Broadly neutralizing antibodies recognizing different antigenic epitopes act synergistically against the influenza B virus.

The discovery of broadly neutralizing monoclonal antibodies against influenza viruses has raised hope for the successful development of new antiviral drugs. However, due to the speed and variety of mutations in influenza viruses, single-component antibodies that recognize specific epitopes are susceptible to viral escape and have limited efficacy when administration is delayed. Hence, it is necessary to develop alternative strategies with better antiviral activity. Influenza B virus infection can cause severe illness in children and the elderly. Commonly used anti-influenza drugs have low clinical efficacy against influenza B virus. In this study, we investigated the antiviral efficacy of combinations of representative monoclonal antibodies targeting different antigenic epitopes against the influenza B virus. We found that combinations of antibodies recognizing the hemagglutinin (HA) head and stem regions showed a stronger neutralizing activity than single antibodies and other antibody combinations in vitro. In addition, we found that pair-wise combinations of antibodies recognizing the HA head region, HA stem region, and neuraminidase enzyme-activated region showed superior antiviral activity than single antibodies in both mouse and ferret in vivo protection assays. Notably, these antibody combinations still displayed good antiviral efficacy when treatment was delayed. Mechanistic studies further revealed that combining antibodies recognizing different epitope regions resulted in extremely strong antibody-dependent cell-mediated cytotoxicity, which may partly explain their superior antiviral effects. Together, the findings of this study provide new avenues for the development of better antiviral drugs and vaccines against influenza viruses.

Humoral immune response to authentic circulating severe acute respiratory syndrome coronavirus 2 variants elicited by booster vaccination with distinct receptor-binding domain subunits in mice.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants could induce immune escape by mutations of the spike protein which are threatening to weaken vaccine efficacy. A booster vaccination is expected to increase the humoral immune response against SARS-CoV-2 variants in the population. We showed that immunization with two doses of wild type receptor-binding domain (RBD) protein, and booster vaccination with wild type or variant RBD protein all significantly increased binding and neutralizing antibody titers against wild type SARS-CoV-2 and its variants in mice. Only the booster immunization by Omicron (BA.1)RBD induced a strong antibody titer against the omicron virus strain and comparable antibody titers against all the other virus strains. These findings might shed the light on coronavirus disease 2019 booster immunogens.

Hepatitis B surface antigen kinetics after discontinuation of and retreatment with oral antivirals in non-cirrhotic HBeAg-positive chronic hepatitis B.

The outcome of nucleos(t)ide analogues (NAs) discontinuation and retreatment is still uncertain. We evaluated hepatitis B surface antigen (HBsAg) kinetics after NAs discontinuation and during retreatment due to off-treatment clinical relapse among non-cirrhotic HBeAg-positive CHB patients. Four groups were studied: 129 HBeAg-positive patients from a prospective cohort who stopped NAs therapy after achieving sustained response (Group A), 39 patients who received retreatment after off-treatment clinical relapse in the discontinuation group (Group B), 214 patients who maintained treatment after achieving sustained response (Group C) and 291 patients who firstly initiated antiviral treatment (Group D). During a 5-year follow-up, the cumulative incidence of HBsAg loss was significantly higher in Group A than Group C (22.3% vs. 1.6%, p < .001). The quantitative HBsAg (qHBsAg) level at enrolment and NAs discontinuation were independently associated with HBsAg loss. Additionally, patients in Group B showed significantly greater HBsAg loss than those in the Groups C and D, with 5-year cumulative incidences of 9.0%, 1.6% (p = .040) and 0.6% (p < .001), respectively. Moreover, patients in the Group B exhibited better virologic response (100% vs. 98.8%, p < .001) and HBeAg seroconversion (92.6% vs. 69.8%, p < .001) than those in Group D at year 5. Propensity score-matched analysis also showed the similar trend of HBsAg decline. NAs discontinuation with or without subsequent retreatment resulted in a more profound reduction of HBsAg in non-cirrhotic HBeAg-positive patients, suggesting that discontinuation may be a potential cure strategy for those with sustained virological suppression.

Preoperative false-negative transthoracic echocardiographic results in native valve infective endocarditis patients: a retrospective study from 2001 to 2018.

