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8 global impact of rv vaccines expt rev vaccines 2010

  1. 1. Review For reprint orders, please contact reprints@expert-reviews.com Global impact of rotavirus vaccines Expert Rev. Vaccines 9(4), 395–407 (2010)Jacqueline E Tate†, The WHO has recently recommended the inclusion of rotavirus vaccine in the nationalManish M Patel, immunization programs of all countries. In countries in the Americas, Europe and Australia thatA Duncan Steele, have adopted routine childhood immunization against rotavirus, significant reductions in the burden of severe childhood diarrhea have been observed. Besides protecting vaccinated children,Jon R Gentsch, disease rates also appear to be reduced in unvaccinated children, suggesting indirect benefitsDaniel C Payne, from vaccination (i.e., herd protection). Early clinical trial data from Africa and Asia are promising,Margaret M Cortese, and further efforts are needed to optimize the benefits of vaccination in developing countriesOsamu Nakagomi, where vaccines are likely to have their greatest impact.Nigel A Cunliffe,Baoming Jiang, Keywords : diarrhea • rotavirus • rotavirus vaccination • vaccine effectivenessKathleen M Neuzil, Every year, over half a million children under In this review, we briefly review the epide-Lucia H de Oliveira, 5 years of age die from rotavirus diarrhea, the miology of rotavirus and the history of vaccineRoger I Glass and most common cause of severe, dehydrating development efforts. We then summarize earlyUmesh D Parashar diarrhea worldwide. More than 80% of these data on the effectiveness and impact of vaccin-† Author for correspondence rotavirus-related deaths occur in developing ation from high- and middle-income countriesNational Center for countries of sub-Saharan Africa and south Asia that have adopted routine childhood immun-Immunization and Respiratory (Figure 1) [1–3] . Moreover, rotavirus is responsible ization against rotavirus. Finally, we outline keyDiseases, Centers for DiseaseControl and Prevention, 1600 for 25–50% of all diarrheal hospitalizations in outstanding questions and potential areas forClifton Rd. NE, MS-A47, Atlanta, both developing and developed countries, and further research, especially to optimize the ben-GA 30333, USA 23 million outpatient healthcare encounters efits of vaccination in developing countries whereTel.: +1 404 639 4559 annually in young children [1] . Almost all chil- vaccines are likely to have their greatest impact.Fax: +1 404 639 8665 dren by 5 years of age will have been infectedjqt8@cdc.gov with rotavirus (Figure 2) . Epidemiology of rotavirus Owing to the tremendous global burden of Rotavirus is a nonenveloped, dsRNA virus with a rotavirus disease, development of vaccines against segmented genome [10,11] . The genotypes (glyco- this pathogen has been a priority for the past three protein [G] and protease-cleaved [P] types) are decades. Two live, orally administered rotavirus defined by two structural viral proteins (VPs) in vaccines, RotaTeq® (Merck and Co., Inc., PA, USA the outer capsid: VP4, the P protein; and VP7, and Sanofi Pasteur MSD SNC, Lyon, France) the G protein. Natural fluctuations in genotype and Rotarix™ (GSK Biologicals, Rixensart, prevalence occur over time and by region of the Belgium), with good efficacy against severe rota- world, with G1, G2, G3 and G4 being the most virus disease and reassuring safety profiles in clini- common genotypes worldwide. G9 emerged as a cal trials [4,5] have been licensed in many countries globally important strain in the 1990s and G12 worldwide. In 2006, WHO’s Strategic Advisory strains have been documented in many countries Group of Experts (SAGE) reviewed the results over the last decade [12] . of the pivotal safety and efficacy trials for these Rotavirus infects the proximal small intestine, vaccines conducted in the Americas and Europe resulting in destruction of the epithelial surface and strongly recommended their inclusion into and blunting of the microvilli, leading to mal- national immunization programs of countries absorption and diarrhea [11] . A nonstructural pro- in these regions [6] . In April and October 2009, tein (NSP4) of rotavirus acts as an enterotoxin in SAGE reviewed additional efficacy data from tri- the mouse model and probably plays a role early als in Africa and Asia, and postlicensure studies in in human disease pathogenesis [13] . The clinical the Americas, and extended the recommendation spectrum of rotavirus disease in children ranges for vaccination to all regions of the world [7–9] . from mild, watery diarrhea of limited durationwww.expert-reviews.com 10.1586/ERV.10.17 ISSN 1476-0584 395
