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HeberNasvac is a recently developed therapeutic vaccine for chronic hepatitis B (CHB) administered by intranasal (IN) and subcutaneous (SC) routes in a 14 days/10 doses schedule. To compare different schedules and routes of immunizations, a group of patients received four different vaccination regimens in a placebo-controlled factorial study. Subsequently, patients were followed for a minimum time of 48 weeks. Samples collected at the end of the follow-up were compared with initial samples. Groups I and II received the product by IN/SC routes, every 14 and 7 days, respectively. Groups III and IV were treated by SC route alone following a 14 and 7 days schedule. A group of 21 CHB patients received the vaccine in four different schedules and eight patients received placebo for a total of 29 patients enrolled. The 61.9% of vaccinees reduced their VL ≥2Log compared with baseline levels and 25% in placebo group. The 47.6% of vaccines reduced HBV levels to undetectable, 25% in placebo. HBeAg loss and seroconversion to anti-HBeAg was only achieved in vaccinees, 4 out of 9 (44.4%), and 40% (8 out of 20) developed anti-HBs response, none in placebo group. Reduction of HBsAg level in ≥1Log was achieved in the 35.0% of vaccinees and in none of the placebo-treated patients. Considering the individual and factorial analysis, significant HBV DNA reduction was detected in groups I and II, immunized by IN/SC routes. A significantly higher proportion of patients reducing VL to ≥2Log was also detected grouping the patients treated by IN/SC routes (G I + II) and grouping those inoculated every 14 days (G I + III), with 72.7% and 63.6%, respectively, compared with the placebo group (25.0%). The patients immunized every 14 days (G I + G III) also reduced the HBsAg levels compared with baseline. In conclusion, after more than 48 weeks of treatment-free follow-up, HeberNasvac-treated patients demonstrated superior responses compared with the placebo group in terms of antiviral and serological responses. The factorial analysis evidenced that the schedule combining the IN route of immunization and the frequency of 14 days resulted in the stronger antiviral and serological responses. Present results support the study of IN-only immunization schedules in future and was consistent with previous results. Long-lasting follow-ups were done to explore histological variables and the progression of serological variables in order to detect late responders. How to cite this article: Freyre FM, Aguiar JA, Cinza Z, et al. Impact of the Route and Schedule of Immunization on the Serological and Virological Response of Chronic Hepatitis B Patients Treated with HeberNasvac. Euroasian J Hepato-Gastroenterol 2023;13(2):73-78.
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INTRODUCTION: More than 180 million people have been infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and more than 4 million coronavirus disease-2019 (COVID-19) patients have died in 1.5 years of the pandemic. A novel therapeutic vaccine (NASVAC) has shown to be safe and to have immunomodulating and antiviral properties against chronic hepatitis B (CHB). MATERIALS AND METHODS: A phase I/II, open-label controlled and randomized clinical trial of NASVAC as a postexposure prophylaxis treatment was designed with the primary aim of assessing the local and systemic immunomodulatory effect of NASVAC in a cohort of suspected and SARS-CoV-2 risk-contact patients. A total of 46 patients, of both sexes, 60 years or older, presenting with symptoms of COVID-19 were enrolled in the study. Patients received NASVAC (100 µg per Ag per dose) via intranasal at days 1, 7, and 14 and sublingual, daily for 14 days. RESULTS AND DISCUSSION: The present study detected an increased expression of toll-like receptors (TLR)-related genes in nasopharyngeal tonsils, a relevant property considering these are surrogate markers of SARS protection in the mice model of lethal infection. The HLA-class II increased their expression in peripheral blood mononuclear cell's (PBMC's) monocytes and lymphocytes, which is an attractive property taking into account the functional impairment of innate immune cells from the periphery of COVID-19-infected subjects. NASVAC was safe and well tolerated by the patients with acute respiratory infections and evidenced a preliminary reduction in the number of days with symptoms that needs to be confirmed in larger studies. CONCLUSIONS: Our data justify the use of NASVAC as preemptive therapy or pre-/postexposure prophylaxis of SARS-CoV-2 and acute respiratory infections in general. The use of NASVAC or their active principles has potential as immunomodulatory prophylactic therapies in other antiviral settings like dengue as well as in malignancies like hepatocellular carcinoma where these markers have shown relation to disease progression. HOW TO CITE THIS ARTICLE: Fleites YA, Aguiar J, Cinza Z, et al. HeberNasvac, a Therapeutic Vaccine for Chronic Hepatitis B, Stimulates Local and Systemic Markers of Innate Immunity: Potential Use in SARS-CoV-2 Postexposure Prophylaxis. Euroasian J Hepato-Gastroenterol 2021;11(2):59-70.
