RESUMEN

The ongoing co-circulation of multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains necessitates advanced methods such as high-throughput multiplex pseudovirus systems for evaluating immune responses to different variants, crucial for developing updated vaccines and neutralizing antibodies (nAbs). We have developed a quadri-fluorescence (qFluo) pseudovirus platform by four fluorescent reporters with different spectra, allowing simultaneous measurement of the nAbs against four variants in a single test. qFluo shows high concordance with the classical single-reporter assay when testing monoclonal antibodies and human plasma. Utilizing qFluo, we assessed the immunogenicities of the spike of BA.5, BQ.1.1, XBB.1.5, and CH.1.1 in hamsters. An analysis of cross-neutralization against 51 variants demonstrated superior protective immunity from XBB.1.5, especially against prevalent strains such as "FLip" and JN.1, compared to BA.5. Our finding partially fills the knowledge gap concerning the immunogenic efficacy of the XBB.1.5 vaccine against current dominant variants, being instrumental in vaccine-strain decisions and insight into the evolutionary path of SARS-CoV-2.

Asunto(s)

Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19 , SARS-CoV-2 , SARS-CoV-2/inmunología , SARS-CoV-2/genética , Animales , Humanos , COVID-19/inmunología , COVID-19/virología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/sangre , Cricetinae , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/genética , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Pruebas de Neutralización/métodos , Fluorescencia , Células HEK293 , Antígenos Virales/inmunología , Anticuerpos Monoclonales/inmunología , Mesocricetus

RESUMEN

Hepatitis B virus (HBV) infection is a significant global health concern due to elevated immunosuppressive viral antigen levels, the host immune system's inability to manage HBV, and the liver's immunosuppressive conditions. While immunotherapies utilizing broadly reactive HBV neutralizing antibodies present potential due to their antiviral capabilities and Fc-dependent vaccinal effects, they necessitate prolonged and frequent dosing to achieve optimal therapeutic outcomes. Toll-like receptor 7/8 (TLR7/8) agonists have been demonstrated promise for the cure of chronic hepatitis B, but their systemic use often leads to intense side effects. In this study, we introduced immune-stimulating antibody conjugates which consist of TLR7/8 agonists 1-[[4-(aminomethyl)phenyl]methyl]-2-butyl-imidazo[4,5-c]quinolin-4-amine (IMDQ) linked to an anti-hepatitis B surface antigen (HBsAg) antibody 129G1, and designated as 129G1-IMDQ. Our preliminary study highlights that 129G1-IMDQ can prompt robust and sustained anti-HBsAg specific reactions with short-term administration. This underscores the conjugate's potential as an effective strategy for HBsAg clearance and seroconversion, offering a fresh perspective for a practical therapeutic approach in the functional cure of CHB. Highlights: HBV-neutralizing antibody 129G1 was linked with a TLR7/8 agonist small molecule compound IMDQ.Treatment with 129G1-IMDQ has shown significant promise in lowering HBsAg levels in AAV/HBV mice.129G1-IMDQ were eliciting a strong and lasting anti-HBsAg immune response after short-term treatment in AAV/HBV mice.

RESUMEN

With advanced computational methods, it is now feasible to modify or design proteins for specific functions, a process with significant implications for disease treatment and other medical applications. Protein structures and functions are intrinsically linked to their backbones, making the design of these backbones a pivotal aspect of protein engineering. In this study, we focus on the task of unconditionally generating protein backbones. By means of codebook quantization and compression dictionaries, we convert protein backbone structures into a distinctive coded language and propose a GPT-based protein backbone generation model, PB-GPT. To validate the generalization performance of the model, we trained and evaluated the model on both public datasets and small protein datasets. The results demonstrate that our model has the capability to unconditionally generate elaborate, highly realistic protein backbones with structural patterns resembling those of natural proteins, thus showcasing the significant potential of large language models in protein structure design.