  2. 2. Review Tate, Patel, Steele et al. <10 deaths per 100,000 10–50 deaths per 100,000 50–100 deaths per 100,000 100–500 deaths per 100,000 Figure 1. Estimated rotavirus mortality rates in children under 5 years of age worldwide. Adapted with permission from [2] .to severe diarrhea with vomiting and fever that, in some children, food or water, but these improvements have had a lesser impactcan result in rapid dehydration with shock, electrolyte imbalance on infection with rotavirus, which is most commonly spread fromand death [14–17] . Natural rotavirus infections may commonly person to person [14,23–27] . Instead, early studies that followedspread beyond the intestines into the blood stream, causing sys- cohorts of children in their first 2–3 years of life identified epi-temic viremia [18–22] . Rotavirus antigen has been detected in the demiologic features of rotavirus that indicated the disease mightserum of greater than 90% of rotavirus-positive children until best be controlled through vaccination. Specifically, these studiesapproximately 5 days following symptom onset [18] . demonstrated that children previously infected with rotavirus Although rotavirus infects virtually all children by 5 years of age were protected against subsequent disease. Protection was great-in both developed and developing countries, there are significant est against moderate-to-severe disease and the level of protectiondifferences between the two settings in terms of the age at which increased with each new infection [23,28] . These data implied thatdisease first occurs, the seasonality of rotavirus illness, the distribu- an attenuated rotavirus vaccine that mimics natural infectiontion of serotypes and the proportion of severe outcomes, particularly could provide protection against disease and that multiple vaccinemortality. In high-income countries, few children die from rota- doses would probably be required to confer optimal protection.virus and, globally, most children who die each year from rotavirusinfection are from low-income countries [1] . The increased risk of Historymortality in low-income settings is probably due to a combination Since early animal models suggest that local intestinal immu-of factors, including limited access to healthcare (hydration therapy) nity is important in protection from disease, rotavirus vaccineand a greater prevalence of malnutrition and other comorbidities. development has focused on orally administered vaccines [29] . First- generation rotavirus vaccines used a ‘Jennerian’ approach whereRotavirus vaccines vaccines were developed using animal rotavirus strains that areImprovements in sanitation and hygiene have had a great impact naturally attenuated for humans and whose serotypes were hetero-on reducing diarrheal disease and deaths due to bacterial and typic compared with the most common human rotaviruses [30] .parasitic agents that are spread primarily through contaminated The performance of these vaccines was variable, with high efficacy396 Expert Rev. Vaccines 9(4), (2010)
  3. 3. Global impact of rotavirus vaccines Reviewagainst severe rotavirus disease in Finlandbut little or no efficacy in developing coun-tries [31–40] . The best efficacy in a developingcountry setting of one such vaccine, a rhesus 527,000 deathsrotavirus vaccine, was observed for a clinicaltrial in Venezuela where the serotype of thepredominate circulating G3 strain matched 2.3 million hospitalizationsthe serotype of the vaccine [41,42] . This find-ing suggested that serotype-specific immu-nity might be required to achieve optimal 23 million outpatient visitsprotection and led to efforts to developsecond-generation multivalent vaccines. Second-generation rotavirus vaccines used 114 million episodesa ‘modified Jennerian’ approach where anaturally attenuated animal strain was usedas the backbone for the vaccine and genescoding for the most common human rota-virus G types were substituted for the ani-mal rotavirus G type by reassortment in cell Figure 2. Global rotavirus disease burden.culture [30] . Pivotal clinical efficacy studies Adapted from [130] .of the rhesus human rotavirus reassortantvaccine were conducted in Finland, the USA and Venezuela, where Currently licensed pentavalent (RotaTeq, RV5) &the vaccine showed 91, 82 and 88% efficacy against severe rotavirus monovalent (Rotarix, RV1) rotavirus vaccinesgastroenteritis during the first year of follow-up, respectively [43–45] . Despite the setback with the withdrawal of a licensed and recom- In August 1998, a rhesus-based, tetravalent rotavirus vaccine mended rotavirus vaccine, the burden of rotavirus disease was still(RRV-TV) with three of the four common human rotavirus G types deemed substantial by the public health community and develop-(G1, G2 and G4) and the rhesus parent with G3 closely related to ment of other rotavirus vaccines continued. In 2006, results fromthe human G3, the fourth common serotype, was introduced in the clinical trials of two new rotavirus vaccines were published [4,5] .USA [46] . By May 1999, almost 1 million doses of the vaccine had Both are live, attenuated, orally administered vaccines (Table 1) .been administered [46] . In July 1999, the vaccination program was One, RotaTeq is a pentavalent, human–bovine reassortant vac-suspended after the vaccine was associated with a rare adverse event, cine (RV5) that contains a bovine rotavirus backbone with singleintussusception, a form of bowel obstruction in which one por- human rotavirus gene substitutions for each of the five commontion of the bowel telescopes into a distal portion [47,48] . In the first G and P human rotavirus genotypes (G1, G2, G3, G4 and P[8])3–14 days after receipt of the first dose of RRV-TV, risk of intus- and is administered on a three-dose schedule [55] . The second vac-susception was most elevated (>20-fold) and a smaller increased cine, Rotarix, is a monovalent, two-dose vaccine (RV1) based onrisk (~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 