Uncovering the biology behind the RSV vaccine

Unveiling Integrated Functional Pathways Leading to Enhanced Respiratory Disease Associated With Inactivated Respiratory Syncytial Viral Vaccine. Russell MS, Creskey M, Muralidharan A, Li C, Gao J, Chen W, Larocque L, Lavoie JR, Farnsworth A, Rosu-Myles M, Hashem AM, Yauk CL, Cao J*, Van Domselaar G*, Cyr T, Li X. Front Immunol 2019 Mar 29;10:597. doi: https://doi.org/10.3389/fimmu.2019.00597

This science story explains how an integrated systems biology approach was used to unravel a complex, abnormal immune response to a respiratory virus vaccine. The research provides a biological explanation for previously unexplained phenomena and may inform future efforts to understand the effects of vaccines.

What was known about this area prior to your work, and why was the research done?

Respiratory syncytial virus (RSV) is a common respiratory virus that can result in mild, cold-like symptoms in healthy adults. Yet, it is the most frequent cause of serious respiratory illness in infants, the elderly, and the immunocompromised and commonly results in lower respiratory tract infections such as pneumonia or bronchiolitis. Despite decades of research, there is currently no approved vaccine against RSV. Viruses used in vaccines are commonly inactivated (killed) by chemicals, such as formalin. These viruses are too weak to establish an infection, but they can trigger an immune response, thereby providing protection. A clinical trial conducted in the 1960s with a formalin-inactivated RSV vaccine resulted in severe respiratory disease—including deaths—in vaccinated children that were later infected with RSV during a seasonal outbreak. This phenomenon is termed vaccine-associated enhanced respiratory disease (VERD). Later attempts to develop alternatives to formalin-inactivation failed and were also believed to induce VERD. In order to develop a safe and effective RSV vaccine, it is important to understand the mechanisms that lead to VERD. This research used a systems biology approach to examine how VERD progresses in cotton rats, an animal that mirrors the human response in RSV infection. Systems biology is a method that analyzes the interactions of complex biological systems at the molecular and cellular level.

What are your most significant findings from this work?

The study found an increase in activity for several important genetic pathways responsible for the production of specific immune-related substances, known as cytokines. Some of these cytokines play an important role in smooth muscle contraction and contribute to lung constriction, consistent with the laboured breathing and airway obstruction observed for cotton rats vaccinated with formalin-inactivated RSV. Other biological responses to these cytokines include an increase of different types of white blood cells, a hallmark of immune infection response. These outcomes related to VERD further our understanding of molecular response to vaccines. Interestingly, an imbalance in substances controlling how blot clots are formed and degraded was observed with VERD for the first time. This finding illuminates the mechanisms contributing to bronchiolitis symptoms.

What are the implications or impact of the research?

Host response to vaccines involves complex and interdependent biological pathways resulting in changes to host genetic activity and immune-related cell populations. The integrated systems biology approach used in this research attempts to examine the interplay between biological systems to understand complications associated with certain vaccine formulations. The work illuminates the molecular mechanisms underlying the abnormal immune response that can occur after vaccination with formalin-inactivated RSV. This information will contribute to the development and evaluation of safe and effective vaccines against RSV infection.

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