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Published in final edited form as: Vaccine. 2014 Aug 11;32(Suppl 1):A171–A178. doi: 10.1016/j.vaccine.2014.03.029

Insights from Global Data for Use of Rotavirus Vaccines in India

TS Rao 1, Rashmi Arora 2, Ajay Khera 3, Jacqueline E Tate 4, Umesh Parashar 4, Gagandeep Kang 5; the Indian Rotavirus Vaccine Working Group
PMCID: PMC12011198  NIHMSID: NIHMS2071835  PMID: 25091672

Abstract

Rotavirus vaccines are being introduced in several low- and middle-income countries across the world with and without support from the GAVI Alliance. India has the highest disease burden of rotavirus based on morbidity and mortality estimates and several indigenous vaccine manufacturers are developing rotavirus vaccines. One candidate has undergone phase III testing and others have completed evaluation in phase II. Global data on licensed vaccine performance in terms of impact on disease, strain diversity, safety and cost-effectiveness has been reviewed to provide a framework for decision making in India.

Introduction

Two live, attenuated, orally administered rotavirus vaccines - a monovalent human rotavirus vaccine (RV1; Rotarix™ (GSK Biologicals, Rixensart, Belgium)) and a pentavalent bovine-human reassortant vaccine (RV5; RotaTeq® (Merck and Co, Inc, Pennsylvania)) - are licensed for use in more than 100 countries worldwide, including India.[1, 2] Promising clinical trial data from the United States of America (USA), Latin America, and Europe showing that these newly developed rotavirus vaccines were highly efficacious and safe in preventing severe rotavirus gastroenteritis lead to the World Health Organization (WHO) recommendation in 2006 that vaccines against rotavirus be introduced into the national immunization programmes of countries in regions where clinical trial data are available.

In 2009, following additional clinical trials in low income countries and the availability of post-marketing data from early introducing countries in the Americas, Europe, and Australia, WHO extended its recommendation to include rotavirus vaccines in the routine immunization programs in all countries globally and particularly those countries with high child mortality due to diarrhea. Following further analysis, in 2013 the WHO recommended that all countries consider immunization along with the primary immunization series at whatever age the series is administered. [3] Since 2006, over 50 countries have introduced rotavirus vaccine into their national immunization programs.

Of the estimated 453,000 annual deaths due to rotavirus diarrhea in children <5 years of age globally, approximately 99,000 (22%), occur in Indian children.[4] (Figure 1). In addition, rotavirus is a significant cause of childhood morbidity in India and is estimated to account for approximately 457,000–884,000 hospitalizations and 2 million outpatient clinic visits each year, incurring health care costs of Rs 2.0–3.4 billion (US$41–72 million) annually.[5] Thus, the potential health and economic impact of a national rotavirus vaccination programme in India is immense. In addition to having both internationally licensed vaccines in the market, Indian manufacturers are developing several candidate rotavirus vaccines. The most advanced of these vaccines is a candidate based on the indigenous 116E strain, a natural reasssortant of the human rotavirus G9P[11] strain with the VP4 protein from a bovine rotavirus strain, that was isolated from a neonate with an asymptomatic infection in Delhi (Table 1). This vaccine has undergone a phase III clinical trial at three centres in India (Delhi, Pune, and Vellore) and results from this trial indicate efficacy at least equivalent to licensed vaccines in developing countries. [6]

Figure 1.

Figure 1.

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Rotavirus disease burden globally and in India

Table 1.

