Arthritogenic Alphavirus Vaccines: Serogrouping Versus Cross-Protection in Mouse Models

Abstract

Chikungunya virus (CHIKV), Ross River virus (RRV), o’nyong nyong virus (ONNV), Mayaro virus (MAYV) and Getah virus (GETV) represent arthritogenic alphaviruses belonging to the Semliki Forest virus antigenic complex. Antibodies raised against one of these viruses can cross-react with other serogroup members, suggesting that, for instance, a CHIKV vaccine (deemed commercially viable) might provide cross-protection against antigenically related alphaviruses. Herein we use human alphavirus isolates (including a new human RRV isolate) and wild-type mice to explore whether infection with one virus leads to cross-protection against viremia after challenge with other members of the antigenic complex. Persistently infected Rag1-/- mice were also used to assess the cross-protective capacity of convalescent CHIKV serum. We also assessed the ability of a recombinant poxvirus-based CHIKV vaccine and a commercially available formalin-fixed, whole-virus GETV vaccine to induce cross-protective responses. Although cross-protection and/or cross-reactivity were clearly evident, they were not universal and were often suboptimal. Even for the more closely related viruses (e.g., CHIKV and ONNV, or RRV and GETV), vaccine-mediated neutralization and/or protection against the intended homologous target was significantly more effective than cross-neutralization and/or cross-protection against the heterologous virus. Effective vaccine-mediated cross-protection would thus likely require a higher dose and/or more vaccinations, which is likely to be unattractive to regulators and vaccine manufacturers.

Sequencing of Historical Isolates, K-mer Mining and High Serological Cross-Reactivity with Ross River Virus Argue against the Presence of Getah Virus in Australia

“…An original vial of N554, frozen in 1961 ( Figure S1 ), and a vial of N544 (frozen in 1983) were thawed, cultured in C6/36 cells and sequenced. The collection also contained the 1955 Malaysian GETV MM2021 isolate (frozen in 1986), for which we previously provided the complete genome sequence [ 8 ] (Genbank ID: MN849355). Partial sequence for GETV MM2021 uploaded independently (Genbank ID: AF339484) showed 99.69% percent nucleotide identity with our GETV MM2021 sequence (Genbank ID: MN849355).…”

“…Approximately 0.01% of reads in this submission mapped to RRV, with similar read counts for structural and non-structural genes ( Figure S4 ). The closest match being the prototype RRV T48 strain [ 8 ] (97.63% identity), with mismatches mostly uncalled nucleotides ( Figure S4 ). These results perhaps argue against replicating or circulating RRV in China.…”

“…H&E of feet day 6 post-infection showed inflammatory infiltrates in the muscle (myositis) and around tendons (tendonitis), with mild edema and occasional hemorrhage, all features seen previously in mouse models of alphaviral arthritides ( Figure 2 B) [ 51 , 52 , 53 , 54 , 55 , 56 ]. Mice were vaccinated twice with 20 µg of the JE/GETV vaccine (Nisseiken) [ 8 ], which contains the 1978 Japanese GETV MI-110 horse isolate [ 11 ]. All mice produced antibodies detectable by GETV antigen ELISA ( Figure 2 C), and 4/6 mice showed neutralizing activity against GETV MM2021 ( Figure 2 D).…”

“…Another member of this family of alphaviruses is Getah virus (GETV), which causes disease primarily in horses and pigs, with evidence for human infections limited to a small number of early serology studies undertaken before the advent of ELISA-based technologies [ 6 , 7 ]. GETV belongs to the Semliki Forest virus antigenic complex, that includes RRV, CHIKV, MAYV and ONNV, and is most closely related to RRV [ 8 , 9 ].…”

“…Herein, we recover N554 from an original vial frozen in 1961 and N544 (frozen in 1983) and show that that they are virtually identical to the GETV MM2021 virus isolated in Malaysia from Culex gelidus mosquitoes in 1955 [ 8 ]. Bioinformatic interrogation of the >40,000 terabases of open access sequence data publicly available via the Sequence Read Archive (SRA), also failed to identify GETV sequences in biosamples collected in Australia.…”