Worldwide, diarrhea is the second most common cause of fatal childhood disease, estimated to cause approximately 1.34 million deaths among children aged <5 years.1 Rotavirus is the leading cause of severe diarrhea in young children and is responsible for approximately one-third of all diarrheal deaths.2 Two effective rotavirus vaccines, a single-strain attenuated human rotavirus vaccine (Rotarix, GlaxoSmithKline Biologicals) and a multistrain bovine-human reassortant vaccine (RotaTeq, Merck and Company), are now available and recommended for routine immunization of all infants by the World Health Organization (WHO).3 Efficacy of these vaccines has ranged from 80% to 98% in industrialized countries,4–7 including Latin America, and 39% to 77% in developing countries, such as Africa and Asia.8–10 On the basis of efficacy data from Europe and America, the WHO initially approved use of the vaccines in these regions in 2006 and within 2 years several countries added rotavirus vaccination into their routine immunization programs. Subsequently, after proof of efficacy in Asia and Africa, the WHO recommendation was expanded to all infants worldwide in 2009.3
As rotavirus vaccines are implemented within national childhood immunization programs, evaluation of their effect is important for several reasons.11,12 First, routine immunization occurs in real-world conditions different from ideal clinical trial settings. Thus, monitoring postlicensure impact on rotavirus disease is crucial for ensuring that appropriate gains in terms of expected vaccination benefits are attained. Second, changes in the epidemiology of rotavirus disease might occur in the postlicensure era, such as shifts in average age at infection, seasonality of disease, and serotype distribution after vaccination or appearance of unusual genetic variants. Third, ensuring that protection is conferred through the first and second years of life when most severe disease and mortality from rotavirus occur will be crucial for the success of a rotavirus vaccination program. Finally, assessing whether vaccination has an affect on rotavirus transmission in the community, thus providing benefits to unvaccinated groups, is important. Monitoring impact with focus on these public health considerations will not only allow assessment of the effectiveness of rotavirus vaccines in routine use, but also generate the necessary evidence to inform public health policy decision-making and continued investment in rotavirus vaccines.
The articles in this supplement elegantly describe the experience of early-introducer countries in Europe, America, and Australia, and address these relevant postlicensure topics (Table 1). The effect of rotavirus vaccines on burden of severe childhood diarrhea in these early introducer countries has been rapid, easily measured, and substantial, demonstrating the health value of rotavirus vaccination. Two of the most interesting and unanticipated findings in the early rotavirus vaccine era have included indirect protection and changes in rotavirus seasonality.13,14 The lessons learned to-date will be valuable for other countries, considering the introduction of rotavirus vaccines into their childhood immunization programs.
HEALTH IMPACT OF ROTAVIRUS VACCINATION
Some of the questions related to vaccine performance, duration of protection, and indirect benefits can be answered by clinical trials, and targeted studies designed to specifically address a priori study questions. However, a more cost-efficient and practical assessment that comprehensively addresses the question of whether the country investments are providing intended results could include analysis of pre-existing databases to assess issues suitable for the needs of decision-makers and parents.12 The first set of articles in the supplement use existing databases to evaluate the health impact of rotavirus vaccination in a variety of low-middle, middle, and high income countries. Yen et al demonstrate a large reduction in laboratory-confirmed rotavirus disease that was sustained for 2 years after rotavirus vaccine introduction in El Salvador, a low-middle income country in Central America.15 Moreover, the substantial nationwide reductions in diarrhea from all causes, and of all severity, in this study show the overall value of vaccination for improving child health in developing regions of the world. In the neighboring country of Mexico, where a previously published study showed a large decline in diarrhea mortality after rotavirus vaccination,16 Quintanar-Solares et al also reported significant reductions in hospitalizations for childhood diarrhea during the winter months when rotavirus predominates, confirming the value of investments in vaccination in a large middle income setting.17 Similarly, impressive reductions in all-cause diarrhea hospitalizations were also observed by Molto et al in Panama, another middle-income country in the Americas.18 In the United States, Belgium, and Australia, data from national passive surveillance systems of rotavirus testing were evaluated by Tate et al,19 Braeckman et al,20 and Buttery et al,21 respectively, to illustrate that rotavirus vaccination has dramatically reduced childhood rotavirus disease within a year or 2 of vaccine introduction in these high income countries.
