Gastroenteritis (GE) is a serious health problem and remains a major cause of deaths in infants and childhood throughout the world, accounting for 1.34 million deaths in children younger than 5 years (15% of all child deaths) and more than 98% occurring in developing countries. Patients with GE present clinically with diarrhea and often vomiting (Elliott, 2007; Boschi-Pinto et al., 2008). Rotavirus (RV) is the most common causative agent of acute GE in young children worldwide, accounting for approximately 2 million hospitalization, and 352,000 – 592,000 deaths each year (Ramig, 2004). Severe RV infection can result in dehydration, electrolytes imbalance, and death (Dennehy, 2008).
As a result of the high incidence of RV infection especially in the developing countries, World Health Organization (WHO) recommended the employment of RV vaccine to be in the routine childhood immunization schedule, as a protective measure to prevent RV infection and RV associated complications (Ichihara et al., 2014). The UK has introduced the RV vaccine (Rotarix) in July 2013. Since the introduction of Rotarix in the UK, GE cases and hospitalization has been reduced significantly (Marlow et al., 2015).
PATHOGENESIS AND IMMUNITY
- RV Structure
Rotaviruses are members of the Rotavirus genus of the Reoviridae family which contains 11 dsRNA segments. The 11 segments of the viral genome are surrounded with 3 concentric protein layers (icosahedral capsid). These segments encode six structural proteins (VP1, VP2, VP3, VP4, VP6 & VP7) and six non-structural proteins (NSP1-6), each encoded by a unique genome segment with the exception of NSP5 and 6 (Greenberg and Estes, 2009).
RV shows a significant seasonality, occurring mainly during winter, and much less during the rest of the year. Infections mostly appear in cooler and drier months of the year in temperate regions, while in tropical areas, RV infections may occur throughout the year. G1, G2, G3, G4, G9, and G12, are the most common G‐genotypes, and P, P, and P are the most common human P‐genotypes. The most common G/P genotypes combinations worldwide are G1P, G2P, G4P, G9P, and G12P. These genotypes are responsible for almost 90% RV infections globally, with G1P is the most common worldwide (Li et al., 2016; Matthijnssens and Van Ranst, 2012). RV is transmitted mainly by fecal-oral route, and spreading can occur through contaminated hands, environmental surfaces, water, and foods. One gram of fecal material can shed up to 100 billion RV particles. RV is extremely contagious with a very minimal infectious dose (100-1000 particles) able to cause infection in a susceptible host (Parashar et al., 2013).
- RV-Induced Diarrhea
RV-induced diarrhea thought to be due to several different mechanisms, including malabsorption secondary to enterocyte destruction, a virus-encoded toxin, villus ischemia, and stimulation of the enteric nervous system (ENS) (Ramig, 2004). Malabsorption considered to be secondary to enterocyte destruction and down-regulation of the absorptive enzymes. Furthermore, NSP4 can disrupt tight junctions between enterocytes, resulting in paracellular leakage. NSP4 which acts as a viral enterotoxin can activate calcium channels and increasing chloride secretion resulting in water and electrolytes loss. Activation of the ENS by NSP4 will increase the intestinal motility and more loss of water and electrolytes (secretory diarrhea). It was estimated that ENS is responsible for about 67% of fluid and electrolytes loss in RV diarrhea. RV infection reduces disaccharidases activity, resulting in accumulation of undigested sugars in the intestinal lumen with a subsequent increase in the osmotic gradient and further fluid secretion. Prostaglandin E2 was estimated to play a crucial role in the stimulation of water secretion. (Ramig, 2004).
- RV Genome Replication
Host cell attachment is the first step in the RV life cycle. Attachment is initially mediated by VP4 (RV spike protein) which bind to specific host receptors (sialic acid) and coreceptors (Dormitzer et al., 2002). VP4 is then cleaved with trypsin‐like proteases into VP5 and VP8. This conformational change results in exposing additional attachment sites. This conformational change will form a rigid dimeric VP5 which increases the infectivity of RV particles. The VP8 subunit of VP4 will interact with terminal or subterminal sialic acid receptors to mediate the attachment process, which will induce the virus entry to the cell via receptor-mediated endocytosis clathrin‐mediated endocytosis (Li et al., 2017; Nava et al., 2004).