RESUMEN

Therapeutics for eradicating hepatitis B virus (HBV) infection are still limited and current nucleos(t)ide analogs (NAs) and interferon are effective in controlling viral replication and improving liver health, but they cannot completely eradicate the hepatitis B virus and only a very small number of patients are cured of it. The TCR-like antibodies recognizing viral peptides presented on human leukocyte antigens (HLA) provide possible tools for targeting and eliminating HBV-infected hepatocytes. Here, we generated three TCR-like antibodies targeting three different HLA-A2.1-presented peptides derived from HBV core and surface proteins. Bispecific antibodies (BsAbs) were developed by fuzing variable fragments of these TCR-like mAbs with an anti-CD3ϵ antibody. Our data demonstrate that the BsAbs could act as T cell engagers, effectively redirecting and activating T cells to target HBV-infected hepatocytes in vitro and in vivo. In HBV-persistent mice expressing human HLA-A2.1, two infusions of BsAbs induced marked and sustained suppression in serum HBsAg levels and also reduced the numbers of HBV-positive hepatocytes. These findings highlighted the therapeutic potential of TCR-like BsAbs as a new strategy to cure hepatitis B.

Asunto(s)

Anticuerpos Biespecíficos , Modelos Animales de Enfermedad , Virus de la Hepatitis B , Hepatitis B , Hepatocitos , Animales , Anticuerpos Biespecíficos/inmunología , Anticuerpos Biespecíficos/farmacología , Hepatocitos/virología , Hepatocitos/inmunología , Ratones , Humanos , Virus de la Hepatitis B/inmunología , Virus de la Hepatitis B/genética , Hepatitis B/inmunología , Hepatitis B/virología , Antígeno HLA-A2/inmunología , Antígenos de Superficie de la Hepatitis B/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/inmunología

RESUMEN

Human enteroviruses (HEV) can cause a range of diseases from mild to potentially life-threatening. Identification and genotyping of HEV are crucial for disease management. Existing typing methods, however, have inherent limitations. Developing alternative methods to detect HEV with more virus types, high accuracy, and sensitivity in an accessible manner presents a technological and analytical challenge. Here, a sequence-specific nanoparticle barcode (SSNB) method is presented for simultaneous detection of 10 HEV types. This method significantly increases sensitivity, enhancing detection by 10-106 times over the traditional multiplex hybrid genotyping (MHG) method, by resolving cross-interference between the multiple primer sets. Furthermore, the SSNB method demonstrates a 100% specificity in accurately distinguishing between 10 different HEV types and other prevalent clinical viruses. In an analysis of 70 clinical throat swab samples, the SSNB method shows slightly higher detection rate for positive samples (50%) compared to the RT-PCR method (48.6%). Additionally, further assessment of the typing accuracy for samples identified as positive by SSNB using sequencing method reveals a concordance rate of 100%. The combined high sensitivity and specificity level of the methodology, together with the capability for multiple type analysis and compatibility with clinical workflow, make this approach a promising tool for clinical settings.

Asunto(s)

Infecciones por Enterovirus , Enterovirus , Nanopartículas , Humanos , Nanopartículas/química , Infecciones por Enterovirus/virología , Infecciones por Enterovirus/diagnóstico , Enterovirus/genética , Enterovirus/clasificación , Enterovirus/aislamiento & purificación , Código de Barras del ADN Taxonómico/métodos , Sensibilidad y Especificidad , Técnicas de Genotipaje/métodos , Genotipo , ARN Viral/genética

