Exacerbated lung inflammation following secondary RSV exposure is CD4+ T cell-dependent and is not mitigated in infant BALB/c mice born to PreF-vaccinated dams

Abstract

Respiratory syncytial virus (RSV) is the leading cause of childhood hospitalizations due to bronchiolitis in children under 5 years of age. Moreover, severe RSV disease requiring hospitalization is associated with the subsequent development of wheezing and asthma. Due to the young age in which viral protection is needed and risk of vaccine enhanced disease following direct infant vaccination, current approaches aim to protect young children through maternal immunization strategies that boost neutralizing maternal antibody (matAb) levels. However, there is a scarcity of studies investigating the influence of maternal immunization on secondary immune responses to RSV in the offspring or whether the subsequent development of wheezing and asthma is mitigated. Toward this goal, our lab developed a murine model of maternal RSV vaccination and repeat RSV exposure to evaluate the changes in immune response and development of exacerbated lung inflammation on secondary RSV exposure in mice born to immunized dams. Despite complete protection following primary RSV exposure, offspring born to pre-fusion F (PreF)-vaccinated dams had exaggerated secondary ILC2 and Th2 responses, characterized by enhanced production of IL-4, IL-5, and IL-13. These enhanced type 2 cellular responses were associated with exaggerated airway eosinophilia and mucus hyperproduction upon re-exposure to RSV. Importantly, depletion of CD4+ T cells led to complete amelioration of the observed type 2 pathology on secondary RSV exposure. These unanticipated results highlight the need for additional studies that look beyond primary protection to better understand how maternal immunization shapes subsequent immune responses to repeat RSV exposure.

Lung ILC2s are activated in BALB/c mice born to immunized mothers despite complete protection against respiratory syncytial virus

“…Importantly, ILC2s trained during neonatal activation are more functionally competent upon restimulation, demonstrating more vigorous responses to stimulation than newly established adult ILC2s (2). Consistent with this work, we previously identified a hyperresponsive ILC2 (hILC2) population in maternally vaccinated offspring following secondary exposure to respiratory syncytial virus (RSV) (3). As a prior stimulation is necessary to "train" a more functionally competent ILC2 population in adulthood, the presence of hILC2s in offspring born to dams immunized with an adjuvated prefusion RSV F vaccine, led us to theorize that ILC2s were activated during primary neonatal RSV exposure in the presence of RSVneutralizing maternal antibody (matAb).…”

“…ILC2s were identified as previously described (3). Specifically, lung cells were surface stained with CD16/32 (Fc block; 2.4G2), LIVE/DEAD ™ Fixable Blue Dead Cell Stain Kit, Lineage Cocktail (CD3 (17A2), Ly6G/Ly6C (RB6-8C5), CD11b (M1/70), CD45R (RA3-6B2), TER-119 (Ter-119)), CD49b (DX5), CD45 (30-F11), ST2 (DIH9), ICOS (C398.4A), CD127 (A7R34) and CD25 (PC61) and intracellularly stained for IL-5 (TRFK5) and IL-13 (ebio13A), as previously reported (3). Samples were run on a BD Fortessa or Cytek Aurora managed by the United Flow Core of the University of Pittsburgh.…”

Meeting the Challenge of Controlling Viral Immunopathology

“…As mentioned above, there is one example of a viral immunoinflammatory lesion that occurs with RSV that is orchestrated primarily by CD4+ Th2 cells [126,127]. These types of lesions are more characteristic of inflammatory reactions to parasites and to allergens.…”