Live Oral Pentavalent Rotavirus Vaccine May Be Safe, Effective in Developing Countries

Laurie Barclay, MD

August 11, 2010

August 11, 2010 — Live, oral, pentavalent rotavirus vaccine is as safe and effective for the prevention of severe rotavirus in developing countries as it is in middle-high income nations in Europe and in America, according to the results of 2 large-scale, multicenter, randomized, double-blind, placebo-controlled trials (one in Asia and one in Africa) reported August 6 Online First in The Lancet.

"Rotavirus-related diarrhea is a major cause of infant death in the developing world," Roger I. Glass, MD, PhD, director of the Fogarty International Center and associate director for international research at the National Institutes of Health, Bethesda, Maryland, told Medscape Medical News. "If we can reduce rotavirus-related hospitalizations by 25%, as these studies suggest, this would have an incredible impact on child survival. Not many U.S. children die of rotavirus disease, because the vaccine keeps them out of hospitals and doctors' offices. In the developing world, where over one-half million children die of this disease, these vaccines could be life savers."

Although rotavirus vaccines were not as effective in regions tested in Asia and Africa as they were in the United States, they could provide a "massively new intervention to reduce overall mortality and diarrhea-related mortality in developing countries," said Dr. Glass, who coauthored an editorial accompanying the 2 studies. "We're excited because these studies represent the culmination of a very long research period, from discovering the virus, to developing the vaccine, to understanding the disease burden, to getting global recommendations for vaccine use. Rotavirus vaccine is a big help toward achieving the Milllennium goal of reducing diarrhea-related mortality worldwide, and something we've been working on for over 3 decades."

"Our main goal is to prevent the most severe disease that might lead to death in areas where treatment is inaccessible," said Asian study coauthor John C. Victor, from PATH in Seattle, Washington, in a news release. "Because we saw indications that the vaccine is even more efficacious in preventing the most severe disease children experience, I am very optimistic about the impact that rotavirus vaccines will have on mortality in these settings."

Asian Study

The goal of the first study, by K. Zaman, PhD, from the International Centre for Diarrhoeal Disease Research in Dhaka, Bangladesh, and colleagues, was to determine the clinical efficacy of live oral pentavalent rotavirus vaccine to prevent severe rotavirus gastroenteritis in infants in rural Matlab, Bangladesh, and in urban and periurban Nha Trang, Vietnam. Infants aged 4 to 12 weeks with no gastrointestinal tract symptoms were assigned by computer-generated randomization sequence in blocks of 6 to receive 3 oral doses of pentavalent rotavirus vaccine 2 mL or placebo at approximately 6 weeks, 10 weeks, and 14 weeks old, in addition to oral poliovirus vaccine and other routine infant vaccines.

For infants seen at study medical facilities, clinical information regarding gastroenteritis episodes was obtained from clinical staff and parent recall. The main study outcome was severe rotavirus gastroenteritis, defined as a Vesikari score of at least 11, occurring at least 14 days after the third dose of placebo or vaccine to study completion on March 31, 2009, when participants were approximately 21 months old.

This was a per-protocol analysis including infants who received scheduled doses of vaccine or placebo and had complete clinical and laboratory data, without intervening laboratory-confirmed naturally occurring rotavirus disease earlier than 14 days after the third dose.

Of 2036 infants randomly selected, 1018 were assigned to pentavalent rotavirus vaccine and 1018 to placebo, and the per-protocol analysis included 991 infants assigned to pentavalent rotavirus vaccine and 978 assigned to placebo. Median follow up was 498 days (interquartile range, 480 - 575 days) from 14 days after the third dose of placebo or vaccine until final disposition.

In the vaccine group, 38 cases of severe rotavirus gastroenteritis were reported during more than 1197 person-years of follow-up (nearly 2 years of follow-up) vs 71 cases in more than 1156 person-years in the placebo group, yielding 48.3% vaccine efficacy against severe disease (95% confidence interval [CI], 22.3 - 66.1; P = .0005 for efficacy > 0%).

One or more serious adverse events within 14 days of any dose occurred in 25 (2.5%) of 1017 infants randomly selected to vaccine and in 20 (2.0%) of 1018 infants randomly selected to placebo. Pneumonia was the most frequent serious adverse event, occurring in 12 (1.2%) in the vaccine group and in 15 (1.5%) in the placebo group. No serious adverse event was thought to be related to the study intervention.

"In infants in developing countries in Asia, pentavalent rotavirus vaccine is safe and efficacious against severe rotavirus gastroenteritis, and our results support expanded WHO [World Health Organization] recommendations to promote its global use," the study authors write.

The investigators note that efficacy estimates in this trial might not be comparable to those reported in trials in the developed world, because the studies were designed differently and used different clinical scoring systems. This study used broad inclusion criteria, and severity scores might have been less precise than in other trials because clinical measurement procedures were done only during a stay in a medical facility, with reliance on parental recall. Furthermore, the study was not designed to make statistical comparisons between countries.

"With a WHO recommendation for rotavirus vaccines now in place, governments of developing countries in Africa and Asia are deciding how to prioritise introduction of rotavirus vaccine in their public health agendas," the study authors conclude. "Alongside efficacy results for this vaccine in Africa, our study supports WHO's strong recommendation for expansion of rotavirus vaccine use to the poorest nations in Africa and Asia. Rotavirus vaccines have the potential to protect the lives of nearly 2 million children in the next decade alone."

