Reactions to and antigenicity of two human-rhesus rotavirus reassortant vaccine candidates of serotypes 1 and 2 in Venezuelan infants

Abstract

The reactions to and antigenicity of two human-rhesus rotavirus (RRV) reassortants (human rotavirus strain D x RRV and human rotavirus strain DS1 x RRV) with the VP7 neutralization specificity of a serotype 1 or serotype 2 rotavirus were evaluated in a placebo-controlled double-blind trial in 116 1to 5-month-old infants in Caracas, Venezuela. The children were randomly divided into five groups to receive orally the following inocula: (i) 104 PFU of D x RRV reassortant; (ii) i04 PFU of DS1 x RRV reassortant; (iii) 1 PFU of RRV; (iv) 5 x 103 PFU of D x RRV and 5 x 103 PFU of RRV; and (v) placebo. The children were examined daily for 7 days following vaccine administration; 8 to 26% of the vaccinated infants developed a mild febrile reaction which in most cases lasted only 1 day. Seroresponses to rotavirus were observed in 39 to 65% of the vaccinees by plaque neutralization assay and in 57 to 88 % by an immunoglobulin A enzyme-linked immunosorbent assay. Vaccine shedding was detected in 53 to 86% of the vaccinees. Analysis of neutralization antibody responses indicates that the VP4 protein represents an important component of the response induced by the vaccines.

Homotypic serum antibody responses to rotavirus proteins following primary infection of young children with serotype 1 rotavirus

“…It was apparent that the technique of immunoblotting underestimated the responses to VP4, since parallel tests by radioimmunoprecipitation on the same serum samples identified anti-VP4 in all patients (unpublished data). VP4 (VP3) responses have been detected in 25 to 100% of patients in other studies by immunoblotting (25) or radioimmunoprecipitation (20) and have been reported as the major component of the response in adults (27) or in children vaccinated with rotavirus strains from animals (8,10,19,21). The intensities of reaction detected by immunoblotting in this study were extremely low compared with those to VP2, VP6, and VP7.…”

Distribution of VP4 gene alleles in human rotaviruses by using probes to the hyperdivergent region of the VP4 gene

“…Overall, serotype P1 strains comprised 70% of all the specimens examined. This has important implications for future vaccine strategies should the VP4 antigen be shown to strongly influence the success or failure of candidate vaccine strains (7).…”

“…It has been suggested that the differences in the VP4 proteins between current rotavirus vaccine candidate strains and wild-type rotavirus strains may be related to the lack of consistent efficacy exhibited by such vaccine candidate strains (4,20). In studies of the rhesus rotavirus vaccine and rhesus rotavirus x human rotavirus reassortants in young infants, the responses to VP4 have been predominantly homotypic (7,16). Similarly, recent studies in infants undergoing natural primary rotavirus infection indicate that the responses to both VP4 and VP7 are mostly homotypic (7a).…”

Rotavirus gene structure and function.

“…Reassortants containing a single gene which codes for the outer capsid glycoprotein from human virus serotypes on a rhesus rotavirus background have been produced as possible candidate vaccines to induce homotypic immunity to the four human serotypes (223). These strains are now in phase I trials to evaluate their reactogenicity and immunogenicity and to determine whether administration of a polyvalent vaccine will affect "takes" of individual strains (109,143).…”