All in all, the countries represented in this section of the supplement have a combined birth cohort of ∼7 million infants, most of whom are now receiving rotavirus vaccination. The rigorous national-level data from these settings published in this supplement provide a real-world measure of the large toll of severe and fatal rotavirus disease that is preventable through rotavirus vaccination of these infants. The observed reductions in these early introducer countries suggest that the fraction of diarrhea caused by rotavirus is greater than that estimated on the basis of prevaccine surveillance, further emphasizing the importance of rotavirus as one of the most common cause of preventable childhood diseases.
INDIRECT BENEFITS (ie, HERD IMMUNITY) AFTER ROTAVIRUS VACCINATION
Indirect protection occurs as a result of decreased transmission of the infectious agent in the community, and amplifies the direct benefits of vaccination among both vaccinated and unvaccinated individuals.22 From the perspective of other diseases where large indirect benefits have been noted after routine vaccination (eg, pneumococcal), perhaps the findings of indirect benefits in El Salvador,15 United States,23 and Australia21 that are published in this supplement should not be surprising. However, the demonstration of indirect effects in several countries has led to a paradigm shift in our understanding of rotavirus transmission. Rotavirus is a highly infectious pathogen, suspected to be transmitted through the fecal-oral route, with repeat mild and asymptomatic infections being common throughout life.24–26 Although protection from natural rotavirus infection against subsequent severe disease is high, protection against infection and milder disease is lower.24 For these reasons, secondary spread of rotavirus infection occurs at a high rate after all primary and repeat infections, whether symptomatic or asymptomatic, leading to the suspicion that interruption of transmission would be unlikely to occur after rotavirus vaccination. However, the postvaccination data from the early years after vaccination indicate large reductions in rotavirus disease among members of age groups who are too old to be vaccinated.13–15,21,23 Because these indirect benefits are noted in the first or the second year after vaccine introduction when only infants are eligible to receive vaccination, these data potentially implicate infants as the primary transmitters of infection. That is, not all rotavirus infections transmit as efficiently as the first infection, which generally results in the most severe disease.
Why is it important to measure indirect benefits? Perhaps indirect benefits are less relevant in the longer term in industrialized countries where efficacy and coverage exceed 90%. In contrast, in developing country settings, where efficacy and coverage tend to be lower, a vaccine with indirect protection could provide substantially greater benefits than expected on the basis of direct efficacy. However, these vaccines would have to protect children from infection, not just from severe disease, for indirect protection to be realized. Although clinical trials show that rotavirus vaccines protect against severe rotavirus disease, the level of vaccine protection against infection is unknown in developing country settings. Population level impact data could help improve our understanding of rotavirus transmission dynamics in developing country settings and realize the full potential of these vaccines. If indirect benefits of rotavirus vaccination in industrialized settings were replicated in other poor regions of the world, this would be welcome news for oral rotavirus vaccines with lower efficacy in these challenging populations.
CHANGING EPIDEMIOLOGY AND SEASONALITY OF ROTAVIRUS DISEASE AFTER VACCINATION
Surveillance and disease monitoring after vaccine introduction can yield valuable information addressing issues relevant to a broader public health perspective, including duration of protection, changes in age-specific and seasonal incidence of disease, and timing of epidemics.12 For example, although rotavirus vaccines have shown sustained efficacy for first 2 to 3 years of life in the United States and Europe,4–7,27 preliminary data from developing countries indicate decrease in protection after the first year of life.8,10,28,29 However, from a public health perspective this decrease in protection may not be relevant for 2 reasons. First, a vast proportion of severe rotavirus disease (60%–80%) occurs by 12 to 15 months of age in these settings. Second, if indirect benefits occur in African and Asian countries, and infants experiencing their first rotavirus infection are the primary source of transmission of rotavirus, a higher protection during the first year of life could reduce transmission in the community and offset the effect of waning immunity among older individuals. Findings from El Salvador support this contention.15 In a recent study, vaccine effectiveness in El Salvador decreased from 82% during infancy to 59% among those older than 1 year of age.28 However, the study by Yen et al15 in this supplement indicated that the effect of the reduced protection on the total burden of disease was minimal.
