Global impact of rotavirus vaccines

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Global impact of rotavirus vaccines Expert Rev. Vaccines 9(4), 395–407 (2010)

Jacqueline E Tate†, Manish M Patel, A Duncan Steele, Jon R Gentsch, Daniel C Payne, Margaret M Cortese, Osamu Nakagomi, Nigel A Cunliffe, Baoming Jiang, Kathleen M Neuzil, Lucia H de Oliveira, Roger I Glass and Umesh D Parashar Author for correspondence National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, 1600 Clifton Rd. NE, MS-A47, Atlanta, GA 30333, USA Tel.: +1 404 639 4559 Fax: +1 404 639 8665 [email protected]

www.expert-reviews.com

The WHO has recently recommended the inclusion of rotavirus vaccine in the national immunization programs of all countries. In countries in the Americas, Europe and Australia that have adopted routine childhood immunization against rotavirus, significant reductions in the burden of severe childhood diarrhea have been observed. Besides protecting vaccinated children, disease rates also appear to be reduced in unvaccinated children, suggesting indirect benefits from vaccination (i.e., herd protection). Early clinical trial data from Africa and Asia are promising, and further efforts are needed to optimize the benefits of vaccination in developing countries where vaccines are likely to have their greatest impact. Keywords : diarrhea • rotavirus • rotavirus vaccination • vaccine effectiveness

Every year, over half a million children under 5 years of age die from rotavirus diarrhea, the most common cause of severe, dehydrating diarrhea worldwide. More than 80% of these rotavirus-related deaths occur in developing countries of sub-Saharan Africa and south Asia (Figure 1) [1–3] . Moreover, rotavirus is responsible for 25–50% of all diarrheal hospitalizations in both developing and developed countries, and 23  million outpatient healthcare encounters annually in young children [1] . Almost all children by 5 years of age will have been infected with rotavirus (Figure 2) . Owing to the tremendous global burden of rotavirus disease, development of vaccines against this pathogen has been a priority for the past three decades. Two live, orally administered rotavirus vaccines, RotaTeq® (Merck and Co., Inc., PA, USA and Sanofi Pasteur MSD SNC, Lyon, France) and Rotarix™ (GSK Biologicals, Rixensart, Belgium), with good efficacy against severe rotavirus disease and reassuring safety profiles in clinical trials [4,5] have been licensed in many countries worldwide. In 2006, WHO’s Strategic Advisory Group of Experts (SAGE) reviewed the results of the pivotal safety and efficacy trials for these vaccines conducted in the Americas and Europe and strongly recommended their inclusion into national immunization programs of countries in these regions [6] . In April and October 2009, SAGE reviewed additional efficacy data from trials in Africa and Asia, and postlicensure studies in the Americas, and extended the recommendation for vaccination to all regions of the world [7–9] . 10.1586/ERV.10.17

In this review, we briefly review the epidemiology of rotavirus and the history of vaccine develop­ment efforts. We then summarize early data on the effectiveness and impact of vaccin­ ation from high- and middle-income countries that have adopted routine childhood immun­ ization against rotavirus. Finally, we outline key outstanding questions and potential areas for further research, especially to optimize the benefits of vaccination in developing countries where vaccines are likely to have their greatest impact. Epidemiology of rotavirus

Rotavirus is a nonenveloped, dsRNA virus with a segmented genome [10,11] . The genotypes (glyco­ protein [G] and protease-cleaved [P] types) are defined by two structural viral proteins (VPs) in the outer capsid: VP4, the P protein; and VP7, the G protein. Natural fluctuations in genotype prevalence occur over time and by region of the world, with G1, G2, G3 and G4 being the most common genotypes worldwide. G9 emerged as a globally important strain in the 1990s and G12 strains have been documented in many countries over the last decade [12] . Rotavirus infects the proximal small intestine, resulting in destruction of the epithelial surface and blunting of the microvilli, leading to mal­ absorption and diarrhea [11] . A nonstructural protein (NSP4) of rotavirus acts as an enterotoxin in the mouse model and probably plays a role early in human disease pathogenesis [13] . The clinical spectrum of rotavirus disease in children ranges from mild, watery diarrhea of limited duration ISSN 1476-0584

