Safety and Immunogenicity Study of Live Attenuated Indian Rotavirus Vaccine Candidate Strains 116E and I321 in Infants

• - Safety
• Prevalence of fever, diarrhea, blood in stools, gastrointestinal cramps and vomiting in subjects in the vaccine and placebo groups in the 4-week period following administration of vaccine/placebo. Safety was also assessed for by observation of laboratory
• - Vaccine Take
• IgA or IgG antibody titers in subjects in vaccine and placebo groups 28 days after administration of vaccine/placebo or shedding of rotavirus vaccine strains by antigen detection ELISA on days 3, 7 and 28 post administration.

It has been observed that in children who get a severe rotavirus infection, subsequent infections cause either no symptoms or generally only mild or moderate diarrhea. This evidence is the basis for developing a vaccine since it suggests that the first infection immunizes the child against disease upon re-infection.

It was found that neonatal avirulent strains 116E and I321 induce protective immunity and offer clinical protection for at least one year. Both these strains are well characterized and the safety studies have been done in animal models. These candidate vaccine strains have been evaluated for safety and immunogenicity in adults and children (2 to 12 years of age) by a randomized double blind placebo controlled trial in Cincinnati, USA. In India, the diversity of rotavirus strains is greater and there is greater prevalence of malnutrition and co-infection with other enteric pathogens. These vaccines have therefore, also been tested in India.

This study was a phase I randomized, double blind, safety and immunogenicity study of live, attenuated neonatal rotavirus vaccine candidate strains 116E or I321 in healthy non-malnourished infants aged 8-12 weeks. Informed, written, witnessed consent was obtained from the parents before infants were screened at 6 weeks of age. Infants (n=90) were randomized (30 per group) to receive one dose of either the 116E or I321 vaccines (10^5 fluorescence focus units, FFu) or placebo at 8 weeks of age. The rotavirus vaccine was administered at a different time than DPT (Diptheria-Pertussis-Tetanus), OPV (Oral Polio Vaccine) and HBV (Hepatitis B vaccine) immunization since the trial represented the first safety study in infants with these strains. The DPT, OPV and HBV vaccines were given at the regular EPI schedule of 6, 10 and 14 weeks with the precautions and techniques routinely in place for these.

The test article was administered orally two weeks after the first DPT, OPV and HBV dose, after half an hour of administering 2.5 ml bicarbonate to buffer stomach acidity.

Evaluation of reactogenicity consisted of daily recording of symptoms reported by the mother/caregiver and twice-daily axillary temperature measurements for 14 days post administration of vaccine/placebo. Stool specimens were collected before administration of vaccine/placebo, twice during the week following administration (days 3 and 7), and at day 28 after administration to evaluate for vaccine virus shedding. Weekly recording of adverse events was also done for the next 2 weeks i.e. on days 21 and 28 post administration of vaccine/placebo. If gastrointestinal signs or symptoms occurred any time during the 4 weeks observation period, attempts were made to collect stool samples daily (maximum 2 per day) while the illness persisted, to be examined for the presence of the vaccine strains.

Immunogenicity was determined by analysis of sera obtained before immunization and 28 days after immunization for changes in titers of rotavirus antibodies.

• Biological: 116E AGMK
  Single dose of 116E 10^5 FFu
• Drug: I321
  Single dose of I321 10^5 FFu
• Drug: Placebo
  1 crystal of potassium permanganate dissolved in the bicarbonate buffer to colour match the vaccine

• Experimental: 1
  116E AGMK
  Intervention: Biological: 116E AGMK
• Experimental: 2
  I321 AGMK
  Intervention: Drug: I321
• Placebo Comparator: 3
  Placebo
  Intervention: Drug: Placebo

Inclusion Criteria:

• Healthy infants
• Consent available

Exclusion Criteria:

• Evidence of renal, cardiovascular, liver or other reticuloendothelial, neurological, gastrointestinal, hematologic, rheumatologic or immunologic disease

• All India Institute of Medical Sciences, New Delhi
• National Institutes of Health (NIH)
• Centers for Disease Control and Prevention
• Stanford University
• Indian Institute of Science
• Children's Hospital Medical Center, Cincinnati
• Ministry of Science and Technology, India
• Program for Appropriate Technology in Health