beenone 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 intussusceptionassociated with RRV-TV was age dependent and that the abso- Efficacy of RV5 & RV1 in pivotal prelicensure trialslute number of intussusception events and possibly the relative In clinical trials performed predominantly in the USA andrisk of intussusception associated with the first dose of RRV-TV Finland, RV5 reduced hospitalizations due to rotavirus gastro-increased with increasing age at vaccination [51,52] . However, the enteritis by 96% (95% CI: 91–98%), emergency departmentWHO Global Advisory Committee on Vaccine Safety (GACVS), visits by 94% (95% CI: 89–97%) and doctor’s office visits byafter reviewing all the available data, concluded that there was a 86% (95% CI: 74–93%) [5] . While the per-protocol analysishigh risk of RRV-TV-associated intussusception in infants immu- examined the efficacy against G1–G4 strains, the majority ofnized after day 60 and that insufficient evidence was available cases in the clinical trial were G1. Only sufficient numbers ofto conclude that the use of RRV-TV at any age under 60 days cases were enrolled to detect significant serotype-specific effi-was associated with a lower risk [53] . The GACVS noted that the cacy against G1 and G2 strains but significant reductions inpossibility of an age-dependent risk of intussusception should be rates of rotavirus hospitalizations and emergency departmenttaken into account in testing future rotavirus vaccines. RRV-TV visits were detected for G1, G3, G4 and G9 [5] . The RV5 safetyvaccine was voluntarily withdrawn from the market and is not in trial enrolled over 70,000 infants specifically to evaluate theuse today. A Phase II trial to evaluate the safety, immunogenicity risk of intussusception. No association with this adverse eventand potentially efficacy of two doses of RRV-TV administered to was found within 42 days after any dose of RV5 (relative riskyoung 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 397
  4. 4. Review Tate, Patel, Steele et al. vaccines were subsequently introducedTable 1. Characteristics of available rotavirus vaccines. into numerous countries in the Americas,Characteristic RV5 RV1 Europe and Australia, and Phase III clini-Manufacturer Merck & Co. (PA, USA) GlaxoSmithKline (Rixensart, cal trials of both candidate vaccines were Belgium) conducted in Africa and Asia.Parent strain Bovine rotavirus strain WC3, Human rotavirus strain 89–12, type G6P7[5] type G1P1A[8] Efficacy of RV5 & RV1 in Africa & Asia Phase III clinical trials for RV1 wereFormulation Five reassortants: G1xWC3, No reassortants G2xWC3, G3xWC3, G4xWC3, performed in South Africa and Malawi, P1A[8]xWC3 and Phase II immunogenicity studies for RV1 were conducted in Bangladesh. Vaccine titer ≥2.0–2.8 × 10 infectious units ≥10 median cell culture 6 6 per strain, depending on infective dose after Trials for RV5 were performed in Kenya, serotype (1.15 × 107 infectious reconstitution, per dose Ghana, Mali, Bangladesh and Vietnam. units per dose) Vaccine performance with both vaccines Method of attenuation Naturally attenuated (animal Passaged 43-times was observed to be lower in these setting strain); passage varied by when compared with the pivotal studies reassortant 7–69-times described in previous sections. In South Cell culture substrate Vero cells Vero cells Africa, two doses of RV1 administered to infants at 10 and 14 weeks of age were 72% Dose volume (ml) 2 1 (95% CI: 40–88%) efficacious in prevent- Buffer Sodium citrate and phosphate Calcium carbonate ing severe rotavirus gastroenteritis and effi- Dose regimen Three oral doses Two oral doses cacy increased to 82% (95% CI: 55–94%) Shedding following 9–21 35–80 when a three-dose schedule administered at first dose (%) 6, 10 and 14 weeks was used [7,62] . In Malawi, RV: Rotavirus the two- and three-dose schedules of RV1 Adapted from [97]. yielded similar results with a two-dose vac- 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 muchlife in clinical trials in Latin America and 96% (95% CI: 90–99%) greater in Malawi than in South Africa, so despite a lower effi-effective against severe disease in clinical trials in Europe [4,58] . No cacy the vaccine was able to prevent 3.9 episodes of severe rotavi-risk of intussusception in the 30 days post-RV1 vaccination was rus gastroenteritis per 100 vaccinated children in Malawi versusobserved (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 similarP type with the RV1 vaccine strain were uncommon, protection variability by setting as the RV1 trials although the methodologyappeared to be lower (44%; 95% CI: <0–84%) for severe disease for assessing clinical efficacy varied for the two vaccines. In the(Vesikari score ≥11) against these strains [59] . However, in the sec- three African RV5 clinical trial sites (Kenya, Ghana and Mali),ond large efficacy trial conducted in Europe and in results of a a three-dose regimen of RV5 administered at 6, 10 and 14 weeksmeta-analysis integrating all previous trial results, RV1 provided of age was 64% (95% CI: 40–79%) effective against severe rota-statistically significant protection against severe rotavirus diarrhea virus gastroenteritis during the first year of follow-up [8] . Duringcaused by G2P[4] strains (86%; 95% CI: 24–99% and 67%; the first year of follow-up in