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20-fold) and a smaller increased cine, Rotarix, is a monovalent, two-dose vaccine (RV1) based on risk (~fivefold) was also observed within 3–14 days after the sec- a single rotavirus strain of the most common human genotype, ond dose [49] . Overall, the risk of intus­susception was estimated as G1P[8], observed globally [56,57] . Both of these vaccines have been one case per 10,000 children vaccinated with RRV-TV [50] . evaluated in a variety of settings (Table 2) . Some researchers have suggested that the risk of intussusception associated with RRV-TV was age dependent and that the abso- Efficacy of RV5 & RV1 in pivotal prelicensure trials lute number of intussusception events and possibly the relative In clinical trials performed predominantly in the USA and risk of intus­susception associated with the first dose of RRV-TV Finland, RV5 reduced hospitalizations due to rotavirus gastroincreased with increasing age at vaccination [51,52] . However, the enteritis by 96% (95% CI: 91–98%), emergency department WHO Global Advisory Committee on Vaccine Safety (GACVS), visits by 94% (95% CI: 89–97%) and doctor’s office visits by after reviewing all the available data, concluded that there was a 86% (95% CI: 74–93%) [5] . While the per-protocol analysis high risk of RRV-TV-associated intus­susception in infants immu- examined the efficacy against G1–G4 strains, the majority of nized after day 60 and that insufficient evidence was available cases in the clinical trial were G1. Only sufficient numbers of to conclude that the use of RRV-TV at any age under 60 days cases were enrolled to detect significant serotype-specific effiwas associated with a lower risk [53] . The GACVS noted that the cacy against G1 and G2 strains but significant reductions in possibility of an age-dependent risk of intussusception should be rates of rotavirus hospitalizations and emergency department taken into account in testing future rotavirus vaccines. RRV-TV visits were detected for G1, G3, G4 and G9 [5] . The RV5 safety vaccine was voluntarily withdrawn from the market and is not in trial enrolled over 70,000 infants specifically to evaluate the use today. A Phase II trial to evaluate the safety, immunogenicity risk of intussusception. No association with this adverse event and potentially efficacy of two doses of RRV-TV administered to was found within 42 days after any dose of RV5 (relative risk young infants under the age of 2 months is ongoing in Ghana [54] . [RR]: 1.6; 95% CI: 0.4–6.4) [5] . www.expert-reviews.com

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Characteristic

RV5

RV1

Manufacturer

Merck & Co. (PA, USA)

GlaxoSmithKline (Rixensart, Belgium)

vaccines were subsequently introduced into numerous countries in the Americas, Europe and Australia, and Phase III clinical trials of both candidate vaccines were conducted in Africa and Asia.

Parent strain

Bovine rotavirus strain WC3, type G6P7[5]

Human rotavirus strain 89–12, type G1P1A[8]

Efficacy of RV5 & RV1 in Africa & Asia

Five reassortants: G1xWC3, G2xWC3, G3xWC3, G4xWC3, P1A[8]xWC3

No reassortants

Table 1. Characteristics of available rotavirus vaccines.

