Non-replicating adenovirus based Mayaro virus vaccine elicits protective immune responses and cross protects against other alphaviruses

Abstract

Mayaro virus (MAYV) is an alphavirus endemic to South and Central America associated with sporadic outbreaks in humans. MAYV infection causes severe joint and muscle pain that can persist for weeks to months. Currently, there are no approved vaccines or therapeutics to prevent MAYV infection or treat the debilitating musculoskeletal inflammatory disease. In the current study, a prophylactic MAYV vaccine expressing the complete viral structural polyprotein was developed based on a non-replicating human adenovirus V (AdV) platform. Vaccination with AdV-MAYV elicited potent neutralizing antibodies that protected WT mice against MAYV challenge by preventing viremia, reducing viral dissemination to tissues and mitigating viral disease. The vaccine also prevented viral-mediated demise in IFN⍺R1-/- mice. Passive transfer of immune serum from vaccinated animals similarly prevented infection and disease in WT mice as well as virus-induced demise of IFN⍺R1-/- mice, indicating that antiviral antibodies are protective. Immunization with AdV-MAYV also generated cross-neutralizing antibodies against two related arthritogenic alphaviruses–chikungunya and Una viruses. These cross-neutralizing antibodies were protective against lethal infection in IFN⍺R1-/- mice following challenge with these heterotypic alphaviruses. These results indicate AdV-MAYV elicits protective immune responses with substantial cross-reactivity and protective efficacy against other arthritogenic alphaviruses. Our findings also highlight the potential for development of a multi-virus targeting vaccine against alphaviruses with endemic and epidemic potential in the Americas.

Infection with chikungunya virus confers heterotypic cross-neutralizing antibodies and memory B-cells against other arthritogenic alphaviruses predominantly through the B domain of the E2 glycoprotein

“…Serum was diluted 1:2 from 1:100 to 1:102,400 and mixed with media containing 50 PFU of either MAYV BeAr or CHIKV 181/25 . Neutralization assays were then carried out as previously described [ 42 ].…”

Mayaro Virus Non-Structural Protein 2 Circumvents the Induction of Interferon in Part by Depleting Host Transcription Initiation Factor IIE Subunit 2

“…Given that this emerging alphavirus has the potential to cause large multicontinental outbreaks similar to CHIKV [ 8 , 10 , 62 ], it is critical to understand how it manipulates host pathways during infection. Indeed, there is considerable interest in developing therapeutic and prophylactic therapies against MAYV [ 14 , 15 , 16 , 17 , 18 ]. The findings from the present study may be of use for development and application of therapeutics against MAYV and other alphaviruses.…”

“…Imported cases of MAYV infection have already been reported in Europe and North America and are expected to increase in the future [ 11 , 12 , 13 ]. While therapeutics and vaccine candidates against MAYV are being investigated [ 14 , 15 , 16 , 17 , 18 ], currently there are no specific antiviral measures that could be used in the case of a MAYV outbreak. As such, further understanding of how this virus affects vital host cell pathways may facilitate development of effective antivirals.…”

Development of Viral-Vectored Vaccines and Virus Replicon Particle-Based Neutralisation Assay against Mayaro Virus

“…Despite this, there are no licensed vaccines available to date, and only a few MAYV vaccines were shown to be immunogenic in mouse models, including an inactivated MAYV vaccine [9], a live-attenuated virus vaccine based on a recombinant virus for which the MAYV subgenomic promotor was replaced by an internal ribosome entry site (IRES) [10], and a DNA-based vaccine or a non-replicating human adenovirus encoding the MAYV structural polyprotein [11,12].…”