Induction and Subversion of Human Protective Immunity: Contrasting Influenza and Respiratory Syncytial Virus

Abstract

Respiratory syncytial virus (RSV) and influenza are among the most important causes of severe respiratory disease worldwide. Despite the clinical need, barriers to developing reliably effective vaccines against these viruses have remained firmly in place for decades. Overcoming these hurdles requires better understanding of human immunity and the strategies by which these pathogens evade it. Although superficially similar, the virology and host response to RSV and influenza are strikingly distinct. Influenza induces robust strain-specific immunity following natural infection, although protection by current vaccines is short-lived. In contrast, even strain-specific protection is incomplete after RSV and there are currently no licensed RSV vaccines. Although animal models have been critical for developing a fundamental understanding of antiviral immunity, extrapolating to human disease has been problematic. It is only with recent translational advances (such as controlled human infection models and high-dimensional technologies) that the mechanisms responsible for differences in protection against RSV compared to influenza have begun to be elucidated in the human context. Influenza infection elicits high-affinity IgA in the respiratory tract and virus-specific IgG, which correlates with protection. Long-lived influenza-specific T cells have also been shown to ameliorate disease. This robust immunity promotes rapid emergence of antigenic variants leading to immune escape. RSV differs markedly, as reinfection with similar strains occurs despite natural infection inducing high levels of antibody against conserved antigens. The immunomodulatory mechanisms of RSV are thus highly effective in inhibiting long-term protection, with disturbance of type I interferon signaling, antigen presentation and chemokine-induced inflammation possibly all contributing. These lead to widespread effects on adaptive immunity with impaired B cell memory and reduced T cell generation and functionality. Here, we discuss the differences in clinical outcome and immune response following influenza and RSV. Specifically, we focus on differences in their recognition by innate immunity; the strategies used by each virus to evade these early immune responses; and effects across the innate-adaptive interface that may prevent long-lived memory generation. Thus, by comparing these globally important pathogens, we highlight mechanisms by which optimal antiviral immunity may be better induced and discuss the potential for these insights to inform novel vaccines.

Innate Immune Evasion by Human Respiratory RNA Viruses

“…It may well be that, besides their strong genetic variation, the innate immune evasive activities of the mentioned respiratory viruses play a role in this lack of eliciting protective immunity [180], and to possibly improve our options for effective antiviral strategies, it seems pivotal to further investigate this. For influenza the situation is slightly different, since this virus elicits protective immunity [172]; however, its genetic drift and shift causes new strains that are not, or inefficiently, recognized by existing influenza immunity which generally means that individuals will experience multiple influenza infections in the course of their lives. Besides contributing to the problem of limited immunological protection, viral innate immune evasion may also contribute to often reported immune over-reactions associated with respiratory infections, including cytokine storms, damaging inflammation, and other severe complications [181][182][183][184].…”

Identification of erythroid cell positive blood transcriptome phenotypes associated with severe respiratory syncytial virus infection

“…To date, efforts towards the development of a vaccine has not proven fruitful [18]. Indeed, this may be in part attributed to immune evasion mechanisms established by the virus that prove able of thwarting the development of long-term immunity against the virus [19]. This may be best illustrated by the fact that, unlike what is observed in the case of influenza virus, it is common for individuals infected by RSV to be subsequently reinfected by the same strain of virus.…”

Surviving Deadly Lung Infections: Innate Host Tolerance Mechanisms in the Pulmonary System

“…It leads to an estimated 500,000 deaths annually, in addition to the hospitalizations and loss of productivity from infected people (17). There are also a variety of other viruses that can infect the lower respiratory tract and lead to pneumonia, including respiratory syncytial virus (RSV), parainfluenza, human metapneumonia, and some adenoviruses (14,(18)(19)(20)(21)(22). Rhinoviruses and newly described coronaviruses also infect the respiratory tract and cause disease.…”