Rational design of a cross-type HPV vaccine through immunodominance shift guided by a cross-neutralizing antibody.

In vaccine development, broadly or cross-type neutralizing antibodies (bnAbs or cnAbs) are frequently targeted to enhance protection. Utilizing immunodominant antibodies could help fine-tune vaccine immunogenicity and augment the precision of immunization strategies. However, the methodologies to capitalize on the attributes of bnAbs in vaccine design have not been clearly elucidated. In this study, we discovered a cross-type neutralizing monoclonal antibody, 13H5, against human papillomavirus 6 (HPV6) and HPV11. This nAb exhibited a marked preference for HPV6, demonstrating superior binding activity to virus-like particles (VLPs) and significantly higher prevalence in anti-HPV6 human serum as compared to HPV11 antiserum (90% vs. 31%). Through co-crystal structural analysis of the HPV6 L1 pentamer:13H5 complex, we delineated the epitope as spanning four segments of amino acids (Phe42-Ala47, Gly172-Asp173, Glu255-Val275, and Val337-Tyr351) on the L1 surface loops. Further interaction analysis and site-directed mutagenesis revealed that the Ser341 residue in the HPV6 HI loop plays a critical role in the interaction between 13H5 and L1. Substituting Ser341 with alanine, which is the residue type present in HPV11 L1, almost completely abolished binding activity to 13H5. By swapping amino acids in the HPV11 HI loop with corresponding residues in HPV6 L1 (Ser341, Thr338, and Thr339), we engineered chimeric HPV11-6HI VLPs. Remarkably, the chimeric HPV11-6HI VLPs shifted the high immunodominance of 13H5 from HPV6 to the engineered VLPs and yielded comparable neutralization titers for both HPV6 and HPV11 in mice and non-human primates. This approach paves the way for the design of broadly protective vaccines from antibodies within the main immunization reservoir.

Brugada phenocopy in a patient with acute pulmonary embolism presenting with recurrent syncope.

Brugada phenocopy (BrP) refers to a group of clinical conditions that have etiologies distinct from Brugada syndrome (BrS). Although both demonstrate features of ST-segment elevation in the right precordial leads on the electrocardiogram (ECG), one must be distinguished from the other as their treatment options are different. We report a male patient who presented with recurrent syncope with a Brugada and a S1Q3T3 pattern on the ECG. Acute pulmonary embolism (APE) complicated by BrS was suspected. Twenty-four hours Holter monitoring did not demonstrate any evidence of ventricular arrhythmias. Computed tomography pulmonary angiogram confirmed the presence of an APE. He was treated with low molecular weight heparin and a repeat ECG taken the next day showed resolution of the Brugada and S1Q3T3 patterns. This case report illustrates that APE and BrS can present with similar clinical and electrocardiographic features of recurrent syncope and Brugada pattern, respectively.

[A randomized, double-blind, double-dummy study comparing a fixed dose combination of telmisartan 80 mg plus hydrochlorothiazide 12.5 mg to telmisartan 80 mg in Chinese hypertensive patients who failed to respond adequately to telmisartan 80 mg].

OBJECTIVE: To evaluate the efficacy and safety of a fixed dose combination of telmisartan 80 mg plus hydrochlorothiazide (HCTZ) 12.5 mg (TH) to telmisartan 80 mg (T) in Chinese patients who failed to respond adequately to treatment with T. METHOD: This is a multi-center, randomized, double-blind, double-dummy clinical study. A total of 699 eligible hypertensive patients entered a one-week screening phase prior to the eight-week open-label T period. At the end of eight weeks, 345 patients who failed to respond to T (DBP > or = 90 mm Hg, 1 mm Hg = 0.133 kPa) were randomized to receive either TH (175 patients) or T (170 patients) for another eight weeks. Sitting and standing BP were taken 24 hours post-dose and adverse events were documented at visit with 4 weeks interval. Laboratory, ECG and physical examination were performed at screening, at baseline and at the final visit. RESULTS: After 8 weeks treatment, (1) The mean trough reduction in sitting diastolic blood pressure (SiDBP) from baseline in TH group was greater than that in T group (10.1 mm Hg vs 7.7 mm Hg, P = 0.0017). The mean trough reduction in sitting systolic blood pressure (SiSBP) from baseline was 14.2 mm Hg in TH group and 7.4 mm Hg in T group (P < 0.0001). (2) The mean trough reduction in standing DBP and standing SBP from baseline were significantly greater in TH group (8.7 mm Hg and 12.9 mm Hg) compared those in T group (7.3 mm Hg and 7.0 mmHg, P = 0.0350, P < 0.0001). (3) The number and percentage of responders in TH group (129, 74.6%) were significantly higher than in T group (100, 59.2%, P = 0.0016). (4) The incidence of the study drug-related adverse events was similar between TH and T group (3.5% vs. 3.6%, P > 0.05). CONCLUSION: TH was more effective than T in patients not responded adequately to T in Chinese hypertensive patients.

