The respiratory syncytial virus vaccine landscape: lessons from the graveyard and promising candidates
The global burden of disease caused by respiratory syncytial virus (RSV) is increasingly recognised, not only in infants, but also in older adults (aged ≥65 years). Advances in knowledge of the structural biology of the RSV surface fusion glycoprotein have revolutionised RSV vaccine development by providing a new target for preventive interventions. The RSV vaccine landscape has rapidly expanded to include 19 vaccine candidates and monoclonal antibodies (mAbs) in clinical trials, reflecting the urgency of reducing this global health problem and hence the prioritisation of RSV vaccine development.
The devastating consequences of Zika virus (ZIKV) infection, leading to congenital Zika syndrome (CZS) and neurological complications such as Guillain–Barre Syndrome (GBS), led the World Health Organization (WHO) to declare a Public Health Emergency of International Concern on February 1, 2016, and to call on the global research and product development (R&D) communities to prioritize the development of preventative and therapeutic solutions. The R&D communities responded rapidly, with 45 vaccine candidates being initially evaluated in non-clinical studies and most progressing to active development.
Zika virus (ZIKV), a previously little known arbovirus, caused an unprecedented outbreak in Latin America and the Caribbean throughout 2015 and 2016. The virus has been associated with the congenital Zika syndrome (CZS), which can occur with maternal ZIKV infection during any trimester and can result from asymptomatic infection. There is concern that even low levels of viremia can result in CZS, meaning an effective vaccine will need to induce very high levels of protection. Controlled human infection models (CHIMs), in which subjects are infected with a pathogen of interest, have been used to down-select vaccine candidates and have provided efficacy data in support of vaccine licensure.
Impact of Placental Malaria and Hypergammaglobulinemia on Transplacental Transfer of Respiratory Syncytial Virus Antibody in Papua New Guinea
Protection against RSV-associated disease is primarily antibody (Ab)–mediated, and passively acquired RSV neutralizing Ab can protect infants against RSV ALRI. To address the global burden of RSV, promising vaccines are in development with a focus on maternal immunization (to prevent RSV ALRI in the first months of life) and infant immunization (to prevent RSV ALRI in later infancy and early childhood).
A 12-Month–Interval Dosing Study in Adults Indicates That a Single Dose of the National Institute of Allergy and Infectious Diseases Tetravalent Dengue Vaccine Induces a Robust Neutralizing Antibody Response
A wide variety of dengue vaccine platforms are currently in development, and live attenuated vaccines are furthest along the development pathway . The catalyst for this progress may be recognition of the distinct advantages afforded by live dengue vaccines: live vaccines currently in use for other flavivirus diseases, including yellow fever (YF-17D) and Japanese encephalitis (SA14-14-2), are effective and can be very economical to produce ; live viruses replicate and therefore induce both humoral and cellular immune responses, assisted by the presentation of epitopes in their native conformation; and live attenuated vaccines have been successful against numerous other nonflavivirus pathogens and…
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.