African Study

The second study, by George E. Armah, PhD, from the University of Ghana in Accra, and colleagues, assessed the efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in sub-Saharan Africa (rural areas of Ghana and Kenya, and an urban area of Mali) between April 2007 and March 2009.

Computer-generated randomization sequence (in blocks of 6) assigned infants without gastrointestinal tract symptoms to receive 3 oral doses of pentavalent rotavirus vaccine 2 mL or placebo at approximately 6 weeks, 10 weeks, and 14 weeks old. Infants were 4 to 12 weeks old at study entry, and those with HIV infection were not excluded. When the infants were seen at healthcare facilities, their parents provided information regarding their gastrointestinal tract symptoms, and clinicians prospectively gathered clinical data.

The main study outcome was severe rotavirus gastroenteritis diagnosed by enzyme immunoassay and with a Vesikari score of at least 11, occurring at least 14 days after the third dose of placebo or vaccine to study completion on March 31, 2009, when infants were approximately 21 months old.

The per-protocol analysis included infants who were given scheduled doses of vaccine or placebo without intervening laboratory-confirmed, naturally occurring rotavirus disease earlier than 14 days after the third dose and who had complete clinical and laboratory findings.

Of 5468 infants randomly selected, 2733 were in the pentavalent rotavirus vaccine group and 2735 in the placebo group. The per-protocol analysis included 2357 and 2348 of these infants, respectively. In both groups, median follow-up was 527 days, starting 14 days after administration of the third dose of vaccine or placebo.

In the vaccine group, 79 cases of severe rotavirus gastroenteritis were reported in 2610.6 person-years vs 129 cases in 2585.9 person-years in the placebo group. Vaccine efficacy against severe rotavirus gastroenteritis was 39.3% (95% CI, 19.1 - 54.7; P = .0003 for efficacy > 0%). Serious adverse events within 14 days of any dose were reported in 42 (1.5%) of 2723 infants in the vaccine group and in 45 (1.7%) of 2724 infants in the placebo group. Gastroenteritis was the most frequent serious adverse event, reported in 17 (0.6%) of each group.

"Pentavalent rotavirus vaccine is effective against severe rotavirus gastroenteritis in the first 2 years of life in African countries with high mortality in infants younger than 5 years," the study authors write. "We support WHO's recommendation for adoption of rotavirus vaccine into national expanded programmes on immunisation in Africa."

Study limitations are similar to those in the Asian study. In addition, a negligible efficacy of vaccine against severe disease reported in Mali through age 1 year was partly attributable to failure in case capture. In Mali, for cultural reasons, many cases of severe diarrhea were taken to traditional healers during the first year of the study and therefore were not seen at healthcare facilities.

Although the efficacy in both studies is lower than that reported in trials in high-income countries, the investigators in both studies suggest that rotavirus vaccine use could save many lives in Asia and Africa.

"[Vaccine] protection was especially high through the first year of life (64.2% vaccine efficacy), when the disease burden, including mortality, is highest," the study authors conclude. "...In Africa, where young children are dying from diarrhoeal disease and prompt medical care is often out of reach, the need to prevent rotavirus is especially urgent. Introduction of rotavirus vaccines for African children, along with imminent introduction of pneumococcal and meningococcal conjugate vaccines in parts of Africa, could instigate a new era of reduction of childhood disease and mortality."

Public Health Implications

In an accompanying comment, E. Anthony S. Nelson, from the Chinese University of Hong Kong in Hong Kong Special Administrative Region, China, and Dr. Glass note that the true efficacy of these vaccines in low-income settings and possible benefits of herd immunity cannot be determined until they are in more widespread use.

"These studies had to be performed because in the past, live oral vaccines have not worked as well as parenteral vaccines in developing countries, and WHO recommendations in 2007 required that they be tested in low-income countries before they could be approved for global use," Dr. Glass said. "The main limitations of these studies are that we still need to determine how to get vaccination programs into widespread use."

Dr. Glass explained that the GAVI Alliance may be concerned about running short of funding to implement vaccination in low-income countries, and they have suggested that they may not be able to allow introduction of both the pneumococcal and rotavirus vaccines at the same time in the same country, even for countries that request both vaccines. Nine countries have thus far requested funding from GAVI to implement rotavirus vaccination.

"Reassuring governments in low-income countries that they will be able to purchase vaccine at a reasonable price, when support from the GAVI Alliance ends, will be the quickest way to encourage their introduction and to establish whether these vaccines will stand alongside smallpox, measles, and poliomyelitis vaccines in their public health benefits," Drs. Nelson and Glass write.

They also note that additional research is needed to clarify why the efficacy of both live oral rotavirus vaccines is lower among children in low-income countries vs high-income countries.

"Could simple interventions, such as slightly delaying immunisation, adding an additional dose of vaccine, or withholding breast milk around the time of vaccine administration, improve the efficacy of the vaccine in these challenging settings?" Drs. Nelson and Glass write. "Finding an answer to these questions could add value to these new vaccines while doing much to improve the health and survival of children."

Both studies were funded by PATH (GAVI Alliance grant) and Merck, which employs 5 of the authors of each of the studies. Dr. Glass has disclosed no relevant financial relationships. Dr. Nelson has received funding from Merck and Wyeth for diarrheal and respiratory disease surveillance studies; has participated in vaccine studies funded by Baxter, GlaxoSmithKline, MedImmune, and Wyeth (including a phase 3 Rotarix study); and has received lecture fees and travel support from GlaxoSmithKline, Merck, Intercell, and Wyeth.

Lancet. Published online August 6, 2010.

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