RESUMEN

Persistent infection with high-risk human papillomavirus (HPV) types can lead to the development of cancer in HPV-infected tissues, including the cervix, oropharynx, anus, penis, vagina, and vulva. While current HPV vaccines cover approximately 90 % of cervical cancers, nearly 10 % of cases associated with HPV types not included in the vaccines remain unaddressed, notably HPV59. This study describes the development of a chimeric virus-like particle (VLP) targeting HPV18/45/59, proposed as a vaccine candidate for high-risk HPV type (HPV59) currently lacking commercial vaccines. Given that the majority of neutralizing antibody epitopes are located on the surface loops, we engineered a strategic swap of these loops between the closely related HPV18 and HPV45. This methodology was then extended to incorporate surface loops of HPV59, resulting in the lead candidate construct of the H18-45BCEF-59HI chimeric VLP with two surface loops swapping from HPV45 to HPV18. Characterization confirmed that H18-45BCEF-59HI closely resembled the wild-type (WT) backbone types in particle size and morphology, as verified by Transmission Electron Microscopy (TEM), High-Performance Size-Exclusion Chromatography (HPSEC), and Analytical Ultracentrifugation (AUC), and demonstrated similar thermal stability as evidenced by Differential Scanning Calorimetry (DSC). Immunization studies in mice with the chimeric VLPs assessed their immunogenicity, revealing that the H18-45EF-59HI chimeric VLP exhibited optimal cross-neutralization. Additionally, when produced in a Good Manufacturing Practice (GMP)-like facility, the H18-45BCEF-59HI VLP was selected as a promising vaccine candidate for the prevention of HPV18/45/59 infection. This study not only offers a potential solution to the current vaccination gap but also provides a foundational approach for the design of vaccines targeting viruses with multiple subtypes or variants.

Asunto(s)

Anticuerpos Neutralizantes , Anticuerpos Antivirales , Infecciones por Papillomavirus , Vacunas contra Papillomavirus , Vacunas de Partículas Similares a Virus , Vacunas contra Papillomavirus/inmunología , Vacunas contra Papillomavirus/administración & dosificación , Vacunas contra Papillomavirus/genética , Infecciones por Papillomavirus/prevención & control , Infecciones por Papillomavirus/inmunología , Femenino , Vacunas de Partículas Similares a Virus/inmunología , Animales , Humanos , Ratones , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/sangre , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/sangre , Papillomavirus Humano 18/inmunología , Papillomavirus Humano 18/genética , Virus del Papiloma Humano

RESUMEN

Hepatitis B virus (HBV) expresses co-terminal large (L), middle (M), and small (S) envelope proteins containing preS1/preS2/S, preS2/S, and S domain alone, respectively. S and preS1 domains mediate sequential virion attachment to heparan sulfate proteoglycans and sodium taurocholate cotransporting polypeptide (NTCP), respectively, which can be blocked by anti-S and anti-preS1 antibodies. How anti-preS2 antibodies neutralize HBV infectivity remains enigmatic. The late stage of chronic HBV infection often selects for mutated preS2 translation initiation codon to prevent M protein expression, or in-frame preS2 deletions to shorten both L and M proteins. When introduced to infectious clone of genotype C or D, both M-minus mutations and most 5' preS2 deletions sustained virion production. Such mutant progeny viral particles were infectious in NTCP-reconstituted HepG2 cells. Neutralization experiments were performed on the genotype D clone. Although remaining susceptible to anti-preS1 and anti-S neutralizing antibodies, M-minus mutants were only partially neutralized by two anti-preS2 antibodies tested while preS2 deletion mutants were resistant. By infection experiments using viral particles with lost versus increased M protein expression, or a neutralization escaping preS2 deletion only present on L or M protein, we found that both full-length L and M proteins contributed to virus neutralization by the two anti-preS2 antibodies. Thus, immune escape could be a driving force for the selection of M-minus mutations, and especially preS2 deletions. The fact that both L and M proteins could mediate neutralization by anti-preS2 antibodies may shed light on the underlying molecular mechanism.IMPORTANCEThe large (L), middle (M), and small (S) envelope proteins of hepatitis B virus (HBV) contain preS1/preS2/S, preS2/S, and S domain alone, respectively. The discovery of heparan sulfate proteoglycans and sodium taurocholate cotransporting polypeptide (NTCP) as the low- and high-affinity HBV receptors could explain neutralizing potential of anti-S and anti-preS1 antibodies, respectively, but how anti-preS2 neutralizing antibodies work remains enigmatic. In this study, we found two M-minus mutants in the context of genotype D partially escaped two anti-preS2 neutralizing antibodies in NTCP-reconstituted HepG2 cells, while several naturally occurring preS2 deletion mutants escaped both antibodies. By point mutations to eliminate or enhance M protein expression, and by introducing preS2 deletion selectively to L or M protein, we found binding of anti-preS2 antibodies to both L and M proteins contributed to neutralization of wild-type HBV infectivity. Our finding may shed light on the possible mechanism(s) whereby anti-preS2 antibodies neutralize HBV infectivity.