the Asian trial sites (Vietnam and95% CI: 15–87%, respectively) [58,60,61] . Bangladesh), three doses of RV5 were 51% (95% CI: 13–73%) In 2006, based on the initial clinical trial data from Latin effective against severe rotavirus gastroenteritis [8] .America, Europe and the USA, the SAGE recommended the useof rotavirus vaccines in countries where successful Phase III effi- Effectiveness & impact of RV5 & RV1 under routine usecacy trials had been performed and where data from these trials in the Americas, Australia & Europesuggested that the public health impact could be great [6] . This USASAGE recommendation did not include countries in Africa and To assess the impact and field effectiveness of rotavirus vaccination,Asia, where rotavirus disease burden and mortality is high, because post-introduction surveillance commenced in 2006 in the USAefficacy data were not available from these regions and the perfor- after the recommendation for routine use of rotavirus vaccine inmance and efficacy of live, oral vaccines in these regions has been all US infants [63] . In a case–control study of field effectiveness ofvariable. Rather, the SAGE reiterated earlier recommendations that vaccination conducted at a large pediatric hospital in Houston, TX,Phase III clinical trials be conducted in representative low-income USA, RV5 was 85–89% effective in preventing severe rotaviruscountries of Asia and Africa to demonstrate vaccine efficacy in these gastroenteritis, resulting in hospitalization or emergency depart-settings. Following the 2006 SAGE recommendation, rotavirus ment care, similar to the efficacy seen in prelicensure trials of398 Expert Rev. Vaccines 9(4), (2010)
  5. 5. Global impact of rotavirus vaccines Review Beginning/end of rotavirus season Peak week of activity 70 60 2000–2006 maximum 2000–2006 median % of tests rotavirus positive 50 2000–2006 minimum 2007–2008 season 40 2008–2009 season 30 20 Week of year 10 0 27 29 31 33 35 37 39 41 43 45 47 49 51 1 3 5 7 9 11 13 15 17 19 21 23 25 Week of year Figure 3. Proportion of tests positive for rotavirus by week of year, USA, National Respiratory and Enteric Viruses Surveillance System (NREVSS), July 2000–June 2009. Adapted from [66] .RV5 [64] . In addition, in a national network of sentinel clinical Austrialaboratories where results of rotavirus tests ordered by physicians A similar impact was also observed in Austria following the intro-were analyzed, the timing and magnitude of the first two rotavirus duction of rotavirus vaccine into the universal mass vaccinationseasons following vaccine introduction were delayed by 6–15 weeks program in 2007 [71] . In the first 18 months of the program, ratesand decreased in peak magnitude by 42–60% (Figure 3) [65,66] . of hospitalization due to rotavirus fell 74% among age-eligibleSimilarly, declines in hospitalizations and doctor’s office visits for children. Vaccine effectiveness was estimated to be 61–98%.acute gastroenteritis were observed during the 2007–2008 seasonin many regions of the country [67] . Declines in disease were seen in Brazilall children under 5 years of age and not solely in age-eligible chil- In March 2006, Brazil initiated universal immunization ofdren suggesting possible indirect protection among unvaccinated infants with RV1. Since vaccine introduction, two cities inpopulations who were still at risk [67] . northeast Brazil (Aracaju and Recife), each with vaccine cov- erage of greater than 50%, have identified a predominance ofAustralia G2P[4] strains in children with severe rotavirus diarrhea [72–74] .The impact of the vaccination program in Australia has been Although rotavirus now accounts for a substantially lower pro-similar to that in the USA. RV1 was introduced in Queensland, portion of hospitalizations for diarrhea post vaccine introduc-Australia, in July 2007 and the proportion of positive rotavirus tion compared with the prevaccine era [75] , these findings havetests in children under 2 years of age detected through laboratory prompted debate about whether a possible lower effectivenesssurveillance declined by 45% in 2007 and 43% in 2008 compared of RV1 against G2P[4] strains has led to their predominancewith the prevaccine baseline [68] . Declines in the proportion of for over 2 years [72–74,76] . Two recent evaluations have affirmedrotavirus-positive tests were also observed in older children who that RV1 is effective against severe rotavirus diarrhea causedwere ineligible to be vaccinated which also suggests that the vaccine by G2P[4] strains [75,77] , although questions about effectivenessmay offer indirect benefits. In a post-introduction vaccine-effec- during the second year of life remain.tiveness evaluation among indigenous children in central Australiain 2007, RV1 was 85% effective against confirmed rotavirus infec- Mexicotion (84% effective against G9P[8] strains), 83% effective against Mexico introduced RV1 in a phased manner between Februarysevere all-cause gastroenteritis and 78% effective against all-cause 2006 and May 2007. By May 2007, rotavirus vaccination wasgastroenteritis of any severity [69] . In another similar study from the available for all Mexican infants. A recent investigation foundsame population in 2009, RV1 was 86% effective against rotavirus that in 2008, when coverage for one or more doses among infantshospitalization due to the G2P[4] strain [70] . under 12 months of age exceeded 70%, there was a 42% decline inwww.expert-reviews.com 399
