A Prime-Boost Strategy Using Virus-Like Particles Pseudotyped for HCV Proteins Triggers Broadly Neutralizing Antibodies in Macaques

Virus-like particles pseudotyped with heterologous viral envelopes stimulate broadly cross-neutralizing antibodies against HCV. Formulating a Multitalented Vaccine With increasing pressure to always be connected, people now use their phones while simultaneously engaged in most of life’s activities. Yet multitasking while dining, running errands, or even commuting isn’t as easy as it seems: Texting while driving greatly increases the risk of accidents, and phone chatter during dinner raises ire in other patrons (or family members). Difficulty with multitasking can also occur at the cellular level. Now, Garrone et al. find a way to help immune cells to multitask when mounting a response to a vaccine. Between 170 and 200 million people are chronically infected with hepatitis C virus (HCV) worldwide. HCV infection is associated with high morbidity and mortality resulting from liver failure and liver cancer, but there is currently no vaccine that protects against HCV. The holy grail of successful vaccination is the ability to raise multitasking antibodies—broadly neutralizing agents that respond to multiple viral subtypes and that are still effective after viral mutation. Vaccines can be made from attenuated or inactivated virus, which are prime candidates for inducing broadly neutralizing antibodies; however, these vaccines pose safety concerns because of potential severe side effects. Garrone et al. made an HCV vaccine using safer HCV protein–expressing virus-like particles (VLPs); these reagents look a bit like an intact virus because VLPs are formed with the viral Gag protein but are safer because they lack the viral replication machinery. The authors introduced the HCV-specific envelope glycoproteins E1 and E2 into these VLPs, which were able to raise HCV-neutralizing antibodies in both mice and macaques. Indeed, these antibodies could cross-neutralize five other genotypes of HCV. Thus, the VLP platform induces antibodies that, unlike people with cell phones, can successfully multitask. Chronic hepatitis C virus (HCV) infection, with its cohort of life-threatening complications, affects more than 200 million persons worldwide and has a prevalence of more than 10% in certain countries. Preventive and therapeutic vaccines against HCV are thus much needed. Neutralizing antibodies (NAbs) are the foundation for successful disease prevention for most established vaccines. However, for viruses that cause chronic infection such as HIV or HCV, induction of broad NAbs from recombinant vaccines has remained elusive. We developed a vaccine platform specifically aimed at inducing NAbs based on pseudotyped virus-like particles (VLPs) made with retroviral Gag. We report that VLPs pseudotyped with E2 and/or E1 HCV envelope glycoproteins induced high-titer anti-E2 and/or anti-E1 antibodies, as well as NAbs, in both mouse and macaque. The NAbs, which were raised against HCV 1a, cross-neutralized the five other genotypes tested (1b, 2a, 2b, 4, and 5). Thus, the described VLP platform, which can be pseudotyped with a vast array of virus envelope glycoproteins, represents a new approach to viral vaccine development.