Phase  III clinical trials for RV1 were performed in South Africa and Malawi, and Phase  II immunogenicity studies for RV1 were conducted in Bangladesh. 6 6 Vaccine titer ≥2.0–2.8 × 10 infectious units ≥10 median cell culture Trials for RV5 were performed in Kenya, per strain, depending on infective dose after Ghana, Mali, Bangladesh and Vietnam. serotype (1.15 × 107 infectious reconstitution, per dose Vaccine performance with both vaccines units per dose) was observed to be lower in these setting Method of attenuation Naturally attenuated (animal Passaged 43-times when compared with the pivotal studies strain); passage varied by described in previous sections. In South reassortant 7–69-times Africa, two doses of RV1 administered to Cell culture substrate Vero cells Vero cells infants at 10 and 14 weeks of age were 72% Dose volume (ml) 2 1 (95% CI: 40–88%) efficacious in preventBuffer Sodium citrate and phosphate Calcium carbonate ing severe rotavirus gastroenteritis and efficacy increased to 82% (95% CI: 55–94%) Dose regimen Three oral doses Two oral doses when a three-dose schedule administered at Shedding following 9–21 35–80 6, 10 and 14 weeks was used [7,62] . In Malawi, first dose (%) the two- and three-dose schedules of RV1 RV: Rotavirus yielded similar results with a two-dose vacAdapted from [97]. cine efficacy of 49% (95% CI: 11–72%) RV1 was 85% (95% CI: 71–93%) efficacious in preventing severe and three-dose vaccine efficacy of 50% (95% CI: 11–72%) [7,62] . (Vesikari score ≥11) rotavirus gastroenteritis during the first year of However, the background rates of rotavirus disease were much life in clinical trials in Latin America and 96% (95% CI: 90–99%) greater in Malawi than in South Africa, so despite a lower effieffective against severe disease in clinical trials in Europe [4,58] . No cacy the vaccine was able to prevent 3.9 episodes of severe rotavirisk of intussusception in the 30 days post-RV1 vaccination was rus gastroenteritis per 100 vaccinated children in Malawi versus observed (RR: 0.85; 95% CI: 0.30–2.42)  [4] . In Latin America, 2.5 episodes per 100 vaccinated children in South Africa [7,62] . while fully heterotypic G2P[4] strains that share neither G nor Preliminary results for the clinical trials for RV5 showed similar P type with the RV1 vaccine strain were uncommon, protection variability by setting as the RV1 trials although the methodology appeared to be lower (44%; 95% CI: 16, efficacy against types G1–G4

[5]

USA and Finland

RV5

Efficacy

74 (67–80)

Any severity; efficacy against types G1–G4

[5]

Finland

RV1

Efficacy

90 (10–100)

Vesikari score ≥11

[104]

Finland and Latin America

RV1

Efficacy

85 (75–92)

Vesikari score ≥11

[4]

Europe

RV1

Efficacy

87 (80–92)

Any severity

[58]

Finland

RV1

Efficacy

73 (27–91)

Any severity

[104]

USA

RV5

Effectiveness

88 (68–96)

Hospitalization and ED visit

[64]

Australia

RV1

Effectiveness

85 (23–97)

Hospitalization in indigenous population

[69]

Brazil

RV1

Effectiveness

79 (74–82)

Hospitalization and ED visit; efficacy against G2P[4]

[75]

Brazil

RV1

Effectiveness

85 (54–95)

Hospitalization; efficacy against G2P[4]

[77]

Nicaragua

In Nicaragua, one of the poorest countries in Latin America and eligible for support for vaccine purchase from the GAVI Alliance, a case–control evaluation found that RV5 was 52–63% effective in preventing severe rotavirus gastroenteritis (Vesikari score ≥11) and 73–86% effective in preventing very severe rotavirus gastroenteritis (Vesikari score ≥15) in the first year post vaccine introduction, during a season with G2P[4] rotavirus predominance [79] . During the 2007 rotavirus season in Nicaragua when coverage with at least two doses among children under 12 months of age was still low at approximately 26%, hospitalizations and healthcare visits for diarrhea of any cause declined by 11 and 23%, respectively, compared with the prevaccine baseline [80] . Safety of rotavirus vaccines