BACKGROUND: Infective endocarditis (IE) is a lethal disease that is difficult to diagnosis early. Although echocardiography is one of the most widely used diagnostic technique, it has limited sensitivity. This study surveyed the clinical features of IE patients who underwent surgery and compared transthoracic echocardiography and histological findings to explore the factors related to false-negative echocardiographic results. METHODS: Medical records were extracted from IE patients consecutively hospitalized between June 2001 and June 2018. RESULTS: A total of 182 patients with native valve IE who underwent surgery were included. Compared to the non-surgery group, the surgery group was more likely to have pre-existing valvular lesions and more serious cardiac conditions and a relative lack of signs of infection and cerebrovascular events, leading to a lower proportion of "definite cases" before surgery. The false-negative rate of echocardiography was 14.5%. Echocardiography has significant disadvantages in diagnosing perivalvular abscesses, valve perforations, and left-sided endocarditis, especially for subjects with both aortic and mitral valve infections. The multivariate analysis identified congenital heart disease and small vegetations (< 10 mm) as independent predictors of false-negative echocardiography results. Conversely, fever and heart murmurs on admission served as protective factors. CONCLUSIONS: Under some circumstances, echocardiography provides inconsistent results compared with surgical findings, and negative echocardiography results do not rule out IE. The diagnosis of IE depends on comprehensive evaluations using multiple methods.

A changing profile of infective endocarditis at a tertiary hospital in China: a retrospective study from 2001 to 2018.

BACKGROUND: Infective endocarditis (IE) is a lethal disease which has been changing significantly over the past decades; however, information about IE in China remains scarce. This study surveyed the changes in clinical characteristics of IE at a tertiary hospital in south China over a period of nearly 18 years. METHODS: Medical records with IE patients consecutively hospitalized between June 2001 and June 2018 were selected from the electronic medical records system in Nanfang Hospital of Southern Medical University. Data were divided by admission time into two groups equally: early-period group, June 2001 to December 2009 and later-period group, January 2010 to July 2018. RESULTS: A Total of 313 IE patients were included in our study. Compared with the early-period group, patients in the later-period group included fewer intravenous drug users (IVDUs), older age at onset, reduced development of pulmonary embolism, less renal dysfunction, decreased proportion of Staphylococcus aureus infection and fewer vegetations observed in the right heart by echocardiography. The later-period group also showed a higher proportion of ischemic strokes and higher proportion of positive microbiological findings compared with the early-period group. The in-hospital mortality remained about the same between the two periods and the multivariate analysis identified intravenous drug addicted, prosthetic valve endocarditis, hemorrhagic stroke, acute congestive heart failure, renal insufficiency, left-sided endocarditis, early surgical as independent predictors of in-hospital mortality. CONCLUSIONS: Our study demonstrated a dramatic change in the profile of IE over a period of 18 years at a tertiary hospital in south China and presented several independent predictors of in-hospital mortality. The geographic variations observed in our study will be of important value to profile the clinical feature of China and offer the reference for clinical decisions in our region.

Analysis of binding and authentic virus-neutralizing activities of immune sera induced by various monkeypox virus antigens.

Monkeypox cases continue to increase globally, and there is an urgent need to develop a highly effective vaccine against monkeypox. This study investigated the binding and authentic-virus neutralizing activities of sera from mice immunized with EEV (extracellularly enveloped viruses) antigens B6R and A35R, and IMV (intrinsic material viruses) antigens M1R, A29L, E8L, and H3L against monkeypox virus. The results showed that immunizations of A35R and E8L could only induce lower titers of binding antibodies, in contrast, immunization of M1R induced the highest titers of binding antibodies, while immunization of B6R, H3L, and A29L induced moderate titers of binding antibodies. For the live monkeypox virus neutralization assay, the results showed that immunization with two doses of EEV antigen B6R did not effectively induce humoral immune responses to neutralize monkeypox live virus, immunization with EEV-A35R only induced weak monkeypox-neutralizing antibodies. In contrast, the immunization of the four types of monkeypox virus IMV antigens can all induce neutralizing antibodies against authentic monkeypox virus, among them, A29L and H3L induced the highest neutralizing antibody titers. The results of this study provide important references for the selection of antigens in the development of the next generation of monkeypox vaccines.

Status and Developing Strategies for Neutralizing Monoclonal Antibody Therapy in the Omicron Era of COVID-19.

The monoclonal antibody (mAb)-based treatment is a highly valued therapy against COVID-19, especially for individuals who may not have strong immune responses to the vaccine. However, with the arrival of the Omicron variant and its evolving subvariants, along with the occurrence of remarkable resistance of these SARS-CoV-2 variants to the neutralizing antibodies, mAbs are facing tough challenges. Future strategies for developing mAbs with improved resistance to viral evasion will involve optimizing the targeting epitopes on SARS-CoV-2, enhancing the affinity and potency of mAbs, exploring the use of non-neutralizing antibodies that bind to conserved epitopes on the S protein, as well as optimizing immunization regimens. These approaches can improve the viability of mAb therapy in the fight against the evolving threat of the coronavirus.