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A phase III clinical trial in treatment-naïve patients with chronic hepatitis B (CHB) revealed the safety and considerable therapeutic efficacy of a vaccine containing both hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) (NASVAC) at the end of treatment (EOT) and 24 weeks after EOT. Two years after EOT, we checked HBV DNA, alanine aminotransferase (ALT), and hepatitis B e antigen (HBeAg). The data reveal that 33 of 66 NASVAC-recipient CHB patients became negative for HBV DNA in the blood two years after EOT. The ALT levels were within the upper limit of normal (ULN) in 37 patients, although all 66 CHB patients had elevated ALT (above ULN) before the start of therapy. Out of the total twelve HBeAg-positive patients, eight patients became negative for HBeAg. None of the patients developed cirrhosis of the liver within this period. NASVAC is a finite treatment regimen with sustained antiviral and liver-protecting properties. This study is the first to report follow-up data of immune therapy for CHB. NASVAC, an immune therapy of finite duration, is endowed with sustained antiviral and liver protection properties in CHB patients.
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The coronavirus 2019 (COVID-19) pandemic has resulted in 168 million cases and about 3.5 million deaths (as of May 26, 2021) during the last 18 months. These 18 months of the COVID-19 pandemic have been characterized by phases or waves of new cases, the emergence of new variants of the deadly virus, and several new complications. After providing emergency approval to several drugs and adherence to several public health measures with frequent full and partial lockdowns, the incidence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could not be contained till now on a global basis. Although prophylactic vaccines have inspired optimism, the scarcity of vaccines and several vaccine-related regulations indicate that the vaccine's benefit would not be reaching the people of developing countries anytime soon. In the course of our clinical practice, we used pegylated interferon (Peg-IFN) in 35 patients with chronic liver diseases (CLD), and we found that only two of them were infected with SARS-CoV-2 that was mild in nature. These two patients with CLD have a mild course of disease cured without any specific therapy. Patients with CLD are usually immune-compromised. However, three CLD patients remained free of SARS-CoV-2 although they had COVID-19 patients among their family members. Next, we accomplished two studies for assessing the immune-modulatory capacities of Peg-IFN, 1 and 12 injections following administration of Peg-IFN. The data revealed that peripheral blood mononuclear cells (PBMCs) of Peg-IFN-administered CLD patients produced significantly higher levels of some cytokines of innate immunity in comparison with the cytokines produced by PBMC of CLD patients before Peg-IFN intake. The pattern of cytokine responses and absence of infection of SARS-CoV-2 in 33 of 35 CLD patients represent some preliminary observations indicating a possible role of Peg-IFN in patients with CLD. The study may be extended to other chronic infections and cancers in which patients receive Peg-IFN. The role of Peg-IFN for pre- or postexposure prophylaxis in the acquisition of SARS-CoV-2 infection and influencing the natural course of COVID-19 remains to be clarified. HOW TO CITE THIS ARTICLE: Akbar SMF, Mahtab MA, Aguilar JC, et al. Role of Pegylated Interferon in Patients with Chronic Liver Diseases in the Context of SARS-CoV-2 Infection. Euroasian J Hepato-Gastroenterol 2021;11(1):27-31.
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The objective of the present study was to assess the safety and efficacy of a therapeutic vaccine containing both HBsAg and HBcAg (NASVAC) in patients with chronic hepatitis B (CHB) three years after the end of treatment (EOT) as a follow-up of a phase III clinical trial. NASVAC was administered ten times by the nasal route and five times by subcutaneous injection. A total of 59 patients with CHB were enrolled. Adverse events were not seen in any of the patients. Out of the 59 CHB patients, 54 patients exhibited a reduction in HBV DNA, compared with their basal levels. Although all the patients had alanine transaminase (ALT) above the upper limit of normal (>42 IU/L) before the commencement of therapy, the levels of ALT were within the ULN level in 42 patients. No patient developed cirrhosis of the liver. The present study, showing the safety and efficacy of NASVAC 3 years after the EOT, is the first to report follow-up data of an immune therapeutic agent against CHB. NASVAC represents a unique drug against CHB that is safe, of finite duration, can be administered by the nasal route, is capable of reducing HBV DNA and normalizing ALT, and contains hepatic fibrosis.
