Subclinical reactivation of cytomegalovirus drives CD4+CD28null T-cell expansion and impaired immune response to pneumococcal vaccination in ANCA-associated vasculitis

Background: Infection is the leading cause of death in ANCA-associated vasculitis (AAV). Expansion of CD4+CD28null T-cells is associated with increased risk of infection and mortality, but is only present in cytomegalovirus-seropositive individuals. We hypothesised that subclinical cytomegalovirus reactivation drives CD4+CD28null T-cell expansion; that this is associated with impaired immune response to heterologous antigens, and that anti-viral therapy may ameliorate this.


Methods: In a proof-of-concept open-label clinical trial, 38 cytomegalovirus-seropositive AAV patients were randomised to receive valaciclovir for 6-months or no intervention. Cytomegalovirus reactivation was measured monthly in plasma and urine. CD4+CD28null T-cells were enumerated at baseline and at 6 months. At 6 months, 36 patients were vaccinated with a 13-valent pneumococcal vaccine. Serotype-specific IgG was assayed before and 4 weeks post vaccination to calculate the antibody-response-ratio (ARR).


Results: Valaciclovir treatment suppressed subclinical cytomegalovirus reactivation and reduced CD4+CD28null T-cell proportion. CD4+CD28null T-cell reduction correlated with improved vaccine response, whilst cytomegalovirus reactivation associated with reduced response to CMV infection and response to vaccination 5 vaccination. Furthermore, expansion of CD4+CD28null T-cells was associated with a reduction in the functional capacity of the CD4 compartment.


Conclusion: Suppression of cytomegalovirus may improve the immune response to a T-cell dependent pneumococcal vaccination in patients with AAV, thus offering potential clinical benefit.