Middle-low and low income

Although neither RV5 nor RV1 were associated with intussusception during the clinical trials, post-introduction monitoring of vaccine safety is necessary as a low [8] Africa (Kenya, RV5 Efficacy 64 (40–79) Vesikari score ≥11 level of risk cannot yet be excluded. The Ghana, Mali) USA has conducted postlicensure moni[7] Africa (South RV1 Efficacy 62 (44–73) Vesikari score ≥11 toring since the introduction of RV5 in Africa, Malawi) 2006 through the Vaccine Adverse Events [79] Nicaragua RV5 Effectiveness 46 (18–64) Hospitalization Reporting System, a national passive sur[7] El Salvador RV1 Effectiveness 76 (64–84) Hospitalization veillance system and through the Vaccine † VE stands for vaccine efficacy or vaccine effectiveness, depending on the type of study. Safety Datalink, a cohort of children ED: Emergency department; RV: Rotavirus. enrolled in a managed care network. To all-cause diarrhea mortality among infants in this age group [78] . date available data from these systems do not suggest a risk of Moreover, a 23% reduction was also observed among older chil- intussusception after receipt of RV5 but continued monitoring dren 12–23 months of age who were largely ineligible for rotavi- is necessary as a low level of risk has not yet been excluded for rus immunization [78] . Sustained reduction in mortality among RV5 and additional data are still needed for RV1 [81,82] . As more children under 2 years of age in 2009 and blunting of the sea- countries introduce rotavirus vaccines, continued monitoring is sonal peak in diarrhea deaths when rotavirus is most prevalent in important. While there are no data to suggest that there would Mexico provided further supporting evidence for vaccine effect as be regional differences in risk ratios for intussusception after the major contributing factor towards this reduction in all-cause vaccin­ation, differences in background rates of intussusception gastroenteritis mortality. could result in differences in attributable risk, if any risk after vaccin­ation did exist [83] . El Salvador Vaccine-acquired rotavirus disease after RV5 administration in In El Salvador, a low-to-middle-income country in Central three infants with severe combined immunodeficiency (SCID) America, a case–control evaluation of RV1 effectiveness found has recently been reported suggesting that rotavirus vaccine may that this vaccine was 74% effective against severe rotavirus gas- cause disease in severely immunocompromised children [84] . SCID troenteritis (Vesikari score ≥11) and 88% effective in preventing is now included as a contraindications for RV5 [85] . Rotavirus very severe rotavirus gastroenteritis (Vesikari score ≥15) [7] . The vaccine is not contraindicated for children with other types of Asia (Vietnam, Bangladesh)

400

RV5

Efficacy

51 (13–73)

Vesikari score ≥11

[8]

Expert Rev. Vaccines 9(4), (2010)

Global impact of rotavirus vaccines

immuno­deficiencies but few data are available [85] . HIV-infected and -exposed infants were included in the RV1 clinical trials and no significant safety concerns were identified [62] . Global introduction of rotavirus vaccines

The 2009 global recommendation by the WHO for the inclusion of rotavirus vaccines in the routine childhood vaccine programs in all countries, and specifically in countries where the diarrheal proportion of under-5-year-old mortality is 10% or more [7,9] , is a significant step towards fully utilizing these vaccines. Several other important developments have occurred which will enhance the global impact of these rotavirus vaccines on childhood mortality as they are introduced more widely. First, the efficacy of RV5 and RV1 vaccines in developing countries, although moderate, has demonstrated that the vaccines have a substantial public health impact on disease in these settings where the highest rates of rotavirus mortality occur. Rotavirus vaccines significantly reduced serious rotavirus gastroenteritis in resource-poor settings in Africa and Asia, where the attack rate for severe and fatal rotavirus diarrhea is high. The protection occurred in settings where multiple G and P types circulated, where nonvaccine strains predominated, and where vaccine was administered to children under ‘real world conditions’ – concomitant administration with oral polio vaccine (OPV), no restrictions on breastfeeding and inclusion of children exposed to HIV infection [62] . Significantly, the vaccines do not interfere with the immune response to OPV vaccines [86,87] . These results are very encouraging about the potential for rotavirus vaccines to reduce the significant morbidity and mortality due to rotavirus diarrhea in the world’s poorest children. Second, the currently available vaccines have been shown to be safe with respect to intussusception and other serious adverse events. Recent recommendations by SAGE and the WHO GACVS have relaxed the restriction on the age window for vaccine administration. The SAGE recommendations extend the administration of the first dose of vaccine up to 15 weeks of age, similar to the US Advisory Committee on Immunization Practices (ACIP) recommendations and the last dose of either the two-dose RV1 or the three-dose RV5 vaccine should be administered by 32 weeks of age [7,63] . This expanded age recommendation would increase vaccine coverage in developing countries where children often present late for their routine childhood vaccinations [88,89] . Third, GAVI approved the inclusion of rotavirus vaccines for vaccine subsidy in GAVI-eligible countries and has requested ‘letters of interest’ from countries wanting rotavirus vaccines. Several African and Asian countries submitted proposals to GAVI for review in late 2009. While subsidization by GAVI will make it financially feasible for early adopter countries to use the current rotavirus vaccines, the long-term sustainability of vaccine purchase for all GAVI-eligible countries cannot be guaranteed. The GAVI subsidy of rotavirus vaccine means that the UNICEF will be able to negotiate lower prices for low-income countries, but this support for the vaccines ends in 2015, and countries will be expected to cover the whole cost once the GAVI subsidy closes. www.expert-reviews.com

