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Two-Dose Rotavirus Vaccine Regimen Initiated During Newborn Period Prevents Rotavirus Diarrhea

Rotavirus illness, a viral infection marked by diarrhea and dehydration, causes 453,000 deaths per year among infants and children under 5 years of age. The first vaccine against rotavirus, known as RRV-TV or RotaShield, was licensed in 1998. It was designed to be given to infants in three doses administered at age 2 months, 4 months and 6 months.

However, the success of RRV-TV was temporary, as it was withdrawn a year later after post-marketing studies found an association between vaccination and intussusception, a serious bowel condition in which part of the intestine slides into itself. If not treated promptly, this condition can be life-threatening. It was estimated that about one or two extra cases of intussusception would be caused per 10,000 infants who received the vaccine, mostly after the first dose.

Transmission electron micrograph image of rotavirus particles
Transmission electron micrograph image of rotavirus particles. Credit: CDC/B. Skinner

Background

Research conducted after RRV-TV’s withdrawal suggested that infants who received “catch-up” vaccinations—when the first dose was given after the recommended age of 2 months—were more likely than younger vaccinees to experience intussusception. Other studies have found that infants ages 3 to 9 months are at a much higher risk of intussusception unrelated to the rotavirus vaccine and that from birth to age 2 months, there is a very low risk of intussusception. This age factor is beginning to prove important in the development of strategies for rotavirus vaccines under development.

An international team of researchers from NIAID and other institutions in the United States, Europe, and Africa began exploring the possibility of administering the first dose of RRV-TV before 30 days of age and a second dose before 60 days of age. That way, the scientists reasoned, vaccination could be completed by 3 months of age—generally, when the risk of intussusception increases. In addition, by receiving the vaccine earlier in life, the infants would be protected from rotavirus infection at a younger age.

In a study published online in April 2013, the researchers tested the safety and efficacy of the two-dose vaccine regimen in newborns in rural Ghana, a country with high rates of infant mortality. The trial included 998 infants less than 30 days old (intention-to treat), of whom 889 completed the two-dose vaccination course (per-protocol). There were no significant differences in outcomes between the intention-to-treat and per-protocol groups.

Results and Significance

Infants were randomized to receive two doses of either the vaccine or placebo, the first dose at age 0 to 29 days and the second dose at age 30 to 59 days, with at least 21 days between the two doses. The infants were monitored two and four days after each dose and then weekly until one year of age for diarrhea and vomiting, fever, intussusception, and other adverse effects. No significant differences were observed between vaccine and placebo recipients.

Compared to placebo, the vaccine induced an immune response in significantly more infants; 56.7 percent of vaccinated infants generated anti-rotavirus antibodies, compared with 3.4 percent of those who received placebo. The vaccine induced significant protection against rotavirus diarrhea. In the per-protocol group, 2.9 percent of vaccinated infants experienced rotavirus illness of any severity in the year following vaccination, compared with 8.1 percent of those who received placebo, a vaccine efficacy of 64.3 percent.

Next Steps

According to the researchers, the results support vaccination with two doses of RRV-TV, with the first dose administered before 30 days of age. Future studies could address the risk of intussusception and examine the two-dose strategy’s efficacy in preventing severe illness.

If larger trials confirm that the strategy is safe and effective, the researchers note that it has some particular advantages for implementation in developing countries, such as Ghana. For example, infants in Ghana are eligible to receive polio and tuberculosis vaccines as newborns, which means that a rotavirus vaccine could potentially be administered during the same medical visit. This would make vaccination more convenient for parents and thus more likely to occur on time. RRV-TV is also stable at room temperature, which makes it easier to store and transport, especially in resource-poor areas.

Reference

Armah GE et al. (epub April 18, 2013). Efficacy, immunogenicity, and safety of two doses of a tetravalent rotavirus vaccine RRV-TV in Ghana with the first dose administered during the neonatal period. Journal of Infectious Diseases. DOI: 10.1093/infdis/jit174.

Last Updated July 18, 2013

Last Reviewed July 18, 2013