Strain diversity plays no major role in the varying efficacy of rotavirus vaccines: An overview

Highlights

• There is wide geographic and temporal variation and diversity of rotavirus strains.

• Monovalent and pentavalent rotavirus vaccines exert similar broad cross protection against evolving strains over time.

• Lower vaccine efficacy in low-income settings is largely due to factors other than strain diversity.

Abstract

While a monovalent Rotarix® [RV1] and a pentavalent RotaTeq® [RV5] have been extensively tested and found generally safe and equally efficacious in clinical trials, the question still lingers about the evolving diversity of circulating rotavirus strains over time and their relationship with protective immunity induced by rotavirus vaccines. We reviewed data from clinical trials and observational studies that assessed the efficacy or field effectiveness of rotavirus vaccines against different rotavirus strains worldwide. RV1 provided broad clinical efficacy and field effectiveness against severe diarrhea due to all major circulating strains, including the homotypic G1P[8] and the fully heterotypic G2P[4] strains. Similarly, RV5 provided broad efficacy and effectiveness against RV5 and non-RV5 strains throughout different locations. Rotavirus vaccination provides broad heterotypic protection; however continuing surveillance is needed to track the change of circulating strains and monitor the effectiveness and safety of vaccines.

Introduction

Diarrhea is a major cause of death in children under 5 years of age worldwide (Liu et al., 2012). Group A rotaviruses, members of the Reoviridae family, are known to infect nearly all mammalian species, including humans, pigs, cattle, and birds, where they are primarily associated with diarrheal disease (Fields, 2007). Rotavirus A is the leading cause of severe diarrhea that caused 453,000 deaths in 2008, mostly in developing nations (Tate et al., 2012). The viral genome encodes six structural proteins (VP1-VP4 and VP6-VP7) and five or six nonstructural proteins (NSP1–NSP5, sometimes NSP6) (Fields, 2007). Genotypes are classified according to 2 outer capsid proteins that initiate neutralization activity: VP7 and VP4; the VP7 specifies the G (glycoprotein) and VP4 specifies the P (protease-sensitive) genotype (Matthijnssens et al., 2008). These proteins are of particular relevance to disease epidemiology and vaccine efficacy; though, other mechanisms (antibodies to other rotavirus proteins or T cells) are also important (Ward et al., 2010).

Gene reassortment in rotavirus theoretically allows hundreds of different G and P type combinations, forming new reassortant strains, with potentially novel antigen combinations and more than 70 combinations have been identified to date among human rotaviruses (Banyai et al., 2012, Kirkwood, 2010). The vast diversity of strains detected worldwide is produced by multiple mechanisms: continuing genetic variation by sequential point mutations (i.e. genetic drift), genetic reassortment (i.e. antigenic shift), genomic rearrangement (i.e. deletions, duplications or insertions), or intragenic recombination (Desselberger, 1996, Kirkwood, 2010, O’Ryan, 2009). The most common human rotavirus G and P combinations in the pre-rotavirus vaccine era (data from 1996 to 2007) were G1P[8] (38%), G2P[4] (11%), G3P[8] (9%), G4P[8] (6%) and G9P[8] (11%), while numerous strains with less common G-P combinations had a cumulative prevalence of about 10% (Banyai et al., 2012). The combined prevalence of untypeable strains and infections with multiple G and/or P types were 15%. In developed countries, G1 strains constitute the majority of infections in most years, but sporadically other genotypes dominate for reasons that are not well understood. Over the past two decades, G9 strains emerged and spread worldwide and are now considered the second most prevalent genotype. Similarly G12 has emerged to become a medically important strain globally (Banyai et al., 2012). Rotavirus-dominant genotypes commonly vary from year to year and within regions, even in a single small country (Zeller et al., 2010). The reasons for these fluctuations are unknown, but population immunity due to previous virus exposure might play a role (Matthijnssens et al., 2012).