Review

Coordinated efforts with GAVI, the manufacturers and other international partners are needed to ensure the affordability of rotavirus vaccines for low and lower middle-income countries, both now and in the future. Rotavirus vaccines are poised to make a significant public health impact on rotavirus-associated mortality in developing countries, and as funding subsidies are made available and effectiveness data are generated in early adopter countries showing the impact of the vaccines, continued introduction of the vaccines in additional countries is probable. Evaluating & improving performance of rotavirus vaccines in developing countries

While rotavirus vaccines are likely to have a tremendous impact on rotavirus disease in developing countries, live, oral vaccines have had an inconsistent history in the developing world. For example, OPV is less immunogenic and more doses are required to protect children in India and other developing countries compared with children in the developed world [90–92] . Similarly, an oral cholera vaccine was found to be less immunogenic and a higher titer of the vaccine was needed to offer protection against disease in developing countries in Asia and Latin America [93,94] . Early rotavirus vaccines also faced challenges in the developing world, and several candidate rotavirus vaccines (RIT4237, WC3, RRV and RRV-TV) had lower or no measurable efficacy in clinical trials in South America and Africa than in Europe and North America [37–40,95] . Even in clinical trials and in routine use in immunization programs, the effectiveness of current rotavirus vaccines has been inversely correlated with the childhood mortality level in the country where the trial was conducted. Similarly, immune response to RV1, which has been more widely tested in the developing world, appears to decrease with decreasing income level of the country [96] . The reasons why live, oral rotavirus vaccines are less efficacious in developing countries are not clear and are probably multi­faceted [97] . First, children in these countries often have distinct medical conditions from those typically seen among children in the developed world. For example, a higher prevalence of co­morbid infections in young children – HIV, malaria, tuberculosis and intestinal infections with other microorganisms – may adversely affect vaccine performance. Second, malnutrition is more common and may influence vaccine effectiveness. Third, in these developing country settings, levels of maternal rotavirus anti­bodies are passively transferred to babies during gestation and still present in infancy. Furthermore, rotavirusvaccine neutralizing activity of breast milk is usually higher than in developed countries, and may reduce vaccine titer and adversely affect vaccine take; however, further studies are needed to confirm this [98,99] . Also, rotavirus vaccine is almost always administered on the same schedule as OPV, and some data suggest that the immune response to the first dose of rotavirus vaccine in particular could be somewhat reduced when given concomitantly with the first dose of OPV [86,100] . Finally, the diversity of circulating strains in Africa and Asia is substantial and different from that seen in the Americas and Europe [101,102] . 401

