIONThe complement-dependent functional immunogenicity of Pfs230D1-EPA represents a significant improvement over Pfs25-EPA in this comparative study. The rhesus model is more predictive of the functional human immune response to Pfs230D1 than is the mouse model.TRIAL REGISTRATIONClinicalTrials.gov NCT02334462.FUNDINGIntramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.
Asunto(s)
Hidróxido de Aluminio/administración & dosificación , Anticuerpos Antiprotozoarios/inmunología , Antígenos de Protozoos/administración & dosificación , Vacunas contra la Malaria/administración & dosificación , Plasmodium falciparum/inmunología , Proteínas Protozoarias/administración & dosificación , Adulto , Animales , Antígenos de Protozoos/inmunología , Femenino , Humanos , Macaca mulatta , Vacunas contra la Malaria/inmunología , Malaria Falciparum/prevención & control , Malaria Falciparum/transmisión , Masculino , Ratones , Ratones Endogámicos BALB C , Proteínas Protozoarias/inmunologíaRESUMEN
BACKGROUND: Shigella remains in the top four pathogens responsible for moderate to severe diarrhoea in children below 5 years of age. The shigella O-specific polysaccharide (O-SP) is a promising vaccine target. We developed a conjugate vaccine prototype incorporating a unique well defined synthetic oligosaccharide hapten, chemically designed for optimal antigenic, conformational, structural, and functional mimicry of the O-SP from Shigella flexneri 2a (SF2a). We aimed to assess the safety, tolerability, and immunogenicity of this original synthetic oligosaccharide-based vaccine candidate, SF2a-TT15, conceived to drive the antibody response towards the key protective determinants of the native lipopolysaccharide antigen, in a first-in-human phase 1 study. METHODS: We did a first-in-human, dose-escalating, single-blind, observer-masked, randomised, placebo-controlled study at the Clinical Research Center of Tel Aviv Sourasky Medical Center (Israel). Participants were healthy adults aged 18-45 years with low titres of serum SF2a-specific IgG antibodies. 64 eligible participants were assigned to one of two cohorts. 32 participants in each of the two cohorts were randomly assigned via computer-generated algorithm in a stepwise manner to receive the 2 µg (cohort 1) and 10 µg oligosaccharide dose (cohort 2) of the SF2a-TT15 vaccine candidate non-adjuvanted or adjuvanted with aluminium hydroxide (alum) or matching placebos. The vaccine was administered as three single intramuscular injections into the arm, 28 days apart. The primary outcome was the incidence and severity of adverse events, which were assessed in the intention-to-treat safety population analysis including all participants who were randomly assigned and received at least one vaccine or placebo injection. The immunogenicity endpoints were secondary outcomes and were analysed in all participants who were randomly assigned, received all of the assigned injections before the time of the immunogenicity assessment, and provided blood samples for immunological follow-up (per-protocol immunogenicity analysis). The study is registered with ClinicalStudies.gov, NCT02797236 and is completed. FINDINGS: Of 203 volunteers initially screened, 64 participants were enrolled between Sept 20, 2016, and Sept 26, 2017. In each of the two cohorts, 12 participants received the adjuvanted vaccine, 12 received the non-adjuvanted vaccine and eight received the matching placebo (four each). The SF2a-TT15 glycoconjugate was well tolerated at both doses. No serious or severe adverse events occurred. Overall, seven (88%) of eight to 12 (100%) of 12 in each group of volunteers had one adverse event or more after receiving the study agents with the majority of adverse events, 300 (98%) of 307, considered mild in intensity. Of the seven adverse events defined as moderate in severity, one (nausea) was suspected to be related to the vaccine candidate. At all post-immunisation days and for both oligosaccharide doses, whether adjuvanted or not, SF2a-TT15 induced significantly higher serum IgG anti-SF2a lipopolysaccharide geometric mean titres (GMTs) as compared with baseline or with the corresponding GMTs in placebo recipients (p<0·01). After one injection, the non-adjuvanted 10 µg oligosaccharide dose induced a 27-times increase in IgG GMT (5080 vs 189) and the non-adjuvanted 2 µg oligosaccharide dose induced a five-times increase (1411 vs 283), compared with baseline. Alum enhanced the specific IgG response at 2 µg oligosaccharide dose after the third injection (GMTs 3200 vs 1176, p=0.045). INTERPRETATION: SF2a-TT15 was safe and well tolerated and induced high titres of anti-SF2a LPS IgG antibodies. These results support further evaluation of this original synthetic oligosaccharide-protein conjugate vaccine candidate for safety, immunogenicity, and protective efficacy in target populations. FUNDING: The European Union Seventh Framework Programme.
