Establishing a Controlled Human Infection Model with the Chikungunya live attenuated vaccine VLA1553 in healthy volunteers

Chikungunya is a vector-borne viral disease, increasing in incidence and expected to spread worldwide in the coming decades.1 Infection with Chikungunya virus (CHIKV) can lead to acute disease, associated with symptoms such as fever, headache, myalgia and skin rash, but seldomly with lethal outcome. However, up to 60% of infected patients develop debilitating chronic arthralgias, which can last up to years. Outbreaks of CHIKV are characterized by a rapid spread of the virus, leading to a high disease burden in local populations within a short period of time. The intensification of global travel and trade has led to an increase in CHIKV outbreaks; a further 
increase in the coming decades is expected due to climate change, as well as the emergence of alternative CHIKV
transmission vectors beside the Aedes aegypti mosquito, such as Aedes albopticus, which is more tolerant to cold temperatures. The current need for prophylactic measures against Chikungunya disease is urgent and will expectedly increase.

Rapid availability of pharmaceuticals targeting e.g. viruses can limit the impact of infectious diseases; in the case of future local outbreaks or pandemics, a health crisis can be mitigated by swift development and testing of vaccines. The controlled human infection model (CHIM) is an innovative and effective method for testing pharmaceutics targeting infectious diseases in early clinical phase. CHIMs involve active exposure of (healthy) volunteers in a controlled setting, facilitating close safety monitoring, as well as the evaluation of efficacy endpoints and extensive assessment of viral and immunological endpoints. This allows for an early evaluation and understanding of the efficacy of new pharmaceuticals, resulting in early assessment of whether these pharmaceuticals will be worth their investment. CHIMs are often conducted using respiratory viruses, as these 
generally cause shortlasting, mild symptoms. Exposing healthy individuals to CHIKV would be accompanied by a significant risk (up to 60%) of inducing chronic Chikungunya disease, with symptoms that can often not be
effectively managed.

Recently, a live attenuated virus (LAV) was approved by the FDA as a vaccine against Chikungunya. This vaccine, named VLA1553, showed high effectivity, with immunisation rates of up to 100%. In addition, VLA1553 was demonstrated to cause detectable viremia and mild acute Chikungunya associated symptoms, such as fever, headache or joint pains; however, the LAV did not cause chronic Chikungunya disease. Passive transfer of VLA1553 induced antibodies to non-human primates resulted in protection against Chikungunya associated symptoms after exposure to CHIKV, establishing VLA1553 as an effective prophylaxis against natural CHIKV infection. After revaccination in humans, both viremia and symptoms significantly decreased, confirming the immunogenic capacity of VLA1553, as well as its suitability as a challenge agent to test new therapies against CHIKV.8 In this study, we aim to establish a controlled human infection model using the VLA1553 vaccine as challenge agent, to facilitate efficient and closely monitored testing of newly developed drugs against Chikungunya disease.

The main objective of this study is to establish a controlled human infection model for Chikungunya using the VLA1553 vaccine.

Primary objectives:
- To assess the infection rate induced by a single administration of the VLA1553 vaccine
- To assess the symptomatic rate induced by a single administration of the VLA1553 vaccine 

Secondary objectives: 
- To investigate the safety and tolerability of controlled infection after vaccination with the VLA1553 live attenuated Chikungunya virus
- To assess the VLA1553 viral kinetics in blood and urine
- To characterize symptoms after VLA1553 challenge
- To assess the immunological response after VLA1553 challenge

This is an open-label validation study of the VLA1553 Chikungunya vaccine challenge model. The study consists of a screening/enrollment period, a baseline visit, a vaccination period, and a follow-up visit. The subjects will be monitored for vaccine-related symptoms, solicited and unsolicited symptoms, adverse events (AE) and vital signs including tympanic temperature. Routine safety laboratory assessments (hematology and blood chemistry) will be performed; additional safety assessments will be performed if deemed necessary by the investigator. Chikungunya viral load, viral culture and virus neutralizing antibodies will be assessed in serum. PBMCs will be collected on timepoints.

Subjects will receive the VLA1553 vaccine by intramuscular administration. The VLA1553 vaccine is a registered vaccine, containing 1 x 10^4 50% Tissue Culture Infective Dose (TCID50) of live attenuated virus.

VLA1553 has a well-established safety profile, assessed in large clinical trials. Healthy volunteers will receive a single administration containing the approved dose of 1 x 10^4 TCID50.
Study participants may develop symptoms related to the vaccine administration, such as swelling, redness, pain, induration, tenderness or a rash at the location of administration. In addition, systemic symptoms may emerge in the first week after vaccine administration; possible systemic symptoms include headache, fatigue, muscle pain, nausea, vomiting, or joint pain. In clinical studies, local and systemic symptoms generally subsided after 1-4 days. As with any study involving drug administration, other symptoms may arise that are not yet described in literature. Finally, volunteers may experience discomfort during blood sampling. As VLA1553 has demonstrated high immunogenicity and signs of clinical protection against Chikungunya disease, volunteers will benefit from receiving the vaccine in this study. However, as Chikungunya is not endemic in The Netherlands, and since the longevity of the VLA1553-induced antibodies is not fully clear, the significance of this benefit remains unclear.