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Globally, G1P[8] is the most predominant strain causing over 70% of rotavirus infections in North America, Europe and Australia but causes only 30% of rotavirus infections in South America and Asia, and 23% in Africa [101] . In parts of Asia and Africa, G9 strains have emerged as the predominantly circulating strain and G8 strains are isolated with increasing frequency in Africa as well [103] . While the vaccines have demonstrated protection against the most commonly circulating strains (G1–G4 and G9), effectiveness against less common strains has not been fully evaluated [5,58,59,104] . Thus, despite the promising efficacy data from the clinical trials in Africa and Asia, many unanswered questions about vaccine effectiveness and how to improve vaccine performance in these settings remain. As vaccines are introduced into the routine immunization programs in Africa and Asia, ongoing monitoring is critical since vaccine performance varied by setting in clinical trials. Thus, to fully understand the impact of rotavirus vaccine introduction in developing countries, several key epidemiologic issues should be monitored including vaccine performance against severe disease during routine use, vaccine impact on rotavirus disease epidemiology, including changes in burden of severe disease and death, age distribution of cases, seasonality and serotype distribution, indirect benefits for unvaccinated children, and duration of protection [105] . Careful consideration of these issues prior to vaccine introduction will enable development of surveillance systems capable of capturing the full impact of the vaccine program. Initiation of population-based surveillance in a variety of high-disease-burden settings prior to vaccine introduction will enable calculation of baseline rates of disease, hospitalization, and death due to allcause diarrhea and rotavirus gastroenteritis, and documentation of currently circulating strains. After vaccine introduction, these surveillance platforms will enable monitoring of changes in rates of mortality and morbidity, and any shifts in circulating strains as well as serve as a basis for vaccine effectiveness evaluations. Furthermore, these platforms can be used to explore reasons for lower efficacy of rotavirus vaccines in developing countries in contrast to middle- and high-income countries, and to examine the usefulness of potential ways to improve vaccine performance, such as delaying age at first vaccination by 4–6 weeks to reduce interference by maternal antibodies, offering neonatal vaccination to target early disease, increasing the number of doses, altering breastfeeding practices immediately preceding and following immunization, and using zinc or probiotic supplementation to improve the mucosal response to vaccination. The long-term impact of vaccines on circulating strains is unknown and continuous surveillance will be needed to address this issue [12,106] . Studies in countries that have introduced rotavirus vaccines have, in some cases, reported higher prevalence of G2P[4] where RV1 is being used and an increase in G3P[8] where RV5 is in use. However, information to date suggests that these trends may simply reflect natural strain variation rather than escape from vaccine immunity [75,107–113] . Long-term vaccine effectiveness studies could provide a good platform to continuously assess levels of protection against individual serotypes to determine whether 402

strain evolution leads to reduced vaccine effectiveness. Since the rate at which potential strains that evade immunity evolve in an immune population is unknown, conducting such investigations over a period of years after high vaccine uptake has been achieved may be important. Accompanying genetic characterization of rotaviral strains from effectiveness studies will be important to assess possible immune escape mechanisms. To have optimal public health impact, vaccines should protect against severe rotavirus disease during the period when most severe disease occurs, the first 2 years of life in developing countries and the first 3 years of life in developed countries. Data from Europe and Latin America suggest that there is a slight decrease in efficacy from the first to the second rotavirus season of follow-up, but overall protection was sustained at reasonable levels [5,58,59,104] . This decrease in efficacy might be greater in the developing world but further data are needed. Effectiveness of partial vaccination is also important as some severe disease occurs prior to completion of the full series and protection against breakthrough disease is important. Several additional rotavirus vaccines are currently in various stages of development including vaccines based on neonatal rotavirus strains in India [114,115] and Australia [116,117] ; a neonatal dosing schedule of the previously withdrawn RRV-TV to address the intussusception issue [118] ; and a designer vaccine based on a bovine strain that could include additional serotypes such as G8 and G9, which are common in some developing countries [119] , and that has been licensed to vaccine manufacturers in Brazil, China and India. These vaccines may offer less expensive alternatives to the currently available vaccines. Neonatal rotavirus strains have been found in nosocomial outbreaks of asymptomatic infections in newborn units. However, neonatal rotavirus strains usually do not cause disease in infants and have been shown to protect against severe rotavirus disease on reinfection [120,121] . A live, oral vaccine based on a lamb rotavirus strain has been used in China since 2001 but only limited data on safety, immunogenicity and effectiveness of this vaccine are available, which limits its wider use in other immunization programs [122,123] . In addition to these potential new oral vaccines, alternative approaches to rotavirus vaccine administration such as rotavirus antigens for parenteral delivery are also being explored so as to avoid a theoretical risk of intussusception [124–129] . A parenterally administered vaccine is not susceptible to risk factors (e.g., breastfeeding and interference from other floras in the gut) associated with live oral vaccines and thus could be equally immunogenic and effective in children in low-income countries. Expert commentary

