Respiratory syncytial virus vaccine development

Highlights

• The burden of disease that justifies RSV vaccine priorities.

• The rationale for target populations.

• The approach to developing an RSV vaccine including the proteins most relevant to the vaccine.

• The types of vaccines and approach to design for the various types.

• Concepts that may help vaccine development.

Abstract

The importance of RSV as a respiratory pathogen in young children made it a priority for vaccine development shortly after it was discovered. Unfortunately, after over 50 years of vaccine development no vaccine has yet been licensed and it is not certain which if any vaccines being developed will be successful. The first candidate vaccine, a formalin inactivated RSV vaccine (FI-RSV), was tested in children in the 1960s and predisposed young recipients to more serious disease with later natural infection. The ongoing challenges in developing RSV vaccines are balanced by advances in our understanding of the virus, the host immune response to vaccines and infection, and pathogenesis of disease. It seems likely that with efficient and appropriately focused effort a safe and effective vaccine is within reach. There are at least 4 different target populations for an RSV vaccine, i.e. the RSV naïve young infant, the RSV naïve infant >4–6 months of age, pregnant women, and elderly adults. Each target population has different issues related to vaccine development. Numerous vaccines from live attenuated RSV to virus like particle vaccines have been developed and evaluated in animals. Very few vaccines have been studied in humans and studies in humans are needed to determine which vaccines are worth moving toward licensure. Some changes in the approach may improve the efficiency of evaluating candidate vaccines. The complexity of the challenges for developing RSV vaccines suggests that collaboration among academic, government, and funding institutions and industry is needed to most efficiently achieve an RSV vaccine.

Introduction

In 1955, Morris et al. isolated a virus from Chimpanzees, chimpanzee coriza agent [1], and shortly thereafter a similar virus was isolated from young children and designated respiratory syncytial virus (RSV) [2], [3]. The importance of this virus as a cause of acute respiratory illness in young children was quickly recognized and efforts to develop an RSV vaccine began. RSV infections are usually symptomatic and in the young child cause the full spectrum of acute respiratory illnesses including a common cold-like illness, croup, bronchitis, bronchiolitis, and pneumonia [4]. Bronchiolitis, i.e. a lower respiratory tract illness with wheezing, is the signature RSV illness in infants and young children. The virus spreads efficiently and is estimated that 50% of children become infected during their first year of life and nearly 100% by 2 years of age [5]. Since infection provides limited protective immunity, repeat infections and disease occur throughout life. Infants <6 months of age, persons of any age with compromised cardiac, pulmonary and immune systems, and the elderly are especially susceptible to more serious complications with infection [6], [7]. RSV is considered the single most important cause of serious acute respiratory illness in infants and young children world-wide causing an estimated 66,000 to over 200,000 deaths and 3.4 million hospitalizations in children <5 years of age each year [8], [9]. In the United States, it is estimated that between 57,000 and 175,000 children <5 years of age are hospitalized each year with RSV [10], [11], [12]. It is also estimated that RSV is associated with over 500,000 emergency room visits [10] but <500 deaths in children <5 years of age each year in the United States. It also causes substantial disease in elderly persons resulting in an estimated 177,000 hospitalizations and between 10,000 and 15,000 deaths each year in the United States [13], [14], [15]. In temperate climates, most illness occurs in yearly outbreaks in the late fall, winter, and early spring months, e.g. October to April in the northern hemisphere and April to September in the southern hemisphere [16], [17], [18]. Outbreaks often last from 4 to 5 months in a community.

Another potential outcome of RSV infection in the infant is later development of reactive airway disease. Multiple studies have shown that children hospitalized with RSV have a substantially increased risk of having reactive airway or asthma through adolescence [19], [20], [21], [22]. What is still unclear, however, if this occurs because children likely to develop reactive airway disease are also more likely to be hospitalized with RSV and the RSV infection is not causally related to the later reactive airway disease or because infection alters the architecture of the airways or patterns for future immune responses associated with reactive airway disease.

The importance of RSV as a respiratory pathogen in young children made it a priority for vaccine development shortly after it was discovered. Unfortunately, after over 50 years of vaccine development no vaccine has yet been licensed and it is not certain which if any vaccines being developed will be successful. The first candidate vaccine, a formalin inactivated RSV vaccine (FI-RSV), was tested in children in the 1960s and predisposed young recipients to more serious disease with later natural infection [23], [24], [25], [26]. Older children who likely had been previously infected with RSV did not suffer this enhanced disease. It appears that prior infection patterned for a safe immune response to the vaccine and prevented development of enhanced disease. A study in mice showed prior live virus infection prevented enhanced disease in mice later vaccinated with FI-RSV vaccine and challenged with RSV [27]. The experience with FI-RSV continues to effect vaccine development. Because of the FI-RSV trial, only attenuated live RSV or RSV proteins expressed in a live virus vector have, so far, been considered safe for testing in RSV naïve children. Unfortunately, no live attenuated RSV or live virus vectored vaccine has yet been licensed. Since older, RSV primed children are not considered at risk for enhanced disease, a variety of other types of vaccines including purified proteins, virus-like particles (VLPs), nanoparticles, and DNA or vectors expressing RSV proteins are being developed for older children and adults. The efficacy of RSV immune prophylaxis first with polyclonal immune globulin [28] and then a neutralizing, anti-F protein monoclonal antibody shows [29] that an effective RSV vaccine should be achievable.

The ongoing challenges in developing RSV vaccines are balanced by advances in our understanding of the virus, the host immune response to vaccines and infection, and pathogenesis of disease. It seems likely that with efficient and appropriately focused effort a safe and effective vaccine is within reach. A number of recent reviews provide excellent discussions of many aspects of RSV and development of RSV vaccines [30], [31], [32]. In this chapter, I will highlight some less frequently considered strategies that, I believe, may facilitate the quest for an RSV vaccine.