Three neutralizing mAbs induced by MPXV A29L protein recognizing different epitopes act synergistically against orthopoxvirus.

The worldwide outbreak of the monkeypox virus (MPXV) has become a "Public Health Emergency of International Concern" (PHEIC). Severe monkeypox virus infection can be fatal, however, effective therapeutic methods are yet to be developed. Mice were immunized with A35R protein and A29L protein of MPXV, and the binding and neutralizing activities of the immune sera against poxvirus-associated antigens and viruses were identified. A29L protein and A35R protein-specific monoclonal antibodies (mAbs) were generated and their antiviral activities of these mAbs were characterized in vitro and in vivo. Immunization with the MPXV A29L protein and A35R protein induced neutralizing antibodies against the orthopoxvirus in mice. None of the mAbs screened in this study against A35R could effectively neutralize the vaccinia virus (VACV), while three mAbs against A29L protein, 9F8, 3A1 and 2D1 were confirmed to have strong broad binding and neutralizing activities against orthopoxvirus, among which 9F8 showed the best neutralizing activity. 9F8, 3A1, and 2D1 recognized different epitopes on MPXV A29L protein, showing synergistic antiviral activity in vitro against the VACV Tian Tan and WR strains; the best activity was observed when the three antibodies were combined. In the vivo antiviral prophylactic and therapeutic experiments, 9F8 showed complete protective activity, whereas 3A1 and 2D1 showed partial protective activity. Similarly, the three antibodies showed synergistic antiviral protective activity against the two VACVs. In conclusion, three mAbs recognized different epitopes on MPXV A29L protein were developed and showed synergistic effects against orthopoxvirus.

Nomogram based on neutrophil-to-platelet ratio to predict in-hospital mortality in infective endocarditis.

Aim: To develop a nomogram based on neutrophil-to-platelet ratio (NPR) to predict in-hospital mortality in infective endocarditis (IE) patients. Methods: We retrospectively analyzed 294 consecutive patients classified as survivors or nonsurvivors according to hospitalization outcome. Logistic regression analyses were performed to identify independent predictors for in-hospital mortality. A nomogram based on them was established and assessed by receiver operating characteristic (ROC) curve analysis. Results: Admission NPR (odds ratio [OR] = 1.095, 95% CI: 1.037-1.156), positive blood culture (OR = 9.220; 95% CI: 1.478-57.521) and left-sided endocarditis (OR = 5.099; 95% CI: 1.104-23.553) independently predicted in-hospital mortality in IE. The area under the ROC curve for the nomogram based on these predictors was 0.832. Conclusion: The nomogram based on NPR could be used for early risk stratification of IE patients.

Patients with tuberculous meningitis and hepatitis B co-infection have increased risk for antituberculosis drug-induced liver injury and poor outcomes.

BACKGROUND: Tuberculous meningitis (TBM) is one of the most severe forms of tuberculosis. Previous studies reported that hepatitis B virus (HBV) infection could increase the risk of antituberculosis drug-induced liver injury (ATB-DILI) in pulmonary tuberculosis patients. To date, only a few studies exist on the effect of HBV on TBM. METHODS: This inpatient study retrospectively analyzed the medical records of patients who were diagnosed with TBM between June 2002 and June 2018. Statistical analysis was used to reveal the difference between the HBV and non-HBV groups. Univariate analysis and multivariate regression analysis were performed on data to determine the prognostic factors of TBM. RESULTS: A total of 386 patients were enrolled in our study, 57 of whom were included in the HBV group and 329 in the non-HBV group. The HBV group showed a higher frequency of ATB-DILI (HBV group: 14.0% versus non-HBV group: 3.3%, p < .001) and a higher risk of poor outcomes (i.e. death during inpatient period or neurological deficit at discharge, HBV group: 31.6% versus non-HBV group: 19.8%, p = .045) than the non-HBV group. The multivariate regression analysis identified ATB-DILI, scores of 3-8 on the Glasgow Coma Scale and hydrocephalus as independent predictors of poor outcomes in TBM patients. CONCLUSIONS: Our study demonstrated that HBV co-infection could increase the incidence of ATB-DILI and the risk of poor outcomes as identified by three predictors in TBM patients.