The postlicensure studies from various regions in this supplement have also identified a remarkably consistent finding with regard to timing and spread of epidemics. The studies from the United States19 and Belgium20 show that in addition to the overall decline in epidemic peak, a shift in the onset of the epidemic by 1 to 2 months has occurred after rotavirus vaccination—during the 2010 rotavirus season in the United States, rotavirus activity was below the epidemic threshold, a finding that has never occurred in the 19 years of rotavirus surveillance within that system.30,31 In particular, Curns et al elegantly showed the impressive alterations in the spatiotemporal spread of rotavirus disease in the United States after vaccination.32 These findings might have some potential relevance for guiding surveillance programs in other countries. First, biennial epidemic peaks have been predicted to occur after rotavirus vaccination,33 thus emphasizing the need for ongoing surveillance in countries such as the United States, where marked reduction in disease has occurred in the first few years after vaccination. Second, in countries with seasonal epidemics of rotavirus, surveillance might need to be extended to the months of the year when rotavirus is not typically expected, to fully understand the public health importance of shifts in average age of cases and timing of epidemics. Finally, postvaccination data are not available from countries with less seasonal variation of rotavirus disease, and will be important to gather for understanding the epidemiological consequences of vaccination in those settings.
EFFECT OF VACCINATION ON ROTAVIRUS STRAINS
Three inter-related questions remain with regard to effect of vaccination on rotavirus strains. What is the serotype specific efficacy of the vaccines? Will rotavirus vaccination cause an emergence of unusual rotavirus strains or strains escaping vaccine protection? Will significant increases in disease burden occur that relate to strain changes after vaccination?
Two surface rotavirus proteins, VP7 (a glycoprotein—G protein) and VP4 (a protease-cleaved protein—P protein), induce homotypic and heterotypic neutralizing antibody responses that are suspected to partly provide protective immunity after natural infection and vaccination.25,34–36 However, it is important to note that immunity to rotavirus is not fully understood, and other rotavirus proteins (eg, VP6, NSP4) besides VP4 and VP7 have also been suspected to modulate immunity. Surveillance has lead to the characterization of at least 12 G types and 15 P types in human beings and because rotavirus has a segmented genome, gene reassortment could theoretically lead to almost 200 different G and P combinations. However, while >60 G-P combinations have been found in human beings, 5 strains (P, G1; P, G2; P, G3; P, G4; and P, G9) are associated with 80% to 90% of the childhood rotavirus disease burden globally.37–39 Of these common strains, the PG2 rotavirus strain belongs to a different G serotype, P subtype, and genogroup (defined by the total virus genome of 11 segments and not only the G and P types40) than the other globally common strains. Thus, PG2 strains also differ from the human monovalent vaccine strain, Rotarix, by G- and P-type and genogroup. PG2 strains also belong to a different P subtype and genogroup compared with the bovine-human pentavalent vaccine, RotaTeq, which contains a G2 reassortant but not the P reassortant.41 Although the pentavalent vaccine contains either the G or P antigen for all common strains, serotype-specific immune response ranged from ∼21% to 76% in the pivotal clinical trial with the lowest response against the PG3 reference strain.4 Therefore, the question of either vaccine providing sufficient cross-protection against the various strains is pertinent.
