To characterize the epitopes of DENV2 human monoclonal antibodies (hMAbs), we used a panel of three DENV2-specific, strongly neutralizing hMAbs (S1 Table). The hMAbs were isolated from two donors infected in geographically distinct locations with different DENV2 genotypes . The three hMAbs, 3F9, 2D22 and 1L12, bound to whole DENV2 virus (Fig 2A). Recently, it has been reported that human antibodies that strongly neutralize DENVs bind to quaternary structure epitopes displayed on E homo-dimers or higher order surface structures required for virion assembly.
The live attenuated dengue vaccine TV003 elicits complete protection against dengue in a human challenge model.
A dengue human challenge model can be an important tool to identify candidate dengue vaccines that should be further evaluated in large efficacy trials in endemic areas. Dengue is responsible for about 390 million infections annually.
Clinical development and regulatory points for consideration for second-generation live attenuated dengue vaccines.
Licensing and decisions on public health use of a vaccine rely on a robust clinical development program that permits a risk-benefit assessment of the product in the target population. Studies undertaken early in clinical development, as well as well-designed pivotal trials, allow for this robust characterization. In 2012, WHO published guidelines on the quality, safety and efficacy of live attenuated dengue tetravalent vaccines.
Clinical endpoints in the controlled human challenge model for Shigella: A call for standardization and the development of a disease severity score.
Diarrhea and dysentery have long been known as major medical problems during military campaigns, but it was not until the post-World War II era that the impact of travelers’ diarrhea was clearly delineated. Studies in the 1950s and 1960s identified diarrhea as the most common cause of illness for travelers to less-developed countries . The importance of Shigella in military operations has been repeatedly described. As therapeutic options narrow, due to increasing antibiotic resistance, the need for a safe and effective Shigella vaccine becomes more pressing.
Studying bacterial evolution during infection exposes how pathogens adapt and survive in the host. High-resolution whole-genome sequencing enables accurate tracing of pathogen transmission between patients, identification of antibiotic resistance loci and understanding of selective pressures in vivo1–6. These developments have led to the identification of pathogen genetic variants that predict the success of treatments and guide therapy design.
Live Respiratory Syncytial Virus (RSV) Vaccine Candidate Containing Stabilized Temperature-Sensitivity Mutations Is Highly Attenuated in RSV-Seronegative Infants and Children.
RSVcps2, bearing the stabilized 248 (248s) mutation and the 1030s mutation, contains the following changes relative to MEDI-559: (1) the original 248 mutant assignment of 831L(TTA) was changed to 831L(TTG; change underlined) , (2) the 1030 assignment of asparagine [1321N(AAT)] was changed to lysine [1321K(AAA)] , and (3) the nearby codon 1313S(AGC) was changed to 1313S(TCA) to prevent a second-site mutation that compensated for 1321K(AAA).
Live-Attenuated Respiratory Syncytial Virus Vaccine Candidate With Deletion of RNA Synthesis Regulatory Protein M2-2 is Highly Immunogenic in Children
A major effort has been directed at development of a live-attenuated RSV vaccine to avoid the RSV disease enhancement previously observed with the formalin-inactivated RSV vaccine. Disease enhancement has not been observed with live-attenuated RSV vaccine candidates or replicating vaccine vectors. Important potential advantages of intranasal live-attenuated RSV vaccines include induction of a spectrum of protective and immunoregulatory mucosal and systemic immune responses
Determining the outcomes of interventions to prevent respiratory syncytial virus disease in children: what to measure?
Respiratory syncytial virus (RSV) is the most common cause of viral acute lower respiratory tract illness (LRTI) in young children, and a major cause of hospital admissions and health-care utilisation globally. Substantial efforts have been made to develop RSV vaccines and vaccine-like monoclonal antibodies to prevent acute RSV LRTI. Prevention of acute disease could improve long-term lung health, with potential effects on wheezing, asthma, and chronic lung disease. This Personal View describes assessments that should be initiated during clinical trials and continued after licensure to fully evaluate the effect of RSV preventive interventions.