Rotavirus vaccines: The wheel has turned

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Ruiz-Palacios GM, Perez-Scchael I, Velazquez FR, Abate H, Breuer T, Clemens SC, Cheuvart B, Espinoza F, Gillard P, Innis BL, Cervantes Y, Linhares AC, Lopez P, Macias-Parra M, Ortega-Barria E, Richardson V, Rivera-Medina DM, Rivera L, Salinas B, Pavia-Ruz N, Salmeron J, Ruttimann R, Tinoco JC, Rubio P, Nunez E, Guerrero ML, Yarzabal JP, Damaso S, Tornieporth N, Saez-Llorens X, Vergara RF, Vesikari T, Bouckenooghe A, Clemens R, De Vos B, O’Ryan M; the Human Rotavirus Vaccine Study Group. (Instituto Nacional de Ciencas Medicas y Nutricion, Mexico Distrito Federal, Mexico). Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med 2006; 354:11–22.

Vesikari T, Matson DO, Dennehy P, Van Damme JP, Santosham M, Rodriguez Z, Dallas MJ, Heyse JF, Goveia MG, Black SB, Shinefield HR, Christie CD, Tlitalo S, Itzler RF, Coia ML, Onorato MT, Adeyi BA, Marshall GS, Gothefors L, Campens D, Karvonen A, Watt JP, O’Brien KL, DiNubile MJ, Clark HF, Boselgo JW, Offit PA, Heaton PA; Rotavirus Efficacy and Safety Trial (REST) Study Team. (University of Tampere Medical School, Tampere, Finland). Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N Engl J Med 2006;354:23–33.

In the midst of the large number of publications and journal articles one skims through every month, it is not often you come across work that has genuine implications for world health. Rotavirus is well-established as a major cause of morbidity and mortality throughout the world and in 1998 a rotavirus vaccine named Rotashield (a tetravalent human–rhesus reassortment vaccine) was licensed for use. Subsequently reports of an increased rate of intussusception ultimately led to the withdrawal of this vaccine from the market. In the following 8 years, 2 new vaccines have been developed and in January results of 2 very large phase III randomised controlled trials were published in the New England Journal of Medicine (N Engl J Med 2006;354:11–22; N Engl J Med 2006;354:23–33). If their promised efficacy bears out, these are likely to aid the lives of millions of children worldwide.

The 2 products have been produced by Merck and GlaxoSmithKline (GSK), named Rotateq and Rotarix, respectively. Rotateq (Merck) is a pentavalent vaccine based on a bovine strain, WC3, that is naturally attenuated for humans, but it is not broadly cross-protective. To overcome this, Merck has produced 5 human–bovine re-assortment viruses that contain a single gene encoding a major capsid protein from the most common human serotypes (G1, G2, G3, G4, and P[8]). The vaccine is infrequently shed in the stool, so 3 oral doses are required with at least a month between doses starting in the first 3 months of life. Rotarix (GSK) is a monovalent vaccine derived from the most common human rotavirus strain G1P[8], that has been attenuated by serial passage and can be administered in 2 oral doses as it replicates well in the gut and is shed by >50% of patients, as detected by enzyme-linked immunosorbent assay, after receiving 2 doses. Much like natural rotavirus infection, it also provides cross-protection against other serotypes.

Both trials were double-blind, placebo-controlled, randomized studies with a major focus on the safety aspects of the vaccines particularly addressing intussusception. For Rotateq (Merck), 6- to 12-week old healthy infants from 11 countries (the United States and in Europe and South America) were randomly assigned to receive 3 oral doses of the live WC3 strain or placebo at 4- to 10-week intervals in a blinded fashion. In total, there were 34,035 infants in the vaccine group and 34,003 in the placebo group. To test Rotarix (GSK) 63,225 healthy infants were recruited from 11 Latin American countries and Finland. They received 2 oral doses of either the HRV vaccine (31,673 infants) or placebo (31,552 infants) at approximately 2 months and 4 months of age.

Both trials monitored the incidence of intussusception, severe adverse outcomes, and severe gastroenteritis episodes by active surveillance with clearly defined criteria. For Rotateq (Merck), intussusception occurred in 12 vaccine recipients and 15 placebo recipients within 1 year after the first dose. For Rotarix (GSK), 6 vaccine recipients and 7 placebo recipients had definite intussusception during the 31-day window after each dose. For other serious adverse events, there were no differences between the vaccine and placebo group for Rotateq; Rotarix appeared to provide protection against gastroenteritis-associated serious adverse events.

Efficacy of both vaccines was impressive. Rotateq provided 95% efficacy against severe rotavirus gastroenteritis (G1–4 serotypes) requiring hospitalization or emergency department care, and 60% efficacy against all causes of gastroenteritis. In a nested detailed substudy of 5673 subjects, there was an 86% reduction in office or clinic visits owing to rotavirus (G1–4) gastroenteritis. Parent or caregiver lost workdays owing to rotavirus gastroenteritis were reduced by 87%. Rotarix demonstrated 85% efficacy in both reducing episodes of severe rotavirus rotavirus gastroenteritis and the need for hospitalization in the 20,169 infants studied for efficacy. For all causes of gastroenteritis, the incidence and hospitalization rate was reduced by 42%.

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Comment 

Rotavirus remains the most common cause of severe diarrheal disease in children worldwide. Although virtually all children become infected in the first 5 years of life, it is in children aged 3–35 months when severe diarrhea and dehydration primarily occur. Within the United States, it is the cause of a substantial burden on the health services, accounting for 20–40 deaths annually (J Infect Dis 1996;174(Suppl 1):S5–11), and responsible for as many as 50% of pediatric admissions to hospitals because of diarrhea (Emerg Infect Dis 2003;9:565–572). However, globally, developing countries count the cost of infection in mortality. A recent study estimated an annual incidence of about half a million deaths because of rotavirus, of which 85% were in low-income countries (Health Econ 2000;9:19–35). It is vaccination that has been identified as the control measure most likely to have a significant impact on the incidence of these figures (Emerg Infect Dis 2003;9:565–572).