  6. 6. Review Tate, Patel, Steele et al. impact of the vaccine in El Salvador wasTable 2. Vaccine efficacy and postlicensure effectiveness data for also observed through national surveillance1 year of follow-up by setting. data where cases of rotavirus diarrhea haveSetting Vaccine Type of VE† (%) Severity Ref. declined by 79% following the introduction study (95% CI) of RV1.High and middle income [5] NicaraguaUSA and RV5 Efficacy 98 (88–100) Clark score >16,Finland efficacy against types In Nicaragua, one of the poorest countries G1–G4 in Latin America and eligible for support forUSA and RV5 Efficacy 74 (67–80) Any severity; efficacy [5] vaccine purchase from the GAVI Alliance, aFinland against types G1–G4 case–control evaluation found that RV5 was 52–63% effective in preventing severe rota-Finland RV1 Efficacy 90 (10–100) Vesikari score ≥11 [104] virus gastroenteritis (Vesikari score ≥11) andFinland and RV1 Efficacy 85 (75–92) Vesikari score ≥11 [4] 73–86% effective in preventing very severeLatin America rotavirus gastroenteritis (Vesikari score ≥15)Europe RV1 Efficacy 87 (80–92) Any severity [58] in the first year post vaccine introduction,Finland RV1 Efficacy 73 (27–91) Any severity [104] during a season with G2P[4] rotavirus pre- [64] dominance [79] . During the 2007 rotavirusUSA RV5 Effectiveness 88 (68–96) Hospitalization and ED visit season in Nicaragua when coverage with at least two doses among children underAustralia RV1 Effectiveness 85 (23–97) Hospitalization in [69] 12 months of age was still low at approxi- indigenous population mately 26%, hospitalizations and health-Brazil RV1 Effectiveness 79 (74–82) Hospitalization and ED [75] care visits for diarrhea of any cause declined visit; efficacy against by 11 and 23%, respectively, compared with G2P[4] the prevaccine baseline [80] .Brazil RV1 Effectiveness 85 (54–95) Hospitalization; [77] efficacy against G2P[4] Safety of rotavirus vaccinesMiddle-low and low income Although neither RV5 nor RV1 were asso-Asia (Vietnam, RV5 Efficacy 51 (13–73) Vesikari score ≥11 [8] ciated with intussusception during theBangladesh) clinical trials, post-introduction monitor- Africa (Kenya, RV5 Efficacy 64 (40–79) Vesikari score ≥11 [8] ing of vaccine safety is necessary as a low Ghana, Mali) level of risk cannot yet be excluded. The USA has conducted postlicensure moni- Africa (South RV1 Efficacy 62 (44–73) Vesikari score ≥11 [7] Africa, Malawi) toring since the introduction of RV5 in 2006 through the Vaccine Adverse Events Nicaragua RV5 Effectiveness 46 (18–64) Hospitalization [79] Reporting System, a national passive sur- El Salvador RV1 Effectiveness 76 (64–84) Hospitalization [7] 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. Toall-cause diarrhea mortality among infants in this age group [78] . date available data from these systems do not suggest a risk ofMoreover, a 23% reduction was also observed among older chil- intussusception after receipt of RV5 but continued monitoringdren 12–23 months of age who were largely ineligible for rotavi- is necessary as a low level of risk has not yet been excluded forrus immunization [78] . Sustained reduction in mortality among RV5 and additional data are still needed for RV1 [81,82] . As morechildren under 2 years of age in 2009 and blunting of the sea- countries introduce rotavirus vaccines, continued monitoring issonal peak in diarrhea deaths when rotavirus is most prevalent in important. While there are no data to suggest that there wouldMexico provided further supporting evidence for vaccine effect as be regional differences in risk ratios for intussusception afterthe major contributing factor towards this reduction in all-cause vaccination, differences in background rates of intussusceptiongastroenteritis 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 inIn 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 maythat this vaccine was 74% effective against severe rotavirus gas- cause disease in severely immunocompromised children [84] . SCIDtroenteritis (Vesikari score ≥11) and 88% effective in preventing is now included as a contraindications for RV5 [85] . Rotavirusvery severe rotavirus gastroenteritis (Vesikari score ≥15) [7] . The vaccine is not contraindicated for children with other types of400 Expert Rev. Vaccines 9(4), (2010)
  7. 7. Global impact of rotavirus vaccines Reviewimmunodeficiencies but few data are available [85] . HIV-infected Coordinated efforts with GAVI, the manufacturers and otherand -exposed infants were included in the RV1 clinical trials and international partners are needed to ensure the affordability ofno significant safety concerns were identified [62] . rotavirus vaccines for low and lower middle-income countries, both now and in the future.Global introduction of rotavirus vaccines Rotavirus vaccines are poised to make a significant public healthThe 2009 global recommendation by the WHO for the inclusion impact on rotavirus-associated mortality in developing countries,of rotavirus vaccines in the routine childhood vaccine programs and as funding subsidies are made available and effectiveness datain all countries, and specifically in countries where the diarrheal are generated in early adopter