After virus entry, the outer capsid protein is removed forming a double-layered particle (DLP) (Chemello et al., 2002). DLP is then transported into the cytoplasm to be transcriptionally active molecules (Salgado et al., 2017). The transcriptional complex of RV is composed of VP1 and VP3 complexed with 11 segments of viral dsRNA (Trask and Dormitzer, 2006). Assembly of viral protein will take place in the viroplasm to form DLP followed by assembly of VP7 and VP4, resulting in the formation of mature RV particles (Lu et al., 2008). The virus is released from the epithelial cell by lysis or by release from the apical surface (Gardet et al., 2006).
- Immunity to RV Infection
The innate immune system will be rapidly activated following RV infection to provide a potent antiviral state by suppressing the RV replication. This activation is mediated by macrophages and result in the production of interferons type I and type III. Innate immunity is the key for effective adaptive immunity stimulation which will result in the activation of humoral and cell-mediated immunity, resulting in the formation of specific antibodies and long-term memory (Sadiq et al., 2018).
Rotarix is a live-attenuated human RV vaccine developed by tissue culture passage. It was introduced to the UK in July 2013. Rotarix vaccine, which is administered in 2 doses at 2 and 4 months of age, provides protection against 85% of severe RV infection and 42% reduction in hospitalization. It is a G1P1A strain and replicates efficiently in the human gut. (Marlow et al., 2015; Sadiq et al., 2018).
- Rotarix Side Effects
Rotarix was designed to replace the RotaShield vaccine due to its association with the development of intussusception, which is a surgical emergency. Despite the decrease in intussusception cases following Rotarix comparing to RotaShield, but it still significant (Haber et al., 2015). Furthermore, the vaccine virus can grow in a recipient’s gut and spread to naïve individuals. A study identified a previously healthy infant with severe acute GE that was positive for RV in a non-endemic season. Genome sequencing demonstrated that the viral genome segments were highly similar to the Rotarix virus, suggesting that this patient acquired the infection from his sibling after vaccination (Sakon et al., 2017).
- Natural and Passive Immunity
Most mothers have previous history of RV infection. This will play an important role in the formation of antibodies against RV. These antibodies can cross the placenta during pregnancy to provide a protection for the infant later in life. Subsequently, if the infant catches the infection, it will be either asymptomatic or mild disease (Bishop et al., 1983). Additionally, breastfed infants experience less severe disease as breast milk contains mucin-associated glycoprotein, lactaadherin, which is characterized by its high specificity to RV and its ability to inhibit RV replication (Newburg et al., 1998).
Furthermore, a study conducted on Mexican infants demonstrated that children with previous infections, experienced lower risks of RV infection and diarrhea. Later infections were predominantly milder than the initial infections. Each new infection increases the protection significantly, resulting in a less severe subsequent GE (Velazquez et al., 1996).
- Rotarix vaccine cost-effectiveness
The cost-effectiveness of Rotarix has been investigated in several European countries, including the UK. In a study published by Jit and Edmunds (2007), it compared costs and outcomes of vaccination using a cohort model, following children from birth to 5 years of life. The study estimated health provider costs, economic costs and quality adjusted life years (QALYs) lost due to RV related deaths, hospital admissions, nosocomial infections, accident, and emergency attendances, general practitioner consultations and calls to NHS Direct calls. The study concluded that RV immunization would not be cost-effective unless the vaccine is competitively priced (Jit and Edmunds, 2007).
The fact that most RV infection is self-limiting, and can be treated at home with oral rehydration therapy to compensate for fluid and electrolytes loss, should replace the vaccine and the government should make more effort in educating parents how to treat at home and when to visit the hospital (Sadiq et al., 2018). This would be more cost-effective rather than vaccinating millions of infants each year and exposing them to the vaccine side effects such as intussusception.
Despite the reduction in emergency and hospitalization rates after the introduction of Rotarix, this will not be cost-effective since RV diarrhea is a self-limiting disease in most of the cases and can be treated with oral rehydration solutions at home to compensate the fluid loss without hospitalization. Natural and passive immunity would protect infants from severe complications of RV diarrhea. Additionally, Rotarix may result in the development of unpredictable intussusception in some cases, which requires expensive surgical interventions.
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