The much publicized previous attempt at a vaccine, Rotashield was licensed in the United States in 1998 (Acta Paediatr Suppl 1999;88:2–8). It had been shown to be efficacious in reducing the frequency of severely dehydrating rotavirus. Furthermore, it was cost effective and the strategy was clear; to use the high-priced vaccine routinely in industrialized countries to subsidize its use in developing countries. However, postmarketing surveillance detected an apparent increase in a relatively rare event, intussusception (Morbid Mortal Wkly Rep 1999;48:577–581). The relationship was strongest when the first dose of vaccine was given with the first or second dose of the diphtheria–pertussis–tetanus vaccine (Pediatr 2002;110:e67), although this was counterbalanced by a decrease in the incidence in older children (J Infect Dis 2003;187:1301–1308). The overall reduced incidence in immunized infants compared with nonimmunized infants in these studies suggested that the vaccine might actually protect against later adverse events. Nonetheless, in the ensuing controversy, there was a reversal of the recommendation for universal immunization in the United States, leading to a withdrawal of the vaccine from the market, precluding the possibility of its deployment in developing countries (Morbid Mortal Wkly Rep 1999;53:786–789).

Undeterred by the failure of Rotashield, pharmaceutical companies have persisted in developing alternatives. Each of these 2 trials recruited and followed >60,000 infants, making them the largest prelicensure vaccine trials conducted to evaluate vaccine safety. Importantly, neither of the trials have noted a significant difference in cases of intussusception (or other serious adverse events) between vaccine and placebo. This may be because intussusception was a unique complication of Rotashield, although age at administration may also be a contributing factor. Natural intussusception usually spares infants in the first 3 months of life, and because the first doses of both of these new vaccines were administered to infants who were <3 months of age, the absence of an increased risk of intussusception might reflect the safer age at which these vaccines were given.

The substudies concerning efficacy are also encouraging; overall. Rotarix demonstrated 85% efficacy compared to Rotateq’s 95%, impressive given the size of the trials. The difference in efficacy may be attributable to the different populations studied, the different definition of severity as well as the production methods of the vaccine. GSK enrolled its participants from low- or middle-income families in Latin America, whereas the Merck vaccine was tested largely in the developed world.

Also of interest was the reduction in hospitalizations due to diarrhea. For both vaccines, this reduction was greater than expected given the number of diagnosed cases of rotavirus. Rotateq reduced admissions by 59% and Rotarix reduced them by 42% during the first year of life. One explanation is that Rotavirus gastroenteritis may be responsible for more hospitalizations than previously estimated. Another would be that the vaccines offer a degree of cross-protection to other pathogens.

In developed countries, an effective rotavirus vaccine can decrease the number of children admitted to or attending the hospital with dehydration, but should also decrease the burden on primary care practitioners. By reducing the disease burden, the costs of a rotavirus vaccination program should be offset by societal savings, both in terms of a reduction in direct medical costs and in reduced lost time from work of caregivers of affected children. One of the biggest battles will be acceptance by the general public. Continued monitoring of the possible risks of intussusception will go a long way to appeasing the fears raised by Rotashield and a system of surveillance postlicensure will need to be in place to ensure any subsequent reports of unexpected risks can be assessed based on rigorous data.

It is the efficacy of the vaccines in reducing the number of severe rotavirus infections in developing countries that is likely to have the biggest effects on mortality figures. This needs to be clarified with focused studies within the Third World. Host factors such as comorbid diseases, malnutrition, maternal antibodies, and breastfeeding as well as issues of transmission of the rotavirus and the varied serotype prevalence will all have an influence on how effective the vaccine will be both at the patient level and the number required to reach herd immunity. The studies done by GSK in Latin America are particularly encouraging, but there is a need to obtain similar social demographics in Asia and Africa.

The most problematic hurdle concerns issues of finance and distribution in developing countries, where the global health community will be charged with expediting the availability of these life-saving vaccines at an affordable price. A therapeutic vaccine does not automatically translate into lives saved, as evidenced by the fact that in 2002 almost 1.5 million children died from vaccine-preventable diseases such as tetanus, measles, polio, diphtheria, pertussis (whooping cough), hepatitis B, and yellow fever (Children’s Vaccine Program 2002, http://www.childrensvaccine.org/files/CVP_Occ_Paper5.pdf).

The financial rewards are evident; GSK predicts that the market for its rotavirus vaccine could be worth up to $2.4 billion by 2010. This change in mood has been partly driven by Wyeth, which developed the first vaccine to become a billion-dollar drug: the Streptococcus pneumoniae vaccine Prevnar. It can also be partly attributed to governments realizing the benefit of prevention rather than cure. “It is rare that payers are talking more about what the vaccine can do than worrying about the price,” said David Stout, the president of pharmaceuticals at GSK, last year. “There is a growing recognition of the value of vaccines, which makes payers more willing to put money on the table” (The Guardian 2005, July 1).

Irrespective of what headlines these vaccines may or may not be making, the important point is that they appear to have the backing of those who can make a difference. With the Global Alliance for Vaccines and Immunisation, the World Health Organisation, and the Bill and Melinda Gates Foundation supporting the fast track introduction of these vaccines into developing countries, hopefully we will see the benefit sooner rather than later.

The 2 reports documented herein have the potential to aid the disease burden in the West and so go on to help millions worldwide. Overall, the signs are positive, and the initial success with the rotavirus vaccine can only serve as an encouragement to others developing primary prevention strategies for those who require it the most.