How may the genetic differences observed in the current monkeypox virus outbreak impact immune responses induced by VACV vaccines?

By Bhavana KunkalikarJul 12 2022Reviewed by Danielle Ellis, B.Sc.

In a recent study posted to the bioRxiv* preprint server, researchers assessed the impact of the vaccinia virus vaccine on the immune response against the monkeypox virus.

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Background

Since May 2022, an emerging cluster of monkeypox infections has been reported in humans and detected in non-endemic countries. Vaccinia virus vaccines have demonstrated high effectiveness against monkeypox viruses and are deemed an essential control measure. 

About the study

In the present study, researchers reported the effect of the vaccinia virus (VACV) on the human immune response against the monkeypox viruses (MPXV).

The team obtained 75 complete genomic sequences of MPXV-2022 from the Global Initiative on Sharing All Influenza Data (GISAID) database on 7 June 2022. The complete genomic sequences and references for the MPXV and the VACV were obtained from the National Center for Biotechnology Information (NCBI). The team developed an in-house bioinformatics pipeline to align these nucleotide sequences and their translation into amino acid residues. The amino acid translation was achieved based on the coding sequence positions as per the reference sequences corresponding to the VACV, as well as the location of the gene.

The team used multiple alignments using fast Fourier transform (MAFFT) software to assess all multiple sequence alignments. Coding sequences corresponding to 182 genes were described as per the sequence of the VACV reference, and the translated genomic regions present in the MPXV sequences represented the 182 MPXV-2022 ortholog proteins. The team also computed genetic similarities between any pair of protein sequences or nucleotides from pairwise sequence alignments. Furthermore, eight VACVC proteins that elicit neutralizing antibodies (NAbs) were evaluated among the MPXV-congo basin (MPXV-CB) reference and the MPXV-2022 sequences.         

Results

The study results showed that the MPXV-2022 sequences displayed an 84% mean genetic similarity with the reference VACV sequence. Also, approximately 3% of single nucleotide proteins (SNPs) and 13% of indels were detected, which translated to almost 6,500 SNPs and 27,500 indels. The eight immunogenic proteins present in the VACV exhibited genetic similarity ranging between 94% and 98% between the VAXV sequences and the MPXV-CB and MPXV-2022 sequences.

The specific mutations between the eight immunogenic proteins present in the VACV and both the MPXV-CB reference and the MPXV-2022 consensus sequences showed the same mutation groups for four out of the eight proteins. The rest of the proteins also revealed similarities between most of the mutations. Furthermore, the team noted that the MPXV-CB reference and the MPXV-2022 consensus sequences displayed one or two additional sets of mutations. Moreover, common mutations with respect to the VACV were mostly found in the D8L and H3L proteins. Mapping these mutations showed that for H3L, seven out of 19 mutations were exposed and were hence susceptible to targeting antibodies.

The team also noted a high degree of similarity between the VACV proteins that reported a minimum of one T cell epitope and orthologs corresponding to the MPXV-CB and MPXV-2022. This indicated substantial levels of cross-reactivity of T-cell responses stimulated by VACV against MPXV-2022. Among the 121 proteins comprising at least one T cell epitope, 388 were T cell epitopes derived from VACV. Furthermore, the team detected that 71.6% of the epitopes were similar between the MPXV-CB and MPXV-2022 sequences. The rest of the epitopes displayed only 1.55%, 1.8%, and 25% of the variation in only MPXV-2022, MPXV-CB, and both MPXV-CB and MPXV-2022, respectively. Overall, this revealed that while there was a high degree of similarity between the VACV proteins and the MPXV-CB and MPXV-2022 orthologs, genetic variation was significant in more than one-fourth of the T-cell epitopes.

Furthermore, the team observed that 25% of the T-cell epitopes present in the VACV sequences varied in MPXV-CB as well as MPXV-2022. However, 70% of these different T-cell epitopes had epitope mutations that were identical among both MPXV-CB and MPXV-2022. Altogether, this revealed that 89.2% of the T-cell epitope sequences were comparable in MPXV-CB and MPXV-2022.     

Conclusion

Overall, the study findings showed that MPXV displayed high genetic conservation within the immunogenic protein regions as well as epitopes corresponding to the VACV vaccination. The researchers believe that various studies reported the high efficacy of VACV vaccines needs further clinical evaluation.     

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.