Two live, oral rotavirus vaccines are currently available. These vaccines have shown high postlicensure effectiveness in high- and middle-income countries. Furthermore, increasing vaccine coverage has been correlated with decreases in diarrhea and rotavirus morbidity in these settings. Early data from clinical trials in Africa and Asia suggest that vaccines will have moderate efficacy in these settings, but even a moderately effective vaccine would have a substantial public health impact in these settings Expert Rev. Vaccines 9(4), (2010)

Global impact of rotavirus vaccines

with high disease burden. Thus, the WHO has recommended that rotavirus vaccines be introduced into the national immuni­ zations programs of all countries worldwide. To improve vaccine performance and achieve the greatest public health impact, additional research is needed to ensure that these vaccines reach their fullest potential.

Review

in burden of severe disease and death, age distribution of cases, seasonality and serotype distribution, herd protection for unvaccinated children, and duration of protection. This information will enable us to use vaccines to their fullest potential. Financial & competing interests disclosure

Nigel A Cunliffe has received research grant support and lecture fees from GSK Biologicals and SPMSD. Osamu Nakagomi has received research grants from GlaxoSmithKline and Banyu Pharmatheuticals. Jacqueline E Tate, Manish M Patel, A Duncan Steele, Jon R Gentsch, Daniel C Payne, Margaret M Cortese, Baoming Jiang, Roger I Glass and Umesh D Parashar do not have any relevant disclosures. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Five-year view

Postlicensure data showing high effectiveness of rotavirus vaccines in routine use in high- and middle-income countries and promising efficacy data from clinical trials in Africa and Asia suggest that rotavirus vaccine will have substantial impact on global rotavirus morbidity and mortality as these vaccines are introduced into countries’ national immunization programs. However, to reap the full benefit of rotavirus vaccination, further study of rotavirus vaccines in developing countries should continue to explore ways to improve vaccine performance in settings where rotavirus morbidity and mortality is highest. Specifically, these studies could examine the Key issues impact that delaying age at first vaccination, • Two live, orally administered rotavirus vaccines are currently available for use. offering neonatal vaccination, increasing • The WHO recommends the inclusion of rotavirus vaccines in the national immunization the number of doses, altering breastfeedprograms of all countries. ing practices, and using zinc or probiotic • Clinical trials and postlicensure monitoring in high- and middle-income countries have supplementation will have on vaccine perfound rotavirus vaccines to be highly effective against rotavirus gastroenteritis and formance. In addition, new data will enable demonstrate substantial public health impact. us to further understand the impact of the • Studies of rotavirus vaccines in low-income countries have shown moderate efficacy, introduction of rotavirus vaccine on key but even a moderately effective vaccine will have substantial public health benefit in these high-burden settings. epidemiological issues including vaccine performance against severe disease during • Further study of rotavirus vaccines in low-income countries is needed to determine the potential impact of immunization against rotavirus in these settings and identify ways routine use, vaccine impact on rotavirus to improve impact. disease epidemiology, including changes showing that the monovalent rotavirus vaccine is efficacious against severe rotavirus disease.



Presents recommendation of the WHO to include rotavirus vaccine in the national immunization programs of all countries.

5

Vesikari T, Matson DO, Dennehy P et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N. Engl. J. Med. 354(1), 23–33 (2006).

9

Meeting of the Strategic Advisory Group of Experts on immunization, October 2009 – conclusions and recommendations. Wkly Epidemiol. Rec. 84(50), 517–532 (2009).