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A novel therapeutic vaccine for chronic hepatitis B (CHB) treatment comprising the recombinant hepatitis B surface (HBsAg) and nucleocapsid (HBcAg) antigens has been developed. Preclinical and clinical trials (CT) evidenced safety and immunogenicity in animal models as well as in phases I, II, and III clinical trials. A phase I CT has conducted in Cuba in 6 CHB patients refractory or incomplete responders to α-IFN. Patients were immunized ten times every two weeks via. nasal spray, with 100 ug HBsAg and 100 ug HBcAg. Clinical efficacy was monitored by assessing the levels of hepatitis B virus deoxyribonucleic acid (HBV DNA), alanine aminotransferase (ALT), HBeAg, and anti-HBeAg seroconversion as well as by qualitative/ quantitative HBsAg serology during this period. After a 5 year follow-up,HBeAg loss was verified in the three HBeAg (+) patients, in two cases with seroconversion to anti-HBeAg. A reduction to undetectable viral load was observed in 5 out of 6 patients, and in two cases HBsAg seroconversion was also detected. ALT increases above the 2X upper limit of normal (ULN) were only detected in HBeAg (+) patients and associated with HBe antigen loss. All patients had stiffness levels below 7.8 KPa by Fibroscan assessment at the end of this period. Although only a few patients were enrolled in this study, it seems that HeberNasvac may maintain some of the therapeutic effects for a prolonged period. How to cite this article: Fernandez G, Sanchez AL, Jerez E, Anillo LE, Freyre F, Aguiar JA, Leon Y, Cinza Z, Diaz PA, Figueroa N, Muzio V, Nieto GG, Lobaina Y, Aguilar A, Penton E, Aguilar JC. Five-year Follow-up of Chronic Hepatitis B Patients Immunized by Nasal Route with the Therapeutic Vaccine HeberNasvac. Euroasian J Hepatogastroenterol, 2018;8(2):133-139.
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AIM: We studied the functional stability of a primer pair and the standard curve based on a plasmid carrying full-length HBV genome, from a novel low-cost real-time quantitative polymerase chain reaction (qPCR) assay. The assay was developed at the Center for Genetic Engineering and Biotechnology (CIGB) in Havana, to quantify the serum hepatitis B virus (HBV) DNA from chronic HBV-infected (CHB) patients. MATERIALS AND METHODS: In-house generated oligonucleotides and plasmids were incubated at 37°C during 1 month and compared with the same materials incubated at -20, 4, and 25°C during the same time in qPCR experiments. RESULTS: This work shows that the oligonucleotide pair and the plasmid for the quantitative standard curve are functionally stable in severe temperature conditions during 1 month. Polymerase chain reaction amplification with both materials after its incubation 30 days at 37°C produced similar cycle threshold (CT) values and similar degree of sample quantifications compared with the same materials preserved using the conventional storage conditions at -20°C. CONCLUSION: These results are indicative of the robustness of this low-cost qPCR system for HBV DNA quantification. These results also support that this qPCR assay can be used as a low-cost technology in clinical studies to monitor the viral load changes of serum HBV DNA of CHB patients, which could be used by poor people of third world countries, where there are frequent blackouts and temperature changes that can hinder the primer and plasmid stability. HOW TO CITE THIS ARTICLE: Aguiar J, García G, León Y, Canales E, Silva JA, Gell O, Estrada R, Morán I, Muzio V, Guillén G, Pentón E, Aguilar JC. High Functional Stability of a Low-cost HBV DNA qPCR Primer Pair and Plasmid Standard. Euroasian J Hepato-Gastroenterol 2016;6(1):19-24.
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The genetic diversity of HBV in human population is often a reflection of its genetic admixture. The aim of this study was to explore the genotypic diversity of HBV in Cuba. The S genomic region of Cuban HBV isolates was sequenced and for selected isolates the complete genome or precore-core sequence was analyzed. The most frequent genotype was A (167/250, 67%), mainly A2 (149, 60%) but also A1 and one A4. A total of 77 isolates were classified as genotype D (31%), with co-circulation of several subgenotypes (56 D4, 2 D1, 5 D2, 7 D3/6 and 7 D7). Three isolates belonged to genotype E, two to H and one to B3. Complete genome sequence analysis of selected isolates confirmed the phylogenetic analysis performed with the S region. Mutations or polymorphisms in precore region were more common among genotype D compared to genotype A isolates. The HBV genotypic distribution in this Caribbean island correlates with the Y lineage genetic background of the population, where a European and African origin prevails. HBV genotypes E, B3 and H isolates might represent more recent introductions.