countries showing the impact ofproportion of under-5-year-old mortality is 10% or more [7,9] , is a the vaccines, continued introduction of the vaccines in additionalsignificant step towards fully utilizing these vaccines. Several other countries is probable.important developments have occurred which will enhance theglobal impact of these rotavirus vaccines on childhood mortality Evaluating & improving performance of rotavirusas they are introduced more widely. vaccines in developing countries First, the efficacy of RV5 and RV1 vaccines in developing coun- While rotavirus vaccines are likely to have a tremendous impacttries, although moderate, has demonstrated that the vaccines have on rotavirus disease in developing countries, live, oral vaccinesa substantial public health impact on disease in these settings have had an inconsistent history in the developing world. Forwhere the highest rates of rotavirus mortality occur. Rotavirus example, OPV is less immunogenic and more doses are requiredvaccines significantly reduced serious rotavirus gastroenteritis in to protect children in India and other developing countries com-resource-poor settings in Africa and Asia, where the attack rate pared with children in the developed world [90–92] . Similarly, anfor severe and fatal rotavirus diarrhea is high. The protection oral cholera vaccine was found to be less immunogenic and aoccurred in settings where multiple G and P types circulated, higher titer of the vaccine was needed to offer protection againstwhere nonvaccine strains predominated, and where vaccine was disease in developing countries in Asia and Latin America [93,94] .administered to children under ‘real world conditions’ – concomi- Early rotavirus vaccines also faced challenges in the developingtant administration with oral polio vaccine (OPV), no restric- world, and several candidate rotavirus vaccines (RIT4237, WC3,tions on breastfeeding and inclusion of children exposed to HIV RRV and RRV-TV) had lower or no measurable efficacy in clini-infection [62] . Significantly, the vaccines do not interfere with the cal trials in South America and Africa than in Europe and Northimmune response to OPV vaccines [86,87] . These results are very America [37–40,95] . Even in clinical trials and in routine use inencouraging about the potential for rotavirus vaccines to reduce immunization programs, the effectiveness of current rotavirusthe significant morbidity and mortality due to rotavirus diarrhea vaccines has been inversely correlated with the childhood mortal-in the world’s poorest children. ity level in the country where the trial was conducted. Similarly, Second, the currently available vaccines have been shown to immune response to RV1, which has been more widely tested inbe safe with respect to intussusception and other serious adverse the developing world, appears to decrease with decreasing incomeevents. Recent recommendations by SAGE and the WHO level of the country [96] .GACVS have relaxed the restriction on the age window for vac- The reasons why live, oral rotavirus vaccines are less effica-cine administration. The SAGE recommendations extend the cious in developing countries are not clear and are probablyadministration of the first dose of vaccine up to 15 weeks of multifaceted [97] . First, children in these countries often haveage, similar to the US Advisory Committee on Immunization distinct medical conditions from those typically seen amongPractices (ACIP) recommendations and the last dose of either the children in the developed world. For example, a higher preva-two-dose RV1 or the three-dose RV5 vaccine should be admin- lence of comorbid infections in young children – HIV, malaria,istered by 32 weeks of age [7,63] . This expanded age recommen- tuberculosis and intestinal infections with other microorganismsdation would increase vaccine coverage in developing countries – may adversely affect vaccine performance. Second, malnutri-where children often present late for their routine childhood tion is more common and may influence vaccine effectiveness.vaccinations [88,89] . Third, in these developing country settings, levels of maternal Third, GAVI approved the inclusion of rotavirus vaccines for rotavirus antibodies are passively transferred to babies duringvaccine subsidy in GAVI-eligible countries and has requested ‘let- gestation and still present in infancy. Furthermore, rotavirus-ters of interest’ from countries wanting rotavirus vaccines. Several vaccine neutralizing activity of breast milk is usually higherAfrican and Asian countries submitted proposals to GAVI for than in developed countries, and may reduce vaccine titer andreview in late 2009. While subsidization by GAVI will make it adversely affect vaccine take; however, further studies are neededfinancially feasible for early adopter countries to use the current to confirm this [98,99] . Also, rotavirus vaccine is almost alwaysrotavirus vaccines, the long-term sustainability of vaccine pur- administered on the same schedule as OPV, and some data sug-chase for all GAVI-eligible countries cannot be guaranteed. The gest that the immune response to the first dose of rotavirusGAVI subsidy of rotavirus vaccine means that the UNICEF will vaccine in particular could be somewhat reduced when givenbe able to negotiate lower prices for low-income countries, but concomitantly with the first dose of OPV [86,100] . Finally, thethis support for the vaccines ends in 2015, and countries will be diversity of circulating strains in Africa and Asia is substantialexpected to cover the whole cost once the GAVI subsidy closes. and different from that seen in the Americas and Europe [101,102] .www.expert-reviews.com 401