A tetravalent human-rhesus reassortant [RRV-TV] vaccine (RotaShield®, Wyeth, Pearl River, NY, USA) was shown to be safe and effective in preventing severe rotavirus diarrhea among young children (Perez-Schael et al., 1997), and was licensed in the United States in 1998. This RRV-TV contained a mixture of four virus strains, G1 to G4: three reassortant strains containing the VP7 genes of human rotavirus serotypes G1, G2, and G4 that were substituted for the VP7 gene of the parent RRV, and the fourth strain containing serotype G3 of rhesus RRV. Rotaviruses generally show host-range restriction, i.e. most animal rotaviruses are attenuated in ‘heterologous’ human hosts and vice versa. Therefore this vaccine was attenuated because most of its genome was derived from a heterologous simian host. In 1999, however, RotaShield was withdrawn within a year because it was associated with intussusception, a condition in which one portion of the bowel telescopes into another, resulting in a blockage (CDC-MMWR, 1999a, CDC-MMWR, 1999b). Subsequently, two live attenuated oral rotavirus vaccines; Rotarix [RV1] and RotaTeq [RV5] have been licensed to control rotavirus disease in children worldwide. To date, RV1 or RV5 or both vaccines have been licensed for use in more than 100 countries, including 69 that have introduced rotavirus vaccines into their national immunization programs (PATH, 2014).

The pentavalent human-bovine reassortant rotavirus vaccine (RotaTeq^® [RV5], Merck, Whitehouse Station, NJ, USA) is derived from a single bovine rotavirus strain (Wistar calf 3 “WC3”) that was isolated from a calf in Pennsylvania, in 1981 (Clark et al., 1996). This strain, which is naturally attenuated for humans was reassorted in vitro with the five most common serotypes of human rotavirus to form the vaccine (Heaton et al., 2005). The resulting ‘pentavalent’ vaccine that contains five most prevalent genotypes (G1, G2, G3, G4 and P[8]) was designed to induce type-specific protective immunity to these common strains in children. RV5 actually contains 7 neutralizing elements because it includes two bovine rotavirus-neutralizing antigens (G6 and P[5]) and five human rotavirus outer capsid proteins.

RV1, a monovalent human rotavirus vaccine manufactured by GlaxoSmithKline Biologicals (Rixensart, Belgium), was derived from the 89-12 strain that was originally isolated from a naturally infected child with rotavirus gastroenteritis during the 1988–1989 rotavirus season (Bernstein et al., 1991). After acquisition by GlaxoSmithKline, the vaccine strain which contained two plaque variants was cloned and passaged a further 12 times in Rixensart, renamed RIX4414, and eventually, after licensure, Rotarix®. The rationale of a human rotavirus G1P[8] strain vaccine was to induce serotype-specific and heterotypic immunity against the most common human G-type and P-type rotaviruses (Bernstein et al., 1999).

Recently, a monovalent vaccine derived from the human neonatal strain116E was developed in India (Rotavac®, Bharat Biotech International) (Bhandari et al., 2014). It is a naturally occurring reassortant strain G9P[11], having one bovine rotavirus gene P[11] and ten human rotavirus genes. The 116E strain infected neonates in India, and was well adapted to the gut and naturally attenuated, since the neonatal infection was largely asymptomatic (Bhandari et al., 2006).

Vaccine trials and observational studies showed that natural rotavirus infection and vaccination elicit both homotypic [i.e., against the genotype causing natural infection or genotype(s) included in the vaccine] and heterotypic [i.e., against genotypes other than the infecting genotype or genotype(s) included in the vaccine] protection. However, the protection may vary depending on the number of previous infections and/or type of vaccine (e.g., animal, reassortant, or human strain), and even homotypic protection is incomplete (Jiang et al., 2002). Prospective cohort studies proposed that second infections are more likely to be caused by a different genotype than the one causing first infection, but second infections with the same genotype can occur (Gladstone et al., 2011, Moulton et al., 1998, O’Ryan et al., 1990, Reves et al., 1989, Velazquez et al., 1996). Primary infection typically elicits serotype-specific antibody, while reinfection results in broad cross-reactive antibody providing one rationale for administering multiple doses of vaccine (Bishop et al., 1983, Velazquez et al., 1996).

While a monovalent RV1 and a pentavalent RV5 have been extensively tested and found generally safe and equally efficacious in clinical trials, the mechanisms or correlates of protection are still incompletely understood, though serum IgA has been considered a proxy for immunogenicity and protection. The question still lingers about the evolving diversity of circulating rotavirus strains over time and their relationship with protective immunity induced by the current licensed RV1 and RV5, which were isolated in 1989 (Bernstein et al., 1991) and 1981 (Clark et al., 1996) (25 and 33 years ago), respectively. Consequently, we reviewed the clinical efficacy, serum neutralization response, as well as field effectiveness of rotavirus vaccines against different rotavirus strains reported over the last decade in a wide range of settings worldwide.