Biology of Infection and Disease Pathogenesis to Guide RSV Vaccine Development

Abstract

Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract disease in young children and a substantial contributor to respiratory tract disease throughout life and as such a high priority for vaccine development. However, after nearly 60 years of research no vaccine is yet available. The challenges to developing an RSV vaccine include the young age, 2-4 months of age, for the peak of disease, the enhanced RSV disease associated with the first RSV vaccine, formalin-inactivated RSV with an alum adjuvant (FI-RSV), and difficulty achieving protection as illustrated by repeat infections with disease that occur throughout life. Understanding the biology of infection and disease pathogenesis has and will continue to guide vaccine development. In this paper, we review the roles that RSV proteins play in the biology of infection and disease pathogenesis and the corresponding contribution to live attenuated and subunit RSV vaccines. Each of RSV's 11 proteins are in the design of one or more vaccines. The G protein's contribution to disease pathogenesis through altering host immune responses as well as its role in the biology of infection suggest it can make a unique contribution to an RSV vaccine, both live attenuated and subunit vaccines. One of G's potential unique contributions to a vaccine is the potential for anti-G immunity to have an anti-inflammatory effect independent of virus replication. Though an anti-viral effect is essential to an effective RSV vaccine, it is important to remember that the goal of a vaccine is to prevent disease. Thus, other effects of the infection, such as G's alteration of the host immune response may provide opportunities to induce responses that block this effect and improve an RSV vaccine. Keeping in mind the goal of a vaccine is to prevent disease and not virus replication may help identify new strategies for other vaccine challenges, such as improving influenza vaccines and developing HIV vaccines.

Keywords: RSV (respiratory syncytial virus); biology of infection; pathogenesis; protective immunity; vaccine development.

Figure 1

Enhanced disease prevention with the addition of G to an F protein vaccine. The three schematics represent disease pathogenesis associated with no vaccine (1st schematic), an F protein vaccine (2nd schematic), and an F + G protein vaccine (3rd schematic). For all three, two types of disease pathogenesis are represented, one associated with virus replication and cytopathology (above the line) and the other induced by the RSV G protein (below the line). In mice, G induced disease includes increased inflammatory cells and mucus in the lungs and increased signs of obstructive airway disease and is not dependent on level of virus replication (–97). In the second schematic, an F protein vaccine prevents much but not all virus replication and much of the disease pathogenesis represented above the line. In the third schematic, addition of G to an F protein also prevents disease pathogenesis represented below the line. The width of the arrows indicate level of virus replication, cytopathology/inflammation, G-inflammation, or residual disease.