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Disentería Bacilar/prevención & control , Inmunogenicidad Vacunal , Vacunas contra la Shigella/efectos adversos , Shigella flexneri/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/efectos adversos , Adolescente , Adulto , Hidróxido de Aluminio/administración & dosificación , Hidróxido de Aluminio/efectos adversos , Hidróxido de Aluminio/inmunología , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunología , Relación Dosis-Respuesta Inmunológica , Disentería Bacilar/inmunología , Disentería Bacilar/microbiología , Femenino , Voluntarios Sanos , Humanos , Inyecciones Intramusculares , Masculino , Persona de Mediana Edad , Antígenos O/genética , Antígenos O/inmunología , Vacunas contra la Shigella/administración & dosificación , Vacunas contra la Shigella/genética , Vacunas contra la Shigella/inmunología , Método Simple Ciego , Vacunas Conjugadas/administración & dosificación , Vacunas Conjugadas/efectos adversos , Vacunas Conjugadas/genética , Vacunas Conjugadas/inmunología , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/efectos adversos , Vacunas Sintéticas/genética , Vacunas Sintéticas/inmunología , Adulto JovenRESUMEN
A novel STING agonist, CDGSF, ipsilaterally modified with phosphorothioate and fluorine, was synthesized. The phosphorothioate in CDGSF might be a site for covalent conjugation. Injection of CDGSF generated an immunogenic ("hot") tumor microenvironment to suppress melanoma, more efficiently than dithio CDG. In particular, immunization with SARS-CoV-2 spike protein using CDGSF as an adjuvant elicited an exceptionally high antibody titer and a robust T cell response, overcoming the drawbacks of aluminum hydroxide. These results highlighted the therapeutic potential of CDGSF for cancer immunotherapy and the adjuvant potential of the STING agonist in the SARS-CoV-2 vaccine for the first time.
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Adyuvantes Inmunológicos/administración & dosificación , Vacunas contra la COVID-19/administración & dosificación , COVID-19/prevención & control , Melanoma Experimental/tratamiento farmacológico , Proteínas de la Membrana/agonistas , Nucleótidos Cíclicos/administración & dosificación , Neoplasias Cutáneas/tratamiento farmacológico , Adyuvantes Inmunológicos/síntesis química , Hidróxido de Aluminio/administración & dosificación , Hidróxido de Aluminio/química , Animales , Anticuerpos Antivirales/biosíntesis , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Linfocitos B/virología , COVID-19/inmunología , COVID-19/virología , Vacunas contra la COVID-19/química , Ensayo de Immunospot Ligado a Enzimas , Humanos , Inmunoterapia/métodos , Interferón gamma/biosíntesis , Melanoma Experimental/inmunología , Melanoma Experimental/mortalidad , Melanoma Experimental/patología , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Ratones , Nucleótidos Cíclicos/síntesis química , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/inmunología , SARS-CoV-2/patogenicidad , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Glicoproteína de la Espiga del Coronavirus/administración & dosificación , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/inmunología , Análisis de Supervivencia , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/virología , Carga Tumoral/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Vacunación/métodosRESUMEN
OBJECTIVE: The 13C-urea breath test (UBT) is the most widely used non-invasive diagnostic test for Helicobacter pylori. Debate continues to surround the possible interference of antacid intake on its result. This study aims to confirm the non-interference of almagate in the determination of H. pylori by UBT. PATIENTS AND METHODS: Observational, multicentre study in adult patients treated with almagate in whom a UBT (TAUKIT®) was indicated. When the UBT result was negative, use of almagate was stopped for 30 days and the UBT was repeated. When the result was positive, no further determinations were made. The primary endpoint was the percentage of patients who, having had a negative result in the first breath test, were positive in the second after having stopped taking almagate (UBT false negatives, possibly attributable to almagate). RESULTS: Of the 167 evaluable patients, 59% were female, average age was 49 and 97% had gastrointestinal symptoms. The result of the first UBT was negative in 71% of cases. Of these, in the second UBT test after stopping the almagate, the negative result was confirmed in 97.5%. Out of the total number of cases evaluated, the rate of false negatives was 1.8%. CONCLUSIONS: Taking almagate has minimal or no interference in the result of UBT for the diagnosis of H. pylori infection. It can therefore be used in the weeks prior to a UBT.
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Hidróxido de Aluminio/administración & dosificación , Antiácidos/administración & dosificación , Pruebas Respiratorias/métodos , Carbonatos/administración & dosificación , Infecciones por Helicobacter/diagnóstico , Helicobacter pylori , Hidróxido de Magnesio/administración & dosificación , Hidróxido de Aluminio/efectos adversos , Antiácidos/efectos adversos , Pruebas Respiratorias/estadística & datos numéricos , Isótopos de Carbono , Carbonatos/efectos adversos , Dispepsia/tratamiento farmacológico , Reacciones Falso Negativas , Femenino , Reflujo Gastroesofágico/tratamiento farmacológico , Humanos , Hidróxido de Magnesio/efectos adversos , Masculino , Persona de Mediana Edad , España , Factores de Tiempo , UreaRESUMEN
Mouse models of allergic asthma have been utilized to establish the role of T helper type 2 (Th2) cells in driving lung inflammation, airway hyperresponsiveness, and obstruction. Here, we present the allergic asthma models, in which mice are hypersensitized to ovalbumin (OVA) and house dust mite (HDM). These models mimic the major characteristics of human asthma including the eosinophilic inflammation and hyperactivity of the airway, overproduction of Th2 cytokines in the lung, and elevated total and allergen-specific immunoglobulin E (IgE) in serum.