10



Presents results from large Phase III clinical trials in developed countries showing that the pentavalent rotavirus vaccine is efficacious against severe rotavirus disease.

Estes MK, Cohen J. Rotavirus gene structure and function. Microbiol. Rev. 53(4), 410–449 (1989).

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Estes MK, Kapikian AZ. Rotaviruses. In: Field’s Virology (5th Edition). Knipe DM, Howley PM (Eds). Lippincott, Williams and Williams, PA, USA, 1917–1958 (2007).

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Gentsch JR, Parashar UD, Glass RI. Impact of rotavirus vaccination: the importance of monitoring strains. Future Microbiol. 4, 1231–1234 (2009).

13

Ball JM, Tian P, Zeng CQ, Morris AP, Estes MK. Age-dependent diarrhea induced by a rotaviral nonstructural glycoprotein. Science 272(5258), 101–104 (1996).

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Parashar UD, Gibson CJ, Bresse JS, Glass RI. Rotavirus and severe childhood diarrhea. Emerg. Infect. Dis. 12(2), 304–306 (2006).

2

Parashar UD, Burton A, Lanata C et al. Global mortality associated with rotavirus disease among children in 2004. J. Infect. Dis. 200(Suppl. 1), S9–S15 (2009).

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Glass RI, Bresee JS, Turcios R, Fischer TK, Parashar UD, Steele AD. Rotavirus vaccines: targeting the developing world. J. Infect. Dis. 192(Suppl. 1), S160–S166 (2005). Ruiz-Palacios GM, Perez-Schael I, Velazquez FR et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N. Engl. J. Med. 354(1), 11–22 (2006). Presents results from large Phase III clinical trials in developed countries

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Conclusions and recommendations from the Immunization Strategic Advisory Group. Wkly Epidemiol. Rec. 81(1), 2–11 (2006). Meeting of the immunization Strategic Advisory Group of Experts, April 2009 – conclusions and recommendations. Wkly Epidemiol. Rec. 84(23), 220–236 (2009). Rotavirus vaccines: an update. Wkly Epidemiol. Rec. 84(51–52), 533–540 (2009).

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Jon R Gentsch, PhD National Center for Immunization and Respiratory Diseases, US CDC, Atlanta, GA, USA



Daniel C Payne, PhD, MSPH National Center for Immunization and Respiratory Diseases, US CDC, Atlanta, GA, USA



Margaret M Cortese, MD National Center for Immunization and Respiratory Diseases, US CDC, Atlanta, GA, USA



Osamu Nakagomi, MD, PhD Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan

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Nigel A Cunliffe, MBChB, PhD Department of Medical Microbiology and Genitourinary, Medicine, University of Liverpool, Liverpool, UK



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Parashar UD, Hummelman EG, Bresee JS, Miller MA, Glass RI. Global illness and deaths caused by rotavirus disease in children. Emerg. Infect. Dis. 9(5), 565–572 (2003).

Baoming Jiang, PhD National Center for Immunization and Respiratory Diseases, US CDC, Atlanta, GA, USA



Kathleen M Neuzil, MD, MPH Rotavirus Vaccine Program, PATH, Seattle, WA, USA



Lucia H de Oliveira Immunization Unit, Family and Community Health, Pan American Health Organization, 525 23rd Street NW, Washington, DC 20037, USA



Roger I Glass, MD, PhD Fogarty International Center, NIH, Bethesda, MD, USA



Umesh D Parashar, MBBS, MPH National Center for Immunization and Respiratory Diseases, US CDC, Atlanta, GA, USA

Affiliations •

Jacqueline E Tate, PhD National Center for Immunization and Respiratory Diseases, US CDC, 1600 Clifton Rd. NE, MS-A47, Atlanta, GA 30333, USA Tel.: +1 404 639 4559 Fax: +1 404 639 8665 [email protected]



Manish M Patel, MD, MSc National Center for Immunization and Respiratory Diseases, US CDC, Atlanta, GA, USA



A Duncan Steele, PhD Rotavirus Vaccine Program, PATH, Seattle, WA, USA

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