Development of a next-generation chikungunya virus vaccine based on the HydroVax platform

Abstract

Chikungunya virus (CHIKV) is an emerging/re-emerging mosquito-borne pathogen responsible for explosive epidemics of febrile illness characterized by debilitating polyarthralgia and the risk of lethal infection among the most severe cases. Despite the public health risk posed by CHIKV, no vaccine is currently available. Using a site-directed hydrogen peroxide-based inactivation approach, we developed a new CHIKV vaccine, HydroVax-CHIKV. This vaccine technology was compared to other common virus inactivation approaches including β-propiolactone (BPL), formaldehyde, heat, and ultraviolet (UV) irradiation. Heat, UV, and BPL were efficient at inactivating CHIKV-181/25 but caused substantial damage to neutralizing epitopes and failed to induce high-titer neutralizing antibodies in vaccinated mice. HydroVax-CHIKV and formaldehyde-inactivated CHIKV retained intact neutralizing epitopes similar to live virus controls but the HydroVax-CHIKV approach demonstrated a more rapid rate of virus inactivation. HydroVax-CHIKV vaccination induced high neutralizing responses to homologous and heterologous CHIKV clades as well as to other alphaviruses including Mayaro virus, O’nyong’nyong virus, and Una virus. Following heterologous infection with CHIKV-SL15649, HydroVax-CHIKV-immunized mice were protected against viremia, CHIKV-associated arthritic disease, and lethal CHIKV infection by an antibody-dependent mechanism. In contrast, animals vaccinated with Heat- or UV-inactivated virus showed no protection against viremia in addition to demonstrating significantly exacerbated CD4+ T cell-mediated footpad swelling after CHIKV infection. Together, these results demonstrate the risks associated with using suboptimal inactivation methods that fail to elicit protective neutralizing antibody responses and show that HydroVax-CHIKV represents a promising new vaccine candidate for prevention of CHIKV-associated disease.

Development of a hydrogen peroxide-inactivated vaccine that protects against viscerotropic yellow fever in a non-human primate model

“…In addition to using the improved 3-step manufacturing technique, we performed a bridging study to compare the original 3% H 2 O 2 -based inactivation approach (HydroVax-YFV 3%H2O2 ) to a recently developed site-directed oxidation approach containing ∼1,000-fold lower concentration of H 2 O 2 plus copper and methisazone (HydroVax-YFV Adv ). This advanced inactivation approach utilizes copper as a catalyst and methisazone as a copper-chelating agent with an affinity for nucleic acids and together this combination targets the oxidation/destruction of the viral genome while reducing damage to amino acids and neutralizing epitopes 21 , 22 and is performed in a buffer matrix containing 0.05% formaldehyde since brief exposure to formaldehyde can stabilize protein structure and further improve immunogenicity. 35 , 36 , 37 Some virus inactivation approaches used for vaccine production are known to have a “tailing” effect in which the ability to inactivate virus declines substantially over time.…”

“…Here, we describe inactivated whole-virus YF vaccine candidates that were prepared from purified YFV inactivated by hydrogen peroxide (H 2 O 2 ) either alone or in combination with copper and methisazone, resulting in site-directed oxidation of viral nucleic acids while reducing damage to neutralizing epitopes. 21 , 22 Rhesus macaques (RMs) are highly susceptible to viscerotropic YF 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 and provide an important model for determining vaccine-mediated protection against lethal challenge. Following vaccination with different H 2 O 2 -inactivated vaccine candidates, RMs were protected against viremia and lethal disease in a dose-dependent manner.…”

Effective Suppression of Chikungunya Virus Infection in Cell Cultures using Hepatitis Delta Ribozymes

“…A significant amount of work is underway to develop a vaccine for CHIKV. This includes strategies such as chimeric vaccines (16), recombinant CHIKV vaccines (17), adenovirus-based vaccines (18), inactivated virus (19), virus like particles (20), and live attenuated vaccines (21; see 22 for a detailed review). Recently, a promising vaccine candidate entered clinical trials (23), however, even with a viable vaccine there remain significant hurdles to effective prevention, containment, and control of any disease, especially in underdeveloped countries.…”

In silico identification of chikungunya virus replication inhibitor validated using biochemical and cell‐based approaches

“…Non-steroidal anti-inflammatory drugs are suggested for CHIKV-infected individuals with arthritis or arthralgia, along with fluid therapy to prevent dehydration [25]. Vaccination is crucial for preventing CHIKV infection, given the significant cost-benefit ratio associated with the disease [26]. Although there are no licensed vaccines available, several promising vaccine candidates are undergoing clinical testing and may soon begin the marketing authorization process [10,[19][20][21][22][23][24].…”