Rotavirus features relevant to vaccine development

Rotaviruses are 70 nm in diameter, non-enveloped and possess a distinctive double-shelled outer capsid. Within the inner shell is a third layer, the core, which contains the viral genome comprised of 11 segments of double-stranded (ds)RNA. During coinfection with different rotavirus strains, the segmented genomes readily undergo genetic reassortment. With regard to vaccine development, the two outer capsid proteins, VP4 and VP7, deserve special attention (Kapikian & Chanock 1996).

VP7, a glycoprotein, comprises one of two major neutralization antigens located on the outer capsid and is encoded by RNA segment 7, 8 or 9 (depending on strain). The other outer capsid protein, VP4, is encoded by RNA segment 4; it protrudes from the outer capsid in the form of60 spikes. Antibodies to both VP7 and VP4 are independently associated with protection against illness in various animal models. Serotypes are characteristically determined by VP7, but a VP4 serotyping scheme has also been developed recently. Although there are 14 VP7 (or G for glycoprotein) serotypes, 10 in humans, 13 in animals and 9 shared between humans and animals, the antigenic variation is not a formidable problem in vaccine development because only four serotypes, numbered 1, 2, 3 and 4, are of major epidemiological importance; therefore efforts have been focused on developing a vaccine to protect against each of these four serotypes (Hoshino & Kapikian 2000). Although the mechanism of protection is still not certain, early studies in animals suggested that antibodies in the lumen of the small intestine are a major determinant of resistance to rotavirus illness (Offit 1994, Kapikian & Chanock 1996, Matson 1996). In addition, we sought the development of an oral, live, attenuated vaccine which would mimic natural infection, thus inducing local intestinal immunity.

The Jennerian approach

Our initial approach was to adopt the strategy pioneered by Edward Jenner in 1796 for human smallpox vaccination in which a related, live, attenuated agent from a non-human host is used as the immunogen. Early serological and animal studies were instrumental in suggesting the feasibility of the Jennerian approach to rotavirus vaccination (Kapikian et al 1996). We pursued this approach with a rhesus rotavirus strain, designated MMU18006, which belongs to serotype VP7:3 ( = G3), and which grew efficiently in a semi-continuous simian diploid cell strain FRhL2. This vaccine was administered orally in a single 104 or 105 pfu dose to over 1500 infants and young children 1—20 months of age in field trials in the USA and overseas. Vaccine efficacy ranged from 0—85% against moderate-to-severe diarrhoea. It appeared from these studies that serotype specific immunity was an important factor in determining vaccine efficacy (Kapikian et al 1996).

The modified Jennerian approach

The likelihood that serotype-specific immunity was important in protection became the impetus for our modification of the Jennerian strategy. The objective was to evaluate a quadrivalent rotavirus vaccine that incorporates the VP7 specificity of each of the four epidemiologically important serotypes as well as the attenuation phenotype of RRV in order to achieve protection against each of these four human rotavirus serotypes.

This was achieved by generating reassortants which possessed a single VP7 gene from human rotavirus serotypes G1, G2 or G4, and 10 genes from RRV, and combining these three reassortants with the RRV strain, the latter providing coverage for serotype G3 (Midthun et al 1985, 1986) (Fig. 1). This quadrivalent (tetravalent) rotavirus vaccine (RRV-TV) was evaluated in major field trials in the US and overseas. When used at a dose of 4x105 pfu, it characteristically induced about 50% protection against any rotavirus diarrhoea, whereas against severe diarrhoea its protective efficacy reached as high as 100% (Table 1). For example, in Finland, the quadrivalent vaccine induced 68% protection against any rotavirus diarrhoea, 91—100% against severe and very severe rotavirus diarrhoea, respectively, and 100% against hospital admission due to rotavirus (Joensuu et al 1997).

FIG. 1. The development of a quadrivalent (tetravalent) rotavirus vaccine (RRV-TV) in order to achieve protection against each of the four human rotavirus serotypes. Reassortants were generated which possessed a single VP7 gene from human rotaviruses G1, G2 or G4, and 10 genes from RRV, and these three reassortants were combined with the RRV strain, the latter providing coverage for serotype G3. (Reproduced from Kapikian et al 1996, with permission).

FIG. 1. The development of a quadrivalent (tetravalent) rotavirus vaccine (RRV-TV) in order to achieve protection against each of the four human rotavirus serotypes. Reassortants were generated which possessed a single VP7 gene from human rotaviruses G1, G2 or G4, and 10 genes from RRV, and these three reassortants were combined with the RRV strain, the latter providing coverage for serotype G3. (Reproduced from Kapikian et al 1996, with permission).

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