Every year more than 350 million people in over 120 countries contact dengue fever, which can cause symptoms ranging from aching muscles and a skin rash to life-threatening haemorrhagic fever. Researchers have struggled to create effective vaccines against dengue virus, in part because four distinct serotypes of the virus cause dengue fever and a vaccine must immunize against all four individually. Attempts at using live dengue viruses to develop a dengue fever vaccine have often led to an imbalance in immunity to the four dengue serotypes. Previous infection with one serotype of dengue, or protection against just one serotype, can lead to more severe disease if a person contracts other serotypes, so it’s vital that vaccines are available that specifically target all four strains.
To create a new dengue virus vaccine researchers designed nanoparticles of various shapes and sizes. Each nanoparticle was studded with copies of DENV2-E protein, a key protein from serotype 2 of the virus. After immunization with the DENV2-E nanoparticles, mice had a specific antibody response to serotype 2 of the dengue virus, but not the other three serotypes. Compared to mice vaccinated with only the soluble DENV2-E proteins, the nanoparticle formulations led to a stronger immune response.
Clearly this enabling research is still a long way from an effective human vaccine against dengue fever. Future studies will be required to test whether the antibody levels prevent dengue infection as well as whether similar nanoparticles can be develop for all dengue serotypes. At the same time, it is difficult to imagine that the next few years will not bring a host of candidate vaccines based on nanoparticles.
Precisely Molded Nanoparticle Displaying DENV-E Proteins Induces Robust Serotype-Specific Neutralizing Antibody Responses. (2016) PLoS Negl Trop Dis 10(10): e0005071. doi: 10.1371/journal.pntd.0005071
Dengue virus (DENV) is the causative agent of dengue fever and dengue hemorrhagic fever. The virus is endemic in over 120 countries, causing over 350 million infections per year. Dengue vaccine development is challenging because of the need to induce simulta- neous protection against four antigenically distinct DENV serotypes and evidence that, under some conditions, vaccination can enhance disease due to specific immunity to the virus. While several live-attenuated tetravalent dengue virus vaccines display partial effi- cacy, it has been challenging to induce balanced protective immunity to all 4 serotypes. Instead of using whole-virus formulations, we are exploring the potentials for a particulate subunit vaccine, based on DENV E-protein displayed on nanoparticles that have been pre- cisely molded using Particle Replication in Non-wetting Template (PRINT) technology. Here we describe immunization studies with a DENV2-nanoparticle vaccine candidate. The ectodomain of DENV2-E protein was expressed as a secreted recombinant protein (sRecE), purified and adsorbed to poly (lactic-co-glycolic acid) (PLGA) nanoparticles of dif- ferent sizes and shape. We show that PRINT nanoparticle adsorbed sRecE without any adjuvant induces higher IgG titers and a more potent DENV2-specific neutralizing antibody response compared to the soluble sRecE protein alone. Antigen trafficking indicate that PRINT1 nanoparticle display of sRecE prolongs the bio-availability of the antigen in the draining lymph nodes by creating an antigen depot. Our results demonstrate that PRINT© nanoparticles are a promising platform for delivering subunit vaccines against flaviviruses such as dengue and Zika.