Asunto(s)

Anticuerpos Neutralizantes , Antígenos de Superficie de la Hepatitis B , Virus de la Hepatitis B , Proteínas del Envoltorio Viral , Virus de la Hepatitis B/inmunología , Virus de la Hepatitis B/genética , Humanos , Antígenos de Superficie de la Hepatitis B/inmunología , Antígenos de Superficie de la Hepatitis B/genética , Proteínas del Envoltorio Viral/inmunología , Proteínas del Envoltorio Viral/genética , Anticuerpos Neutralizantes/inmunología , Células Hep G2 , Eliminación de Secuencia , Simportadores/inmunología , Simportadores/genética , Precursores de Proteínas/inmunología , Precursores de Proteínas/genética , Anticuerpos contra la Hepatitis B/inmunología , Hepatitis B/inmunología , Hepatitis B/virología , Genotipo , Evasión Inmune , Transportadores de Anión Orgánico Sodio-Dependiente/genética , Transportadores de Anión Orgánico Sodio-Dependiente/inmunología , Transportadores de Anión Orgánico Sodio-Dependiente/metabolismo , Virión/inmunología

RESUMEN

As a sirtuin (SIR2) family protein, defense-associated sirtuin2 (DSR2) has been demonstrated to participate in bacterial anti-phage resistance via depleting nicotinamide adenine dinucleotide (NAD+) of infected cells, which can be activated by tail tube protein (TTP) and inhibited by DSR anti-defense 1 (DSAD1) of diverse phages. However, the regulating mechanism remains elusive. Here, we determined the cryo-electron microscopy structure of apo DSR2, as well as the respective complex structures with TTP and DSAD1. Structural analyses and biochemical studies reveal that DSR2 forms a tetramer with a SIR2 central core and two distinct conformations. Monomeric TTP preferentially binds to the closed conformation of DSR2, inducing conformational distortions on SIR2 tetramer assembly to activate its NADase activity. DSAD1 combines with the open conformation of DSR2, directly or allosterically inhibiting TTP activation on DSR2 NAD+ hydrolysis. Our findings decipher the detailed molecule mechanisms for DSR2 NADase activity regulation and lay a foundation for in-depth understanding of the DSR2 anti-phage defense system.

Asunto(s)

Bacteriófagos , Microscopía por Crioelectrón , Bacteriófagos/metabolismo , NAD+ Nucleosidasa/metabolismo , NAD+ Nucleosidasa/química , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/química , Modelos Moleculares , NAD/metabolismo , Unión Proteica , Conformación Proteica , Sirtuina 2/metabolismo , Sirtuina 2/química , Multimerización de Proteína

RESUMEN

Antibody-drug conjugates (ADCs) are biologically targeted drugs composed of antibodies and cytotoxic drugs connected by linkers. These innovative compounds enable precise drug delivery to tumor cells, minimizing harm to normal tissues and offering excellent prospects for cancer treatment. However, monoclonal antibody-based ADCs still present challenges, especially in terms of balancing efficacy and safety. Bispecific antibodies are alternatives to monoclonal antibodies and exhibit superior internalization and selectivity, producing ADCs with increased safety and therapeutic efficacy. In this review, we present available evidence and future prospects regarding the use of bispecific ADCs for cancer treatment, including a comprehensive overview of bispecific ADCs that are currently in clinical trials. We offer insights into the future development of bispecific ADCs to provide novel strategies for cancer treatment.

Asunto(s)

Anticuerpos Biespecíficos , Inmunoconjugados , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Anticuerpos Biespecíficos/uso terapéutico , Inmunoconjugados/uso terapéutico , Antineoplásicos/uso terapéutico , Sistemas de Liberación de Medicamentos , Terapia Molecular Dirigida

