Zika Vaccines: Role for Controlled Human Infection

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 [4, 5], and passively acquired RSV neutralizing Ab can protect infants against RSV ALRI [6–9]. 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 [6]. 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 [7]; 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…

Human dengue virus serotype 2 neutralizing antibodies target two distinct quaternary epitopes.

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 [34]. 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 [10]. 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.

Campylobacter jejuni transcriptional and genetic adaptation during human infection

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.