Challenges to rotavirus vaccine development

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What challenges can ostensibly remain for rotavirus vaccines, at the time that two safe and efficacious rotavirus vaccines are licensed internationally and on the verge of being introduced in multiple countries in the Americas and in Europe? Certainly, these vaccines will reduce the tremendous costs associated with rotavirus-associated illness and hospitalizations. Nevertheless, for rotavirus vaccines to reach their full potential and impact significantly on reducing childhood mortality, the vaccines need to be introduced in the developing countries of Africa and Asia, where the bulk of global rotavirus mortality lies [5, 7, 8]. There are several challenges to the successful introduction and implementation of rotavirus vaccines in these regions [111].

Efficacy in developing countries in Africa and Asia

The WHO has recommended consistently that the efficacy of the new generation rotavirus vaccines needs to be evaluated in the developing countries of Africa and Asia where the burden of disease and the mortality due to rotavirus disease is highest [4, 19, 112]. The rational reasons for this have been described previously [73, 111], but include issues such as: (i) differences in the immunogenicity and/or efficacy of other oral enteric vaccines, such as OPV and cholera vaccines in populations living in developing countries; and (ii) differences in the epidemiology and strain diversity of rotavirus strains circulating in developing countries, which seem to be different.

Some of the potential questions why a rotavirus vaccine may not be as effective in a developing country population have been investigated. For instance, the immune response to one of the new rotavirus vaccines was demonstrated to be lower in an African infant population [106, 107], and is under evaluation in an Asian infant population. The other vaccine has not been evaluated in this group. Both commercial licensed rotavirus vaccines will be evaluated for clinical efficacy in developing country populations in Africa and Asia, as was recommended by the WHO [19, 112].

Secondly, both the RRV (RotaShield®) and monovalent human vaccine (Rotarix™), have been evaluated in malnourished infant populations. Although the study numbers were relatively small, both studies indicate that there was not a reduced efficacy associated with malnourished status of the infants [113, 114]. Thirdly, the co-administration of a live attenuated OPV has been examined and the immune responses and geometric mean titers (GMT) of the response to the three polio virus serotypes was not shown to be detrimentally affected by the Rotarix™ vaccine [106, 107], as was also seen with the RRV vaccine [115] and is being evaluated with the pentavalent rotavirus vaccine by Merck.

The definitive clinical efficacy studies in infant populations in Africa and Asia, where infants will get the vaccine under the most testing situations (e.g., age of immunization, high maternal antibody, high co-morbidity of other enteric infections, co-administration of OPV, etc.) are ongoing and will only yield results in late 2008 or 2009.

Safety of the vaccines with regards to intussusception

The reported association of the RotaShield® vaccine with intussusception, a rare but serious type of bowel obstruction found in infants worldwide, has had a lasting effect on rotavirus vaccine development [86, 116]. A clear temporal relationship between receipt of the vaccine and the development of intussusception was demonstrated with cases of intussusception clustering between 3 and 14 days following immunization with the first dose of the vaccine [117]. The age at time of receipt of the first dose of RotaShield®

appears to have influenced the risk of intussusception post immunization. No cases of intussusception occurred in infants vaccinated at < 60 days of age despite 16% of all first doses received at that age [89]. Therefore, the risk of intussusception following RotaShield® was highest in infants who received their first dose of vaccine after 3 months of age, perhaps coinciding with the "natural" high-risk period for intussusception.

The reasons for the association between the RRV vaccine and the development of intussusception are not known. In addition, it is not known if non-US populations would have the same risk of intussusception following receipt of this vaccine. The two licensed commercial rotavirus vaccines (Rotarix®, GSK Biologicals and RotaTeq®, Merck & Co., Inc.) completed Phase III clinical trials in 2005, with one or other of the vaccines being given to over 130 000 infants in Latin America, Europe and the U.S. in placebo-controlled studies with no association identified between receipt of the vaccine and intussusception [14, 15].

However, the safety and efficacy of these vaccines outside a clinical trial setting have not yet been demonstrated and need to be evaluated in the real world setting in developing countries [90]. Any risks associated with the newly developed rotavirus vaccines will only be identified after further trials or post-licensure surveillance studies. Therefore, it is likely that post-licensure surveillance in countries that are introducing the rotavirus vaccines will be the final harbinger of the long-term success of the new generation rotavirus vaccines.

Costs and cost effectiveness of vaccines

The future utilization of the new rotavirus vaccines in the populations that need them most, will depend on costs of the vaccine and mechanisms for funding the vaccine procurement for these countries. In turn, this will depend on the cost effectiveness of the rotavirus vaccines. During the last few years, several studies to define the economic burden of rotavirus disease and the impact and cost effectiveness of rotavirus immunization have been conducted and have been reviewed, including studies in Asia [118, 119].

The main drivers of costs and cost effectiveness vary by setting, and were identified as the burden of disease, vaccine effectiveness, timing of vaccination, vaccine cost, additional immunization program costs, model structure, and study perspective. Nevertheless, by various measurements described by the World Bank as indicative of the "cost effectiveness" of vaccines, the new rotavirus vaccines are definitely seen as cost effective [118-120].

Supplies of vaccine and financing

GAVI will soon be reviewing an investment case for the potential future procurement of rotavirus vaccines for infants in some of the poorest coun tries of the world. The investment case has evaluated a demand forecasting model of the numbers of doses of vaccines required during the next decade, and has examined a range of pricing options for the costs of rotavirus vaccines for developing countries. Both industrial partners have committed to a tiered pricing of their vaccines.

The decision by GAVI whether to procure these vaccines for countries with the highest rotavirus mortality should impact directly on the Millennium Development Goals and help to reduce childhood mortality associated with rotavirus infection.

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