A Coxsackievirus B vaccine protects against virus-induced diabetes in an experimental mouse model of type 1 diabetes

Abstract

Aims/hypothesis Epidemiological studies suggest a role for Coxsackievirus B (CVB) serotypes in the pathogenesis of type 1 diabetes, but their actual contribution remains elusive. In the present study, we have produced a CVB1 vaccine to test whether vaccination against CVBs can prevent virus-induced diabetes in an experimental model. Methods NOD and SOCS1-tg mice were vaccinated three times with either a formalin-fixed non-adjuvanted CVB1 vaccine or a buffer control. Serum was collected for measurement of neutralising antibodies using a virus neutralisation assay. Vaccinated and buffer-treated mice were infected with CVB1. Viraemia and viral replication in the pancreas were measured using standard plaque assay and PCR. The development of diabetes was monitored by blood glucose measurements. Histological analysis and immunostaining for viral capsid protein 1 (VP1), insulin and glucagon in formalin-fixed paraffin embedded pancreas was performed. Results The CVB1 vaccine induced strong neutralising antibody responses and protected against viraemia and the dissemination of virus to the pancreas in both NOD mice (n = 8) and SOCS1-tg mice (n = 7). Conversely, 100% of the buffer-treated NOD and SOCS1-tg mice were viraemic on day 3 post infection. Furthermore, half (3/6) of the buffer-treated SOCS1-tg mice developed diabetes upon infection with CVB1, with a loss of the insulinpositive beta cells and damage to the exocrine pancreas. In contrast, all (7/7) vaccinated SOCS1-tg mice were protected from virus-induced diabetes and showed no signs of beta cell loss or pancreas destruction (p < 0.05). Conclusions/Interpretation CVB1 vaccine can efficiently protect against both CVB1 infection and CVB1-induced diabetes. This preclinical proof of concept study provides a base for further studies aimed at developing a vaccine for use in elucidating the role of enteroviruses in human type 1 diabetes.

Rationale for enteroviral vaccination and antiviral therapies in human type 1 diabetes

“…Effective and safe vaccines have been developed against polioviruses and enterovirus 71, but there are no vaccines available for the enteroviruses linked to type 1 diabetes. Recent preclinical studies provided proof-of-concept that a CVB vaccine prevents viral infection and diabetes induction in mice harbouring beta cells genetically permissive to CVB infection [ 52 ]. It is critical to determine which virus serotypes are associated with type 1 diabetes in different geographical regions over various periods.…”

Developing a vaccine for type 1 diabetes by targeting coxsackievirus B

“…Recently, further collaboration studies were set out to test whether the inactivated CVB vaccine preventing CVB infection could also prevent virusinduced diabetes in mice. These studies first confirmed that CVB infection can accelerate diabetes onset in NOD and SOCS-1-Tg mice and then proved that the CVB vaccine protects not only from CVB infection but also against CVB-induced diabetes development in SOCS-1-Tg mice [110].…”

Enterovirus infection and type 1 diabetes: unraveling the crime scene

“…In a followup study, the vaccine was tested on suppressor of cytokine signaling transgenic (SOCS1-tg) mice, in which beta cells are unable to respond to IFNs and have an increased susceptibility to EV infection [80]. Similarly to NOD mice, SOCS1-tg mice developed a robust antibody response, were protected from a CVB1 challenge and from diabetes and had normal pancreas morphology [80]. The studies exposed above and the identification of different EVs serotypes with possible roles in T1D suggest that the development of an EVs vaccine for T1D could have great benefits, but could be challenging to produce.…”