Similar to natural rotavirus infection, the pentavalent and the single-strain rotavirus vaccines both provided good cross-protection against the common circulating strains in trials in Europe and the United States. In the Latin American trial, the single-strain vaccine appeared to provide lesser protection against the fully heterotypic PG2 rotavirus strains (vaccine efficacy = 44%; 95% confidence interval [CI] ≤0–88),6 but it is important to note the wide confidence limits because the PG2 strain was not circulating in Latin America during the study period; only 7 cases of diarrhea occurred from this strain among the placebo group during the entire study period, and thus the study did not attain power to conclusively assess protection against this strain. However, in a 2-year efficacy study conducted in 6 European countries, the single strain vaccine provided 85% protection (95% CI = 24–98) against severe rotavirus gastroenteritis caused by PG2 strains.5 This finding was confirmed in a postlicensure vaccine effectiveness study from Brazil that was conducted during 2 years when PG2 strain circulation predominated.42 In this study, Rotarix effectiveness was 81% (95% CI = 47–93) against severe rotavirus disease caused by this strain during the first year of life. In a similar case-control study from Australia, during an outbreak of PG2-related gastroenteritis among an indigenous population, effectiveness of the single strain vaccine was 86% (95% CI = 24–98).43 The pentavalent vaccine has also been found to have high efficacy against all strains circulating in the clinical trials.4 Of note, a recently published postlicensure study from the United States reported high effectiveness of this vaccine against severe disease due to PG3 strain,44 against which lower neutralizing immune responses were previously noted.4 In more recently published trials from Asia and Africa, both vaccines had similar efficacy against a wide range of strains circulating during the study period.8,10
Against this background of good homo- and heterotypic protection vis-à-vis common circulating strains, 3 nationwide longitudinal strain surveillance studies in this supplement address the issue of strain ecology before and after routine childhood vaccination. Carvalho-Costa et al identified a nationwide predominance of PG2 strains in the first 2 years after introduction of the single strain vaccine in Brazil.45 In the United States, Hull et al noted a surge in PG3 strains after introduction of the pentavalent vaccine.46 In Australia, which uses both vaccines, Kirkwood et al observed a higher prevalence of PG2 strains in states who were exclusively using the single-strain vaccine compared with states with pentavalent vaccine introduction that had a higher prevalence of PG3 strains.47
Although intriguing, all authors appropriately caution against any strong conclusions with regard to role of vaccination in observing these strain changes postvaccination for several reasons. First, similar findings of periodic strain emergence in the absence of vaccination have been extensively documented in other settings and will likely continue to occur in the postlicensure period. Second, the strain changes in these settings were transient (1 or 2 years), and were followed by increase in prevalence of PG1, which is covered by both vaccines. And finally, vaccine effectiveness studies from all 3 settings have shown high effectiveness against hospitalizations related to these predominant strains (ie, PG2 in Brazil42 and Australia,43 and PG3 in the US44), and large nationwide declines in overall disease burden have been observed.14,48 These robust effectiveness data and the clinical trial efficacy suggest that a natural shift in strain, unrelated to vaccination, is the most plausible explanation for the observed short-term changes postvaccination. However, these studies highlight the need for robust longitudinal surveillance and epidemiologic studies to better assess long-term interaction between rotavirus vaccination and strain ecology. These longer term studies could help assess whether the continued high level of immunity to vaccine serotypes eventually leads to evolution of strains that evade vaccine immunity. Matthijnssens et al estimated that the worldwide spread of such escape mutants may not take more than a decade, supporting the need to conduct monitoring of strain ecology.49
WHERE DO WE GO FROM HERE?
Since the first introduction of rotavirus vaccines in national immunization programs in 2006, dramatic reductions in severe and fatal childhood diarrhea in a variety of low-middle, middle, and high income countries have been observed. The preponderance of existing data on vaccine efficacy and effectiveness support that both vaccines provide protection against severe rotavirus disease from a wide variety of circulating strains in industrialized and developing countries. The decline in deaths and hospitalizations after rotavirus vaccination in low-middle and middle income Latin American countries is perhaps a good litmus test for adequacy of vaccine performance in challenging target populations of Africa and Asia. Despite the lower efficacy of the vaccines in developing countries, trials have also shown that effect was greater in the poorest settings in terms of the absolute number of severe cases of rotavirus prevented through vaccination.9 It remains to be seen whether vaccination reduces transmission in developing country populations to a similar degree as observed in developed countries. If this pattern holds, greater total effectiveness than expected on the basis of direct protection could be attained in developing country settings.
All in all, the powerful data published in this supplement will allow parents, health care providers, and decision makers to appreciate the health benefits of vaccination in reducing the burden of severe rotavirus disease. Decision makers and donors worldwide should urgently recognize that strong reasons exist to introduce rotavirus vaccines today—these vaccines have had a substantial affect on diarrhea deaths and hospitalizations; therefore, they are recommended by WHO for all regions of the world; and donor funding is available for the poorest nations. The time to introduce these lifesaving interventions is now.
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