Rotavirus is a leading cause of diarrheal disease, accounting for approximately 29.3% of global deaths related to diarrhea in children under 5 years of age [1]. Over 90% of these mortalities occur in low- to middle-income countries. Despite a significant drop in the global burden of rotavirus over the past three decades, mainly due to the introduction of rotavirus vaccines, the prevalence of rotavirus remains high in Africa, Oceania, South Asia, and the Middle-East [2,3].
The most common rotavirus genotypes found in children worldwide vary by region and time period. This diversity is linked to the virus’s genomic structure and its geographic evolution, influenced by common host factors and transmission routes. The infectious RVA particle has an icosahedral structure with three layers, consisting of 11 segments of double-stranded RNA encoding six structural proteins (VP) and six non-structural proteins (NSP) [4]. To date, 35 G genotypes and 50 P genotypes have been described for group A rotaviruses. The most prevalent genotypes worldwide are G1P[8], G2P[4], G3P[8], G4P[8], G9P[8], and G12P[8] [5]. These genotypes are determined based on the two outer capsid proteins, VP7 (G type) and VP4 (P type), which function as specific binding sites for neutralizing antibodies [4]. The introduction of rotavirus vaccines has been associated with changes in the distribution of rotavirus genotypes in certain areas, resulting in a decline in the prevalence of vaccine-targeted genotypes and an increase in the prevalence of genotypes not covered by the vaccines [6].
Recent studies have revealed variations in the distribution of RVA genotypes across different age groups. In Canada and Greece, a higher prevalence of G12P[8] and G9P[8] genotypes was observed among older children, specifically those aged between 24 and 59 months [7,8]. In children aged 0 to 12 months, other genotypes like G1P[8] and G9P[4] genotypes were found to be more common [9,10]. Several factors may contribute to this occurrence, including diversity in the expression of certain receptors in the intestinal tract at different age groups, exposure to common genotypes in various geographic areas, induced immunity, and host genetics [11–13]. Similarly, there is evidence of a correlation between rotavirus genotypes and disease symptoms. Studies have shown that different genotypes of rotavirus are associated with varying clinical characteristics and disease severity. In one study, G1P[8] and G9P[8] were the most common genotypes detected in children with moderate and severe acute gastroenteritis (AGE), respectively [9]. A significantly higher frequency of fever in children infected with the G3P[8] genotype was reported in study of Mathew et al. [14]. Additionally, this correlation was detected in the case of emerging genotypes, such as G8P[8], and G9P[4] [15].
The interaction between RVA antigens of various genotypes and the host immune system offers an explanation for variations in disease outcomes among the immunized and non-immunized children. This interaction primarily depends on the immunogenic domains within the VP4 and VP7 proteins. Notably, the VP7 gene, encompassing 326 amino acids, contains nine variable regions, with four serving as antigenic epitopes, specifically identified as 7-1a, 7-1b, and 7 − 2. Activation of the VP4 protein, spanning 776 amino acids, requires proteolytic cleavage into two distinct segments: VP8 and VP5, each containing four (8 − 1–8 − 4) and five (5 − 1–5–5) antigenic epitopes, respectively [4]. Due to the diversity of immunogenic motifs within these proteins, multiple lineages and sub-lineages have been defined. According to the study of Motamedi-Rad et al., within the predominant G-types, there are eleven, six, four, six, and six lineages for G1, G2, G3, G4, and G9 lineage, respectively. In terms of P serotypes, four, five, and five distinct lineages were reported for P[8], P[4], and P[6], respectively [16].
RV vaccination is the most effective strategy for significantly reducing the incidence of severe infections and the number of deaths in children. Rotarix (GlaxoSmithKline) consists of a monovalent G1P[8] strain derived from a single human G1P[8] strain. Conversely, RotaTeq (Merck), is a human-bovine reassortant vaccine, composed of five strains derived from human (G1, G2, G3, and G4) and bovine (P[8]) strains [17]. Both RVA vaccines have demonstrated the ability to elicit homotypic and heterotypic immune responses, resulting in a notable decline in morbidity and mortality. However, the RVA vaccine has proven to be more effective in high-income countries (80–90%) against severe rotavirus disease compared to low- to middle-income countries (40–70%) [18]. Various factors contribute to this disparity, including the genotypic and lineage diversity of RVA strains, which are driven by recombination, rearrangement, reassortment, and mutations. Additionally, host genetic factors, malnutrition, gut microbiota dysbiosis, co-infections, environmental enteropathy, and the passive transfer of maternal antibodies have been suggested as potential determinants of differences in RVA vaccine efficacy between high- and low-income countries [16]. RVA lineages with distinct antigenic properties could potentially allow RVA strains to evade vaccine-induced immunity [19].
With the increasing diversity of RVA strains and the incidence of uncommon fully and partially heterotypic genotypes, such as G1P[6] or G9P[4], particularly in countries without RVA vaccination programs, concerns are growing regarding the reduced effectiveness of approved vaccines against the emerging variants [18]. In this current cross-sectional study, the VP7 and VP4 lineages of human rotavirus A (RVA) strains circulating in children under the age of five with diarrhea were analyzed. Additionally, the amino acid sequences of these RVAs and their potential antigenic distinctions and cytotoxic T cell epitopes compared to the vaccine strains were assessed.