  8. 8. Review Tate, Patel, Steele et al.Globally, G1P[8] is the most predominant strain causing over strain evolution leads to reduced vaccine effectiveness. Since the70% of rotavirus infections in North America, Europe and rate at which potential strains that evade immunity evolve in anAustralia but causes only 30% of rotavirus infections in South immune population is unknown, conducting such investigationsAmerica and Asia, and 23% in Africa [101] . In parts of Asia and over a period of years after high vaccine uptake has been achievedAfrica, G9 strains have emerged as the predominantly circulat- may be important. Accompanying genetic characterization of rota-ing strain and G8 strains are isolated with increasing frequency viral strains from effectiveness studies will be important to assessin Africa as well [103] . While the vaccines have demonstrated pro- possible immune escape mechanisms.tection against the most commonly circulating strains (G1–G4 To have optimal public health impact, vaccines should protectand G9), effectiveness against less common strains has not been against severe rotavirus disease during the period when mostfully evaluated [5,58,59,104] . severe disease occurs, the first 2 years of life in developing coun- Thus, despite the promising efficacy data from the clinical tri- tries and the first 3 years of life in developed countries. Dataals in Africa and Asia, many unanswered questions about vac- from Europe and Latin America suggest that there is a slightcine effectiveness and how to improve vaccine performance in decrease in efficacy from the first to the second rotavirus seasonthese settings remain. As vaccines are introduced into the routine of follow-up, but overall protection was sustained at reasonableimmunization programs in Africa and Asia, ongoing monitoring levels [5,58,59,104] . This decrease in efficacy might be greater inis critical since vaccine performance varied by setting in clinical the developing world but further data are needed. Effectivenesstrials. Thus, to fully understand the impact of rotavirus vaccine of partial vaccination is also important as some severe diseaseintroduction in developing countries, several key epidemiologic occurs prior to completion of the full series and protection againstissues should be monitored including vaccine performance against breakthrough disease is important.severe disease during routine use, vaccine impact on rotavirus Several additional rotavirus vaccines are currently in variousdisease epidemiology, including changes in burden of severe dis- stages of development including vaccines based on neonatal rota-ease and death, age distribution of cases, seasonality and sero- virus strains in India [114,115] and Australia [116,117] ; a neonataltype distribution, indirect benefits for unvaccinated children, and dosing schedule of the previously withdrawn RRV-TV to addressduration of protection [105] . the intussusception issue [118] ; and a designer vaccine based on a Careful consideration of these issues prior to vaccine introduc- bovine strain that could include additional serotypes such as G8tion will enable development of surveillance systems capable of and G9, which are common in some developing countries [119] , andcapturing the full impact of the vaccine program. Initiation of that has been licensed to vaccine manufacturers in Brazil, Chinapopulation-based surveillance in a variety of high-disease-burden and India. These vaccines may offer less expensive alternatives tosettings prior to vaccine introduction will enable calculation of the currently available vaccines. Neonatal rotavirus strains havebaseline rates of disease, hospitalization, and death due to all- been found in nosocomial outbreaks of asymptomatic infectionscause diarrhea and rotavirus gastroenteritis, and documentation in newborn units. However, neonatal rotavirus strains usuallyof currently circulating strains. After vaccine introduction, these do not cause disease in infants and have been shown to protectsurveillance platforms will enable monitoring of changes in rates against severe rotavirus disease on reinfection [120,121] . A live, oralof mortality and morbidity, and any shifts in circulating strains vaccine based on a lamb rotavirus strain has been used in Chinaas well as serve as a basis for vaccine effectiveness evaluations. since 2001 but only limited data on safety, immunogenicity andFurthermore, these platforms can be used to explore reasons for effectiveness of this vaccine are available, which limits its widerlower efficacy of rotavirus vaccines in developing countries in use in other immunization programs [122,123] . In addition to thesecontrast to middle- and high-income countries, and to examine potential new oral vaccines, alternative approaches to rotavirusthe usefulness of potential ways to improve vaccine performance, vaccine administration such as rotavirus antigens for parenteralsuch as delaying age at first vaccination by 4–6 weeks