RESUMEN

The poor prognosis observed in elderly individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a serious clinical burden and the underlying mechanism is unclear, which necessities detailed investigation of disease characteristics and research for efficient countermeasures. To simulate lethal coronavirus disease 2019 (COVID-19) in senescent human patients, 80-week-old male hamsters are intranasally inoculated with different doses of SARS-CoV-2 Omicron BA.5 variant. Exposure to a low dose of the Omicron BA.5 variant results in early activation of the innate immune response, followed by rapid viral clearance and minimal lung damage. However, a high dose of BA.5 results in impaired interferon signaling, cytokine storm, uncontrolled viral replication, and severe lung injury. To decrease viral load and reverse the deterioration of COVID-19, a new bio-mimic decoy called CoVR-MV is used as a preventive or therapeutic agent. Administration of CoVR-MV as a preventive or therapeutic intervention in the early stages of infection can effectively suppress viral load, regulate the immune response, and rescue animals from death and critical illness. These findings underscore the risk associated with SARS-CoV-2 Omicron BA.5 exposure in senescent hamsters and highlight the importance of early intervention to prevent disease progression.

RESUMEN

The emergence of SARS-CoV-2 variants raises concerns about the efficacy of existing COVID-19 vaccines and therapeutics. Previously, we identified a conserved cryptic class 5 epitope of SARS-CoV-2 receptor binding domain (RBD) by two cross-neutralizing antibodies 7D6 and 6D6. Intriguingly, this site remains resistant to substantial mutations occurred in ever-changing SARS-CoV-2 subvariants. As compared to class 3 antibody S309, 6D6 maintains broad and consistent neutralizing activities against SARS-CoV-2 variants. Furthermore, 6D6 effectively protected hamster from the virulent Beta strain. Sequence alignment of approximately 6 million documented SARS-CoV-2 isolates revealed that 6D6 epitope maintains an exceptionally high conservation rate (99.92%). Structural analysis demonstrated that all 33 mutations accumulated in XBB.1.5 since the original strain do not perturb the binding 6D6 to RBD, in line with the sequence analysis throughout the antigenicity evolution of SARS-CoV-2. These findings suggest the potential of this epitope serving as a critical determinant for vaccines and therapeutic design.

RESUMEN

Hepatitis E is a significant cause of acute hepatitis, contributing to high morbidity and mortality rates, and capable of causing large epidemics through fecal-oral transmission. Currently, no specific treatment for hepatitis E has been approved. Given the notably high mortality rate among HEV-infected pregnant women and individuals with underlying chronic liver disease, concerted efforts have been made to develop effective vaccines. The only licensed hepatitis E vaccine worldwide, the HEV 239 (Hecolin) vaccine, has been demonstrated to be safe and efficacious in Phase III clinical trials, in which the efficacy of three doses of HEV 239 remained at 86.6% (95% confidence interval (CI): 73.0-94.1) at the end of 10 years follow-up. In this review, the progress and challenges for hepatitis E vaccines are summarized.

RESUMEN

The recent discovery of public antibodies targeting Plasmodium falciparum-encoded repetitive interspersed families of polypeptides (RIFINs), which contain extracellular immunoglobulin-like domains from LAIR1 or LILRB1, constitutes a significant step forward in comprehending the reactivity of the Plasmodium parasite. These antibodies arise from unique B cell clones and demonstrate extensive cross-reactivity through their interaction with P. falciparum RIFINs. LAIR1 and LILRBs are specialized type I transmembrane glycoproteins, classified as immune inhibitory receptors, restricted to primates and mainly found on hematopoietic cells. They are instrumental in modulating interactions within the tumor microenvironment and across the immune system, and are increasingly recognized as important in anti-cancer immunotherapy and pathogen defense. The presence of LAIR1/LILRB1-containing antibodies offers new insights into malaria parasite evasion strategies and the immune system's response. Additionally, the innovative method of integrating extra exons into the antibody switch region is a noteworthy advancement, enriching the strategies for the generation of a varied array of bispecific and multispecific antibodies.

RESUMEN

Currently, SARS-CoV-2 has evolved into various variants, including the numerous highly mutated Omicron sub-lineages, significantly increasing immune evasion ability. The development raises concerns about the possibly diminished effectiveness of available vaccines and antibody-based therapeutics. Here, we describe those representative categories of broadly neutralizing antibodies (bnAbs) that retain prominent effectiveness against emerging variants including Omicron sub-lineages. The molecular characteristics, epitope conservation, and resistance mechanisms of these antibodies are further detailed, aiming to offer suggestion or direction for the development of therapeutic antibodies, and facilitate the design of vaccines with broad-spectrum potential.

