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.
Highlights
Respiratory syncytial virus (RSV) is estimated to cause 3.4 million hospitalizations and 95,000–150,000 deaths globally and up to 175,000 hospitalizations in the United States in children
The challenges to developing an RSV vaccine include: concern that a non-live virus vaccine in young children may predispose to enhanced RSV disease (ERD) in RSV-infected young children who earlier received a formalin-inactivated RSV plus alum vaccine; difficulty in inducing and assessing protective immunity; cost of clinical vaccine trials; and the young age, 2– 4 months of age, for peak of disease
The first RSV vaccine, formalin-inactivated RSV with alum adjuvant (FI-RSV), given to young, likely RSV naïve, but not older, RSV primed children, led to enhanced RSV disease (ERD) with later infection, i.e., a high rate of hospitalization and two deaths [6,7,8,9]. This experience raised concern that any non-live virus vaccine may induce an aberrant immune response that predisposes to ERD in young children and a focus on live attenuated RSV or virus vector vaccines for this target population
Summary
Reviewed by: Sang-Moo Kang, Georgia State University, United States Cecilia Johansson, Imperial College London, United Kingdom. Understanding the biology of infection and disease pathogenesis has and will continue to guide vaccine development. 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. 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 antiinflammatory effect independent of virus replication. 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.
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