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ADN Viral/genética , Variación Genética , Genoma Viral , Genotipo , Virus de la Hepatitis B/genética , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/virología , Cuba , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/virología , Datos de Secuencia Molecular , FilogeniaRESUMEN
In most tissues, the immune system plays an essential role in protection, repair and healing. Although immunologically privileged, the CNS remains subject to a highly regulated form of immunosurveillance that is of increasing interest. There is evolving evidence that repair mechanisms within the CNS may be enhanced by exploiting an innate process of protective immunity. Understanding the regulation of protective autoimmunity within the CNS is likely to lead to novel therapeutic approaches to neuroinflammatory and neurodegenerative diseases.
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Autoinmunidad/inmunología , Encefalopatías/inmunología , Encefalopatías/prevención & control , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , Fármacos Neuroprotectores/inmunología , Fármacos Neuroprotectores/uso terapéutico , Animales , Autoinmunidad/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Humanos , Modelos InmunológicosRESUMEN
Se evalúa la efectividad de un programa especial de vacunación, mediante el seguimiento evolutivo de marcadores del virus de la hepatitis B (VHB) en poblaciones seleccionadas de alto riesgo de infección, como son los pacientes de servicios de hemodiálisis peritoneal. Se estudiaron marcadores de infección viral en cortes transversales de prevalencia de toda la población de pacientes, además de registrarse los reportes de casos clínicos de hepatitis B en esos grupos ocurridos durante este período. El programa de prevención consistió en la vacunación de todos los pacientes que resultaran negativos a los marcadores virales y la indicación de vacunarse en el período de la enfermedad previo al inicio del tratamiento en las unidades de hemodialisis para los casos nuevos, además de todos los individuos susceptibles de infección que ya estuvieran incluidos en el programa, independientemente del estadio de la enfermedad. Los resultados muestran el beneficio de la vacunación en estos pacientes, pero es más efectiva en el período previo al tratamiento dialítico donde la posibilidad de exposición al virus es menor y el sistema inmune es aún competente. Después de establecido el programa a los 6 años de seguimiento no se han reportado casos nuevos de hepatitis B y la incidencia de la enfermedad ha ido disminuyendo
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Humanos , Masculino , Femenino , Diálisis , Hepatitis B , Inmunización , Infecciones/diagnóstico , Infecciones/terapia , Pacientes/clasificación , Vacunas/administración & dosificación , Cuba , Investigación , VenezuelaRESUMEN
Los anticuerpos monoclonales AcM contra los interferones han demostrado ser una "herramienta" poderosa para la purificación y detección de estas moléculas. En el presente trabajo se reporta la generación de hibridomas de ratón secretores de AcM que reconocen específicamente el interferón alfa 2 recombinante humano (rIFN alfa 2), así como una caracterización más detallada de tres de ellos con respecto a su reconocimiento del antígeno, cuando este es presentado bajo diferentes condiciones. Los AmC CB-IFNA2.1 y CB-IFNA2.3 demostraron su utilidad en la purificación del rIFN alfa 2: el CB-IFNA2.3 fue usado como anticuerpo de recubrimiento en un sistema microELISA para la cuantificación del antígeno, junto al AmC CB-IFNA2.2 como segundo anticuerpo. Este sistema permite detectar niveles de hasta 10 UI/ml del antígeno. El CB-IFNA2.3 mostró además un fuerte efecto neutralizante sobre la actividad antiviral del rIFN alfa 2. Estos AcM están siendo usados sistemáticamente en nuestra institución, tanto en la purificación del rIFN alfa 2 como en el trabajo analítico relacionado con esta molécula
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Ratones , Animales , Anticuerpos Monoclonales/aislamiento & purificación , Interferón Tipo I/aislamiento & purificación , HibridomasRESUMEN
Los anticuerpos monoclonales AcM contra los interferones han demostrado ser una "herramienta" poderosa para la purificación y detección de estas moléculas. En el presente trabajo se reporta la generación de hibridomas de ratón secretores de AcM que reconocen específicamente el interferón alfa 2 recombinante humano (rIFN alfa 2), así como una caracterización más detallada de tres de ellos con respecto a su reconocimiento del antígeno, cuando este es presentado bajo diferentes condiciones. Los AmC CB-IFNA2.1 y CB-IFNA2.3 demostraron su utilidad en la purificación del rIFN alfa 2: el CB-IFNA2.3 fue usado como anticuerpo de recubrimiento en un sistema microELISA para la cuantificación del antígeno, junto al AmC CB-IFNA2.2 como segundo anticuerpo. Este sistema permite detectar niveles de hasta 10 UI/ml del antígeno. El CB-IFNA2.3 mostró además un fuerte efecto neutralizante sobre la actividad antiviral del rIFN alfa 2. Estos AcM están siendo usados sistemáticamente en nuestra institución, tanto en la purificación del rIFN alfa 2 como en el trabajo analítico relacionado con esta molécula
