Tick-borne encephalitis virus (TBEV): a phase II prospective randomized trial using anti-TBEV monoclonal antibodies

Tick-borne encephalitis virus (TBEV): a phase II prospective randomized trial using anti-TBEV monoclonal antibodiesBackgroundTick-borne encephalitis is a severe infection caused by the TBEV virus, which incidence in Switzerland is of about 4.48 cases per 100'000 inhabitants (~400 cases per year for a population of 8'921'981 persons). About 50% of the annual cases (n=200) will get severely sick with meningoencephalitis, leading to neurological sequelae in ~25% (n=50) and to death in ~5% of the cases (n=10). Tick-borne encephalitis is typically a two stages disease, with a first viremia mainly characterized by fever, and a second phase characterized by neurological impairment due to viral replication inside motoneurons (and consecutive inflammation) - often palsy affecting the legs initially. Then, the palsy may progress to all four members, to the trunk and to the respiratory muscles, with need for intubation and ventilation. Since there are no specific treatment, ventilation may be prolonged and during the stay in the intensive-care unit, the patient is at risk of superinfection, that further impact the prognosis linked to the viral tropism for the brain motoneurons. RationaleGiven the negative impact of TBEV infection, the high risk of severe evolution with palsy, often requiring hospitalization in the intensive-care unit for intubation & ventilation, and the common severe neurological sequelae such as paraplegia and a mortality of about 5%, it is important to propose a treatment for TBEV infected subjects. Neutralizing antibodies might represent such a treatment and could possibly reduce by half the proportion of subjects having a severe outcome as compared to placebo. We thus, propose a phase II prospective randomized trial using ant-TBEV monoclonal antibodies.AimsThe primary endpoints aim at: (i)assessing the effect of the therapeutic antibodies on the evolution and outcome of the disease in patients with the TBE infection having received the TBEV antibodies, as compared to subjects randomized into the control group Secondary endpoints aim at:(i)Measuring the neutralizing effect of sera of patients with a TBEV infection in those having received the TBEV antibodies, as compared to subjects randomized into the control group (ii)studying the pharmacokinetics of the therapeutic antibodies (iii)comparing the tolerability to the therapeutic antibodies of patients with a TBEV infection having received the TBEV antibodies as compared to patients randomized into the control group (placebo)(iv)assessing the rate of co-infection and type of co-infection in patients with TBEV having received the TBEV therapeutic antibodies, as compared to subjects randomized into the control group (possible confounders).MethodologyAbout 120 subjects with an early TBEV infection documented by a positive on blood, urines or cerebrospinal fluid and without neurological impairment will be randomized in a controlled therapeutic double-blind study to receive 10 micrograms of the anti-TBEV monoclonal therapeutic antibodies versus placebo intramuscularly Phase II). Please note that these monoclonal antibodies have been developed at the Rockefeller institute in close collaboration with IRB and after a proof of principle project in a rat model, these antibodies will now get tested at CHUV on 10 healthy volunteers (Phase I). Patients included in the randomized Phase II trial will be followed 1, 2, 3, 4, 6, 8, 16, 24 weeks after the tick bite, to assess the evolution of the infection and its outcome.