[Retrospective analysis of drug treatment on inpatients with chronic heart failure].

OBJECTIVE: To investigate drug treatment of inpatients with chronic heart failure(CHF) during the past 30 years in some areas and to provide more information on the treatment strategy of CHF. METHODS: In two centers a retrospective study was conducted. All data were taken from the hospitalized cases with chronic heart failure. The medication distributions in different decade, gender, age heart function grade and etiology were analyzed. RESULTS: 5189 cases were enrolled with the ratio of male to female as 1:1.02. The mean age was (62.93 +/- 13.49) years old. The general causes of chronic heart failure were as follows: coronary heart disease (44.2%), rheumatic heart disease (24.1% ) , pulmonary heart disease (19.0%) and cardiomyopathy (4.8%). The admission cardiac function was mostly seen as grade NYHA IlI and IV, and their proportions were 40.6% and 44.5%. Major medication would include nitride (80.0%), diuretics (71.8% ), digitalis (68.1% ), angiotensin conversion enzyme inhibitors (ACEI) (52.2% ) and beta-blockers (19.5% ) etc. Moreover the frequency of above used medication was essentially increasing decade by decade. The major drug treatment of pulmonary heart disease also included diuretics, nitride, digitalis. ACEI was more commonly used in male than in female cases. The frequency of ACEI and ARB were more commonly used in the group > or = 60 years old than that in the group < 60 years old. The administration frequency of beta- blockers had no significant difference among different age and sexes. CONCLUSION: The conventional drugs such as nitride, diuretics, digitalis were still dominated the treatment of CHF. Although the administration frequency of ACEI and beta-blockers increased quickly, there had been a great gap between the optimal medical strategy and clinical practice in the management of CHF. Data showed the treatment strategy was changing.

[Comparable analysis of in-hospital mortality in patients with acute myocardial infarction].

OBJECTIVE: To investigate the change of the mortality of AMI and influence factors within 20 years. METHODS: Clinic data of 134 AMI patients from 1980 to 1983, 354 AMI patients from 1990 to 1993 and 817 AMI patients from 2000 to 2003 were comparably analyzed. RESULTS: In hospital mortality of AMI was 22.4% from 1980 to 1983, 14.4% from 1990 to 1993 and 9.2% from 2000 to 2003, respectively (P < 0.01). The decrease of in-hospital mortality in male was more significant than in female (P < 0.01). The corresponding factors for decrease of mortality were younger than 60 years old, first onset of AMI, successful rescue of cardiac arrest and reperfusion management of infarction relative artery. The disadvantage factor was female. CONCLUSIONS: Improvement of medical and reperfusion management of AMI conduced in significant decreases of hospital mortality.

[Analysis of factors correlated to death and reinfarction in patients with acute myocardial infarction].

OBJECTIVE: To identify the predictors of death and reinfarction in patients with acute myocardial infarction (AMI) treated with urokinase (UK) thrombolysis or percutaneous transluminal coronary angioplasty (PTCA). METHODS: In ambispective cohort study, 97 cases of AMI were treated with UK thrombolytic therapy, while 93 cases of AMI were treated with PTCA. The patients' data about clinical outcome during hospital and follow-up periods were collected. Death and reinfarction were defined as adverse event. To analyze the correlative factors and independent predictors of death and reinfarction, the spearman rank correlation and multivariate logistic regression modeling were performed. RESULTS: During hospital,incidences of adverse event were 15.46 percent and 6.45 percent in UK and PTCA groups respectively. In follow-up period, they were 30.93 percent and 9.68 percent respectively. Age, Q wave leads, Kill ip class, heart failure in hospital, the history of hypertension and myocardial infarction were positive correlation with adverse event, whereas history of smoking, systolic blood pressure and ejection fraction (EF) showed negative correlation with the adverse event. The interventional therapy, associated with lower mortality and reinfarction rate, was the independent predictor for adverse event in UK and PTCA groups during hospital and follow-up periods. Furthermore, it was the only independent predictor for PTCA group. In UK group, the adverse event also was independently predicted by age, heart failure and Q wave leads in hospital and by age, heart failure during follow-up period. There was negative correlation between preinfarction angina and adverse event, and positive correlation between thrombolysis and adverse event inpatients undergone rescue PTCA. CONCLUSION: Interventional therapy is crucial independent predictor for adverse event of patients suffering from AMI. The adverse event is also predicted by age, Q wave leads and heart failure. The history of preinfarction angina is negative correlation with the adverse event in hospital, due to, maybe, myocardium ischemia preconditioning.