to reduce delivery are also being explored so as to avoid a theoretical risk ofinterference by maternal antibodies, offering neonatal vaccina- intussusception [124–129] . A parenterally administered vaccine istion to target early disease, increasing the number of doses, alter- not susceptible to risk factors (e.g., breastfeeding and interferenceing breastfeeding practices immediately preceding and following from other floras in the gut) associated with live oral vaccines andimmunization, and using zinc or probiotic supplementation to thus could be equally immunogenic and effective in children inimprove the mucosal response to vaccination. low-income countries. The long-term impact of vaccines on circulating strains isunknown and continuous surveillance will be needed to address Expert commentarythis issue [12,106] . Studies in countries that have introduced rota- Two live, oral rotavirus vaccines are currently available. Thesevirus vaccines have, in some cases, reported higher prevalence of vaccines have shown high postlicensure effectiveness in high- andG2P[4] where RV1 is being used and an increase in G3P[8] where middle-income countries. Furthermore, increasing vaccine cover-RV5 is in use. However, information to date suggests that these age has been correlated with decreases in diarrhea and rotavirustrends may simply reflect natural strain variation rather than escape morbidity in these settings. Early data from clinical trials infrom vaccine immunity [75,107–113] . Long-term vaccine effectiveness Africa and Asia suggest that vaccines will have moderate effi-studies could provide a good platform to continuously assess levels cacy in these settings, but even a moderately effective vaccineof protection against individual serotypes to determine whether would have a substantial public health impact in these settings402 Expert Rev. Vaccines 9(4), (2010)
  9. 9. Global impact of rotavirus vaccines Reviewwith high disease burden. Thus, the WHO has recommended in burden of severe disease and death, age distribution of cases,that rotavirus vaccines be introduced into the national immuni- seasonality and serotype distribution, herd protection for unvac-zations programs of all countries worldwide. To improve vac- cinated children, and duration of protection. This informationcine performance and achieve the greatest public health impact, will enable us to use vaccines to their fullest potential.additional research is needed to ensure that these vaccines reachtheir fullest potential. Financial & competing interests disclosure Nigel A Cunliffe has received research grant support and lecture fees fromFive-year view GSK Biologicals and SPMSD. Osamu Nakagomi has received research grantsPostlicensure data showing high effectiveness of rotavirus vaccines from GlaxoSmithKline and Banyu Pharmatheuticals. Jacqueline E Tate,in routine use in high- and middle-income countries and promis- Manish M Patel, A Duncan Steele, Jon R Gentsch, Daniel C Payne,ing efficacy data from clinical trials in Africa and Asia suggest that Margaret M Cortese, Baoming Jiang, Roger I Glass and Umesh D Parasharrotavirus vaccine will have substantial impact on global rotavirus do not have any relevant disclosures. The authors have no other relevantmorbidity and mortality as these vaccines are introduced into affiliations or financial involvement with any organization or entity with acountries’ national immunization programs. However, to reap financial interest in or financial conflict with the subject matter or materialsthe full benefit of rotavirus vaccination, further study of rotavi- discussed in the manuscript apart from those disclosed.rus vaccines in developing countries should continue to explore No writing assistance was utilized in the production of thisways to improve vaccine performance in settings where rota- manuscript.virus morbidity and mortality is highest.Specifically, these studies could examine the Key issuesimpact 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 immunizationthe number of doses, altering breastfeed- programs of all countries.ing practices, and using zinc or probiotic • Clinical trials and postlicensure monitoring in high- and middle-income countries havesupplementation will have on vaccine per- found rotavirus vaccines to be highly effective against rotavirus gastroenteritis andformance. 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 inepidemiological issues including vaccine these high-burden settings.performance against severe disease during • Further study of rotavirus vaccines in low-income countries is needed to determine theroutine use, vaccine impact on rotavirus potential impact of immunization against rotavirus in these settings and identify waysdisease epidemiology, including changes to improve impact. showing that the monovalent rotavirus • Presents recommendation of the WHO to References vaccine is efficacious against severe include rotavirus vaccine in the national Papers of special note have been highlighted as: rotavirus disease. immunization programs of all countries.• of interest 5 Vesikari T, Matson DO, Dennehy P et al. 9 Meeting of the Strategic Advisory Group of1 Parashar UD, Gibson CJ, Bresse JS, Safety and efficacy of a pentavalent Experts on immunization, October 2009 – Glass RI. 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