Defective immunoregulation in RSV vaccine-augmented viral lung disease restored by selective chemoattraction of regulatory T cells

Abstract

Human trials of formaldehyde-inactivated respiratory syncytial virus (FI-RSV) vaccine in 1966–1967 caused disastrous worsening of disease and death in infants during subsequent natural respiratory syncytial virus (RSV) infection. The reasons behind vaccine-induced augmentation are only partially understood, and fear of augmentation continues to hold back vaccine development. We now show that mice vaccinated with FI-RSV show enhanced local recruitment of conventional CD4 + T cells accompanied by a profound loss of regulatory T cells (Tregs) in the airways. This loss of Tregs was so complete that additional depletion of Tregs (in transgenic depletion of regulatory T-cell mice) produced no additional disease enhancement. Transfer of conventional CD4 + T cells from FI-RSV–vaccinated mice into naive RSV-infected recipients also caused a reduction in airway Treg responses; boosting Tregs with IL-2 immune complexes failed to restore normal levels of Tregs or to ameliorate disease. However, delivery of chemokine ligands (CCL) 17/22 via the airway selectively recruited airway Tregs and attenuated vaccine-augmented disease, reducing weight loss and inhibiting local recruitment of pathogenic CD4 + T cells. These findings reveal an unexpected mechanism of vaccine-induced disease augmentation and indicate that selective chemoattraction of Tregs into diseased sites may offer a novel approach to the modulation of tissue-specific inflammation.

A Recombinant G Protein Plus Cyclosporine A–Based Respiratory Syncytial Virus Vaccine Elicits Humoral and Regulatory T Cell Responses against Infection without Vaccine-Enhanced Disease

“…The functional Treg cells express CCR4 and interact with chemokines, including CCL17 (TARC) and CCL22 (MDC), which are important for recruitment of the cells to skin and lung (43,44). These important findings have been recently reported showing that both CCL17 and CCL22 are critical mediators in recruiting CCR4 Treg cells to suppress VED during RSV infection after the FI-RSV prime (45). Based on these findings, strategies for developing a safer RSV vaccine that circumvents FI-RSV-induced VED should include the induction of both Treg cells in lung and high levels of neutralizing Abs (20,45,46).…”

“…These important findings have been recently reported showing that both CCL17 and CCL22 are critical mediators in recruiting CCR4 Treg cells to suppress VED during RSV infection after the FI-RSV prime (45). Based on these findings, strategies for developing a safer RSV vaccine that circumvents FI-RSV-induced VED should include the induction of both Treg cells in lung and high levels of neutralizing Abs (20,45,46). Among all of the 11 viral proteins of RSV, only G and F glycoproteins contain neutralizing epitopes and induce long-term neutralizing Abs (47)(48)(49).…”

The role of Th17 and Treg responses in the pathogenesis of RSV infection

“…Administering this vaccine to mice resulted in a complete absence of Treg cells in the airways, enhanced lung inflammation and augmented clinical severity upon RSV infection. Moreover, increasing the number of Treg cells in the airways by selective chemoattraction with CCL17/22 reversed the enhanced lung inflammation and weight loss (11). An increased severity of RSV disease after FI-RSV vaccination was associated with a Th17-like memory response (90).…”

“…In the 1960s, the development of a formalin-inactivated RSV (FI-RSV) vaccine failed in human trials as it resulted in exacerbated disease and increased need for ventilatory support during subsequent natural RSV infection (11). As a predominant Th2 response was demonstrated in these cases, the imbalance between Th1 and Th2 cells became an important model to explain the differences in clinical severity in individual RSV infections (8).…”

Vaccines in the Prevention of Viral Pneumonia

“…Such vaccines not only fail to prevent infection, but dramatically increase hospitalization rates in young children during natural infection. This appears to be associated with an induction of poorly-neutralizing antibody, skewing towards the production of Th2 cytokines 77,78 and a local deficit in regulatory T cells 79 . These events hampered efforts in vaccine discovery, but in recent years academics, vaccine manufacturers and international organizations such as WHO have made development of safe and effective vaccines a realistic prospect 80 .…”