Prospective study of diarrheal diseases in Venezuelan children to evaluate the efficacy of rhesus rotavirus vaccine

Abstract

The efficacy of a rhesus rotavirus vaccine (MMU 18006, serotype 3) against infantile diarrhea was evaluated by active home surveillance of a group of 320 children 1-10 months of age in Caracas, Venezuela. During a 1 year period following oral administration of vaccine or placebo under a double-masked code, over 600 diarrheal episodes were detected. Etiologic studies revealed that heat-stable toxin (ST) producing enterotoxigenic E. coli (ETEC) was the most common diarrheal agent detected (34%) followed by enteropathogenic E. coli (EPEC, 10.9%), heat-labile toxin (LT) producing ETEC (7.6%), rotavirus (6.9%), Cryptosporidium (4.8%) and Campylobacter (1.3%). ST-producing ETEC were also recovered from over 20% of control stool specimens obtained during diarrhea-free periods, whereas EPEC, rotavirus, Cryptosporidium, and Campylobacter were rarely detected in such control specimens. Rotavirus was responsible for about one-half of the more severe cases of diarrhea. Twenty-two of 151 infants who received placebo (14.6%) and eight of 151 receiving a 10(4) PFU dose of vaccine (5.3%) had rotavirus diarrhea during the follow-up period for an efficacy level of 64% against any rotavirus diarrhea. However, vaccine efficacy reached 90% against the more severe cases of rotavirus diarrhea and was noticeably high in the 1-4 month age group. Serotypic analysis of the rotaviruses detected suggests that the resistance induced by the vaccine was type specific since significant protection was only evident against serotype 3 rotaviruses. A 10(3) PFU dose tested initially in 18 children did not appear to protect against rotavirus diarrhea.

Magnitude of Serum and Intestinal Antibody Responses Induced by Sequential Replicating and Nonreplicating Rotavirus Vaccines in Gnotobiotic Pigs and Correlation with Protection

“…The failure of monovalent live RV vaccines to induce significant protection in children has been attributed to their lack of induction of heterotypic protective antibody responses to multiple RV serotypes. Consequently, a successful RV vaccine may need to induce broadly reactive or neutralizing antibodies to the major serotypes of RV (serotypes G1 to G4) commonly seen in children (29). Natural HRV infections in children induce increased rates of protection from reinfection and diarrhea following each subsequent RV infection, and secondary infections are most often caused by a different G serotype (34).…”

Rotavirus Infection: A Perspective on Epidemiology, Genomic Diversity and Vaccine Strategies

“…In industrialized countries, clinical trials for three Jennerian vaccines using attenuated animal strains demonstrated good efficacy against severe rotavirus disease [20,69,79,91,[95][96][97][98]. In contrast, these vaccines failed to provide protection in challenging impoverished settings where the vaccine would be most critical to saving lives [32,40,41,48,49,85].…”

“…The RRV-MMU strain underwent 9 passages in monkey kidney cell cultures and 7 passages in diploid rhesus cells [55]. Clinical trials for the vaccine in industrialized countries resulted in variable efficacy ranging from 12-90% [20,69,97]. No protection was observed after one dose of RRV-MMU in an impoverished Native American population in the US [85].…”

“…Several findings from these trials were of interest for future vaccine development. First, in the one trial from Venezuela where high efficacy (90%) was observed against severe disease, the predominant circulating strain (G3) was similar to the rhesus vaccine strain, indicating that serotype-specific protection might be of importance for the animalbased rotavirus vaccines, and prompted the addition of more antigens in future modifications of animal based vaccines [69]. Second, the vaccine provided greater protection against severe illness compared to mild and moderate disease.…”

Rotavirus vaccines

“…59 In 1998, a rhesus-human rotavirus vaccine (RotaShield ® , Wyeth Lederle Vaccines) was licensed in the US after clinical trials in Finland, the US, and Venezuela demonstrated vaccine efficacy of 82-91% against severe rotavirus gastroenteritis. [60][61][62][63] However, the vaccine was withdrawn from the US market less than one year after its licensure due to an association with intussusception at a rate of 1 case per 10,000 vaccinated infants that occurred primarily after the first dose. 33,[64][65][66] Fortunately, despite this setback, vaccine development continued due to recognition of the significant public health burden of rotavirus disease, and both currently licensed vaccines, RV1 and RV5, underwent large prelicensure safety trials with approximately 60,000 to 70,000 infants each.…”