Evolutionary changes between pre- and post-vaccine South African group A G2P[4] rotavirus strains, 2003–2017

Abstract

The transient upsurge of G2P[4] group A rotavirus (RVA) after Rotarix vaccine introduction in several countries has been a matter of concern. To gain insight into the diversity and evolution of G2P[4] strains in South Africa pre- and post-RVA vaccination introduction, whole-genome sequencing was performed for RVA positive faecal specimens collected between 2003 and 2017 and samples previously sequenced were obtained from GenBank (n=103; 56 pre- and 47 post-vaccine). Pre-vaccine G2 sequences predominantly clustered within sub-lineage IVa-1. In contrast, post-vaccine G2 sequences clustered mainly within sub-lineage IVa-3, whereby a radical amino acid (AA) substitution, S15F, was observed between the two sub-lineages. Pre-vaccine P[4] sequences predominantly segregated within sub-lineage IVa while post-vaccine sequences clustered mostly within sub-lineage IVb, with a radical AA substitution R162G. Both S15F and R162G occurred outside recognised antigenic sites. The AA residue at position 15 is found within the signal sequence domain of Viral Protein 7 (VP7) involved in translocation of VP7 into endoplasmic reticulum during infection process. The 162 AA residue lies within the hemagglutination domain of Viral Protein 4 (VP4) engaged in interaction with sialic acid-containing structure during attachment to the target cell. Free energy change analysis on VP7 indicated accumulation of stable point mutations in both antigenic and non-antigenic regions. The segregation of South African G2P[4] strains into pre- and post-vaccination sub-lineages is likely due to erstwhile hypothesized stepwise lineage/sub-lineage evolution of G2P[4] strains rather than RVA vaccine introduction. Our findings reinforce the need for continuous whole-genome RVA surveillance and investigation of contribution of AA substitutions in understanding the dynamic G2P[4] epidemiology.

Genomic epidemiology of the rotavirus G2P[4] strains in coastal Kenya pre- and post-rotavirus vaccine introduction, 2012 – 2018

“…We investigated the evolutionary dynamics of G2P [4] strains sampled from children admitted to Kilifi County Hospital, Coastal Kenya between 2012 and 2018. All the recovered genomes showed a typical DS-1 like constellation consistent with findings from several countries using the Rotarix® vaccine in their NIPs [21,22,24,53].…”

“…However, one sample (KLF1033/2018) consistently clustered with sequences from Mozambique and some prevaccine strains were interspersed with global strains for the NSP3 segment, suggestive of limited introduction from other countries. No lineage shift was observed pre-and postperiods in Kilifi inconsistent with findings in South Africa [24] where RVA vaccine introduction resulted in lineage shift. Furthermore, few G2 and P [4] lineages were in circulation within Kilifi compared with the combined global data during the study period.…”

“…However, the strains sampled in July 2014 (early post-vaccine period) clustered with pre-vaccine strains across all the 11 gene segments in our study possibly because the vaccine coverage was low and thus had no impact yet on the circulating genotypes and lineages. Unique clusters of either G2P[4] or G1[P8] strains separated by RVA vaccine period have been reported in South Africa [24], Rwanda [54], Australia and Belgium [55], which were interpreting as reflecting natural genetic fluctuations rather than vaccine induced evolution. However, the study NSP4 and NSP3 genes exhibited some clusters of mixed pre- and post-vaccine sequences, indicating that in some strains the pre-vaccine may have reassorted with post-vaccine introduction strains as similarly suspected in Mozambique, albeit in G1P[8] [56].…”

“…Characterization of South African G2P[4] strains, through comparison of strains occurring during pre-and post-introduction of Rotarix® vaccine, revealed sub-lineage shifts from G2 sub-lineage IVa-1 to G2 IVa-3, and P[4] sub-lineage IVa to P[4] IVb, and these shifts in genetic evolution were attributed to arise due to natural fluctuations and not as a result of vaccine pressure [24]. Similarly, G2P[4] whole genome analysis in Ghana [22], Australia [25,26], South Korea [11], Bangladesh [27], and Brazil [28] showed that implementation of Rotarix® vaccination does not influence genetic diversity of the circulating G2P[4] strains and common amino acid replacements in the VP7 antigenic epitopes including A87T, D96N, S213D were reported, irrespective of the vaccination period.…”

“…Characterization of South African G2P [4] strains, through comparison of strains occurring during pre-and post-introduction of Rotarix® vaccine, revealed sub-lineage shifts from G2 sub-lineage IVa-1 to G2 IVa-3, and P [4] sub-lineage IVa to P [4] IVb, and these shifts in genetic evolution were attributed to arise due to natural fluctuations and not as a result of vaccine pressure [24]. Similarly, G2P [4] whole genome analysis in Ghana [22],…”