The Promise of New Rotavirus Vaccines

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     Rotavirus disease kills approximately half a million children annually in developing countries and accounts for one third of hospitalizations for diarrhea worldwide.1 In 1999, global efforts to control the tremendous health burden of gastroenteritis suffered an abrupt and unanticipated setback. The first licensed rotavirus vaccine (RotaShield) was withdrawn from the U.S. market less than a year after its introduction because it was associated with an uncommon but potentially life-threatening adverse event, intussusception, at an estimated rate of 1 incident per 10,000 vaccine recipients.2

    Debate ensued over the possible use of this vaccine in developing countries, where the health benefits, particularly a reduction in deaths from rotavirus, clearly exceeded the potential risks of the vaccine.3,4 However, it soon became apparent that the introduction of a vaccine that had been withdrawn in the United States was untenable in developing countries and that new vaccines would be needed. The manufacture of the first licensed rotavirus vaccine was halted, and hope was lost for a vaccine that could have prevented much severe diarrhea in children around the world. Despite the prospect that other live oral rotavirus vaccines might also be associated with intussusception and despite the expense of conducting large-scale clinical trials for safety, two manufacturers accepted the challenge.

    This issue of the Journal includes reports on the promising results of large clinical trials of two new rotavirus vaccines whose manufacturers moved ahead with trials despite the many challenges and risks.5,6 The two new products, Rotateq from Merck and Rotarix from GlaxoSmithKline, are both live oral vaccines intended to be given to infants at the same time as their immunizations for diphtheria, pertussis, and tetanus, but they differ in their approaches, strains, and formulations. Rotarix is a monovalent vaccine derived from the most common human rotavirus strain, G1P[8], that has been attenuated by serial passage and is administered in two oral doses one to two months apart. The vaccine strain replicates well in the gut, is shed by more than 50 percent of patients receiving the vaccine after the first dose, and (like natural rotavirus infections) provides cross-protection against most other serotypes. By contrast, Rotateq is a pentavalent vaccine based on a bovine strain, WC3, that contains five human–bovine reassortant viruses. WC3 is naturally attenuated for humans but is not broadly cross-protective, so each reassortant virus contains a single gene encoding a major outer capsid protein from the most common human serotypes. The bovine virus grows less well in the human intestine, so the aggregate titer required to immunize a child is greater. In addition, the vaccine strains are infrequently shed in the stool, and three oral doses are required, with at least a month between doses.

    Despite these differences, both vaccines demonstrate an impressive efficacy profile. The slight differences in observed efficacy against severe rotavirus disease (85 percent for Rotarix and 98 percent for Rotateq) might well be explained by differences in the classification of disease severity and the populations studied. GlaxoSmithKline conducted its trials primarily among infants of poor and middle-income families in Latin America, whereas the Merck vaccine was tested in the United States and Finland. A particularly exciting finding of great importance to public health (and to the economic burden of disease) was the magnitude of the reduction in hospitalizations for diarrhea of any cause, a decrease that was greater than expected given the number of diagnosed cases of rotavirus. In Latin America, Rotarix vaccination decreased hospitalizations for diarrhea among children under one year of age by 42 percent, and in the United States and Finland, Rotateq vaccination reduced hospitalizations by 63 percent during the first year of life. These studies, which identify the fraction of diarrhea attributable to rotavirus, indicate that more of the severe cases of diarrhea leading to hospitalization are probably caused by rotavirus than has been estimated from previous studies. In Latin America, the 42 percent reduction in hospitalizations may predict a similar reduction in mortality that could translate directly into improved child survival. In the United States, Rotateq reduced the number of lost workdays from rotavirus by nearly 87 percent, a welcome benefit with clear economic implications for families.7,8

    Perhaps even more important, the two vaccines demonstrated a reassuring safety profile, particularly with respect to intussusception. Each of the two trials enrolled and monitored more than 60,000 infants, making them the largest prelicensure vaccine trials conducted to evaluate vaccine safety. Fortunately, neither trial identified a significant difference between vaccine and placebo in the risk of intussusception, suggesting that the problem of intussusception may have been a characteristic of RotaShield rather than a problem intrinsic to all live oral rotavirus vaccines. However, epidemiologic observations indicate that natural intussusception spares infants in the first three months of life, and infants immunized with RotaShield who were under three months of age had a substantially lower risk of intussusception (approximately 1 in 30,000) than did those who were older (<1 in 8000).9 Since the first doses of both of the new vaccines were administered to infants who were under three months of age, the absence of an increased risk of intussusception might reflect the safer age at which these vaccines were tested. These trials leave open the question of whether either vaccine might cause intussusception if administered to older infants or to a larger number of infants. Given the troubling legacy of RotaShield and concern among the public and physicians over intussusception, an effective system of surveillance should be put in place after licensure to monitor this rare outcome. Hundreds of thousands of children will need to be immunized before a clean bill of health can be given to these vaccines.

    As these vaccines become licensed and used in Europe, the United States, and many other countries, global interest will focus next on the effect these vaccines will have on reducing the number of clinic visits and hospitalizations, as well as economic costs, in industrialized countries and hospitalizations for diarrhea and deaths among children in the developing world.10 However, a number of issues remain to be faced before rotavirus vaccines can realize their full potential. For the developed world, issues of price, acceptability, public awareness, and fear of intussusception will need to be addressed before the effect of this vaccine will be fully felt. The key question for the global community will be to determine whether these vaccines work equally well among the poorest children in the developing world. Live oral vaccines must replicate and be processed in the infant's gut in order to induce a good immune response and be protective. Replication is highly dependent on the dose of the vaccine administered and host factors that might neutralize the virus, including maternal antibodies, breast-feeding, interfering bacterial or viral agents, and malnutrition. In addition, although both vaccines protected against the full range of serotypes in circulation in the trial population, Rotarix was less efficacious against the G2 strains, and it remains to be seen how the vaccines will perform in settings where nonvaccine serotypes are more prevalent. Both vaccines will need to demonstrate their efficacy in the difficult settings of developing countries if we are to achieve our goal of maximally decreasing global deaths from diarrhea. Fortunately, trials of the Rotarix vaccine have begun in South Africa and will start in Bangladesh and Malawi in the near future. In their report on Rotateq, the investigators indicate the need for Merck to conduct similar trials in the developing world, but no definite plans have been announced.

    Anticipating the results of these trials, the Global Alliance for Vaccines and Immunization, the World Health Organization, and the Bill and Melinda Gates Foundation are encouraging and supporting the accelerated introduction of rotavirus vaccines in the poorest countries of the world, where rotavirus remains a fatal disease. Once the efficacy of these vaccines can be established in these populations, mechanisms to finance the introduction of vaccines, ensure a sustainable and affordable supply of vaccines, and expedite the introduction of these vaccines into routine immunization programs should become a global priority. The two reports in the Journal document these very large trials, conducted before licensure, to demonstrate both the safety and efficacy of these new vaccines against diarrhea, the second most common disease in children. As vaccines become licensed and used in the United States and Europe, we should expect to see a substantial reduction in winter hospitalizations, visits to doctors and clinics, and parents' workdays lost due to childhood diarrhea. With the successful introduction of rotavirus vaccines in industrialized countries, the global health community will be charged with expediting the availability of these lifesaving vaccines at an affordable price in the developing world. After a long period of waiting, the time for a rotavirus vaccine may have finally arrived.

    The views expressed in this article are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.

    No potential conflict of interest relevant to this article was reported

    

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