Asunto(s)

Anticuerpos Antivirales , Anticuerpos ampliamente neutralizantes , COVID-19 , Epítopos , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , SARS-CoV-2/inmunología , Humanos , Anticuerpos Antivirales/inmunología , COVID-19/inmunología , COVID-19/virología , Anticuerpos ampliamente neutralizantes/inmunología , Epítopos/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/genética , Anticuerpos Neutralizantes/inmunología , Evasión Inmune , Vacunas contra la COVID-19/inmunología

RESUMEN

T cell-redirecting bispecific antibodies are specifically designed to bind to tumor-associated antigens, thereby engaging with CD3 on the T cell receptor. This linkage between tumor cells and T cells actively triggers T cell activation and initiates targeted killing of the identified tumor cells. These antibodies have emerged as one of the most promising avenues within tumor immunotherapy. However, despite success in treating hematological malignancies, significant advancements in solid tumors have yet to be explored. In this review, we aim to address the critical challenges associated with T cell-redirecting bispecific antibodies and explore novel strategies to overcome these obstacles, with the ultimate goal of expanding the application of this therapy to include solid tumors.

RESUMEN

Hepatitis E virus (HEV) is an important cause of acute hepatitis, however, is highly neglected and largely underreported. This study aimed to describe the detailed epidemiology of hepatitis E (HE) through a 10-year surveillance. A community-based active hepatitis surveillance was conducted between November 2007 and October 2017 in 11 townships of Dongtai City in China, involving 355,673 residents. Serum samples were obtained from patients presenting with hepatitis symptoms for more than 3 days. Serum alanine aminotransferase (ALT) levels greater than 2.5 times the upper limit of normal (ULN) were considered acute hepatitis. Samples were subsequently tested for IgG and IgM anti-HEV antibodies, HEV RNA, and hepatitis B surface antigen (HBsAg). The data indicated the incidence of HE fluctuated downward from 2007 to 2017, with an average annual age-standardized incidence of 17.50 per 100,000, exceeding the 10.26 per 100,000 in the National Notifiable Disease Report System (NNDRS). The incidence was notably higher among males (20.95 per 100,000) and individuals aged 50-69 years (37.47 per 100,000). Genotype 4 (HEV-4) was the predominantly circulating genotype during the study period. Furthermore, the study revealed the incidence of hepatitis with HEV and hepatitis B virus (HBV) co-infection was 4.99 per 100,000. The active surveillance system identified a higher incidence of HE compared to NNDRS, with a decreased prevalence over a 10-year period. While efforts are still needed to prevent HE in high-risk populations, including individuals with hepatitis B and the elderly.

Asunto(s)

Anticuerpos Antihepatitis , Virus de la Hepatitis E , Hepatitis E , Humanos , Hepatitis E/epidemiología , Hepatitis E/virología , China/epidemiología , Masculino , Persona de Mediana Edad , Virus de la Hepatitis E/genética , Virus de la Hepatitis E/inmunología , Virus de la Hepatitis E/clasificación , Virus de la Hepatitis E/aislamiento & purificación , Femenino , Adulto , Anciano , Adolescente , Adulto Joven , Incidencia , Niño , Preescolar , Anticuerpos Antihepatitis/sangre , Genotipo , Lactante , Hepatitis B/epidemiología , Hepatitis B/virología , ARN Viral/genética , Coinfección/epidemiología , Coinfección/virología , Inmunoglobulina M/sangre , Monitoreo Epidemiológico , Anciano de 80 o más Años , Inmunoglobulina G/sangre , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/inmunología , Virus de la Hepatitis B/aislamiento & purificación , Antígenos de Superficie de la Hepatitis B/sangre , Recién Nacido , Ciudades/epidemiología

RESUMEN

Influenza virus is one of the main pathogens causing respiratory diseases in humans. Vaccines are the most effective ways to prevent viral diseases. However, the limited protective efficacy of current influenza vaccines highlights the importance of novel, safe, and effective universal influenza vaccines. With the progress of the COVID-19 pandemic, live-attenuated vaccines delivered through respiratory mucosa have shown robustly protective efficacy. How to obtain a safe and effective live-attenuated vaccine has become a major challenge. Herein, using the influenza virus as a model, we have established a strategy to quickly obtain a live-attenuated vaccine by mutating the cleavage site of the influenza virus. This mutated influenza virus can be specifically cleaved by chymotrypsin. It has similar biological characteristics to the original strain in vitro, but the safety is improved by at least 100 times in mice. It can effectively protect against lethal doses of both homologous H1N1 and heterologous H5N1 viruses post mucosal administration, confirming that the vaccine generated by this strategy has good safety and broad-spectrum protective activities. Therefore, this study can provide valuable insights for the development of attenuated vaccines for respiratory viruses or other viruses with cleavage sites.

RESUMEN

Antitumor therapies based on adoptively transferred T cells or oncolytic viruses have made significant progress in recent years, but the limited efficiency of their infiltration into solid tumors makes it difficult to achieve desired antitumor effects when used alone. In this study, an oncolytic virus (rVSV-LCMVG) that is not prone to induce virus-neutralizing antibodies was designed and combined with adoptively transferred T cells. By transforming the immunosuppressive tumor microenvironment into an immunosensitive one, in B16 tumor-bearing mice, combination therapy showed superior antitumor effects than monotherapy. This occurred whether the OV was administered intratumorally or intravenously. Combination therapy significantly increased cytokine and chemokine levels within tumors and recruited CD8+ T cells to the TME to trigger antitumor immune responses. Pretreatment with adoptively transferred T cells and subsequent oncolytic virotherapy sensitizes refractory tumors by boosting T-cell recruitment, down-regulating the expression of PD-1, and restoring effector T-cell function. To offer a combination therapy with greater translational value, mRNA vaccines were introduced to induce tumor-specific T cells instead of adoptively transferred T cells. The combination of OVs and mRNA vaccine also displays a significant reduction in tumor burden and prolonged survival. This study proposed a rational combination therapy of OVs with adoptive T-cell transfer or mRNA vaccines encoding tumor-associated antigens, in terms of synergistic efficacy and mechanism.

Asunto(s)

Viroterapia Oncolítica , Virus Oncolíticos , Animales , Ratones , Virus Oncolíticos/genética , Virus Oncolíticos/inmunología , Viroterapia Oncolítica/métodos , Terapia Combinada , Vacunas de ARNm/inmunología , Melanoma Experimental/terapia , Melanoma Experimental/inmunología , Microambiente Tumoral/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T/inmunología , Humanos , Línea Celular Tumoral , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/genética , Vacunas contra el Cáncer/administración & dosificación

RESUMEN

The XBB.1.5 subvariant has garnered significant attention due to its exceptional immune evasion and transmissibility. Significantly, the evolutionary trajectory of SARS-CoV-2 has shown continual progression, with a recent global shift observed from XBB to BA.2.86, exemplified by the emergence of the predominant JN.1 subvariant. This phenomenon highlights the need for vaccines that can provide broad-spectrum antigenic coverage. In this study, we utilized a NS1-deleted (dNS1) influenza viral vector to engineer an updated live-attenuated vectored vaccine called dNS1-XBB-RBD. This vaccine encodes the receptor-binding domain (RBD) protein of the XBB.1.5 strain. Our findings demonstrate that the dNS1-XBB-RBD vaccine elicits a similar systemic and mucosal immune response compared to its prototypic form, dNS1-RBD. In hamsters, the dNS1-XBB-RBD vaccine provided robust protection against the SARS-CoV-2 immune-evasive strains XBB.1.9.2.1 and Beta. Remarkably, nasal vaccination with dNS1-RBD, which encodes the ancestor RBD gene, also effectively protected hamsters against both the XBB.1.9.2.1 and Beta strains. These results provide valuable insights about nasal influenza-vectored vaccine and present a promising strategy for the development of a broad-spectrum vaccine against COVID-19 in the future.