Characteristics of rotavirus vaccines

RV1 RV5 116E
Manufacturer GlaxoSmithKline: Rixensart, Belgium (Rotarix®) Merck: Pennsylvania, USA (Rotateq®) Bharat Biotech International Limited: Hyderabad, India
Parent Strain Human rotavirus strain 89–12, type G1P1A[8] Bovine rotavirus strain WC3, type G6P7[5] Human rotavirus virus G9P[11] strain of the Wa genogroup with a bovine rotavirus strain of genotype P[11]
Formulation No reassortants 5 reassortants
G1xWC3, G2xWC3, G3xWC3, G4xWC3, P1A[8]xWC3		 Natural reassortant
Dosing Regimen 2 oral doses, given with DTP doses 1 and 2 3 oral doses, given with DTP 3 oral doses, given with DTP
Status International Use International Use Application for licensure submitted
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hile rotavirus vaccines are not currently recommended or used in the national immunization programme in India, their use has been included in the Indian Academy of Paediatrics guidelines for immunization. Widespread experience with rotavirus vaccines under conditions of routine use in many countries worldwide coupled with clinical trial data provide much insight into the performance, impact, safety, and cost-effectiveness of rotavirus vaccines. The objective of this paper is to review data from international settings to help address key questions regarding anticipated rotavirus vaccine performance and impact in India.

Pre-Licensure Efficacy of Rotavirus Vaccines

Both internationally licensed rotavirus vaccines, RV1 and RV5, were found to be highly efficacious in clinical trials conducted in the USA, Latin America, Europe, and high income Asian countries. (Table 2). RV1 was 85% (95% CI: 71%−83%) efficacious in preventing severe rotavirus gastroenteritis (Vesikari score ≥11) among Latin American infants.[1] In subsequent trials examining efficacy during the first two years of life, RV1 was 81% (95% CI: 71%−87%) efficacious against severe rotavirus gastroenteritis in Latin American children, 90% (95% CI: 85%−94%) efficacious in European children, and 96% (95% CI: 85%−100%) efficacious in children in high income Asian countries.[7–9] Similarly, in clinical trials conducted mainly in the USA and Finland, RV5 was 96% (95% CI: 91%−98%) efficacious against hospitalizations due to rotavirus gastroenteritis caused by G1-G4 strains, 94% (95% CI: 89%−97%) against emergency department visits, and 86% (95% CI: 74%−93%) against office visits.[2]

Table 2.

Efficacy of rotavirus vaccines against severe rotavirus disease by year of life and country

High and Middle Income Settings Vaccine Schedule Efficacy (95% CI) – 1st year of life Efficacy (95% CI) – 2nd year of life Overall Efficacy (95% CI) – 1st two years of life Ref
Latin America RV1 2, 4 months 83%
(67%, 92%)		 79%
(66%, 87%)		 81%
(71%, 87%)		 [7]
Europe RV1 3, 5 months 96%
(90%, 99%)		 86%
(76%, 92%)		 90%
(85%, 94%)		 [8]
Asia RV1 3, 5 months -- -- 96%
(85%, 100%)		 [9]
US and Finland RV5 2, 4, 6 months 98%
(88%, 100%)		 -- -- [2]
Low Income Settings
South Africa RV1 10, 14 weeks 72%
(40%, 88%)		 -- 32%
(−71%, 75%)		 [18, 20]
South Africa RV1 6, 10, 14 weeks 82%
(55%, 94%)		 -- 85%
(35%, 98%)		 [18, 20]
Malawi RV1 10, 14 weeks 49%
(11%, 72%)		 3%
(−101%, 53%)		 34%
(−2%, 58%)		 [18, 19]
Malawi RV1 6, 10, 14 weeks 50%
(11%, 72%)		 33%
(−49%, 71%)		 42%
(9%, 64%)		 [18, 19]
Africa (Ghana, Kenya, Mali) RV5 6, 10, 14 weeks 64%
(40%, 79%)		 20%
(−16%, 44%)		 39%
(19%, 55%)		 [21]
Ghana RV5 6, 10, 14 weeks 65%
(36%, 82%)		 29%
(−65%, 71%)		 56%
(28%, 73%)		 [21]
Kenya RV5 6, 10, 14 weeks 83%
(26%, 98%)		 −55%
(−1753%, 82%)		 64%
(−6%, 90%)		 [21]
Mali RV5 6, 10, 14 weeks 1%
(−432%, 82%)		 19%
(−23%, 47%)		 18%
(−23%, 45%)		 [21]
Asia (Vietnam, Bangladesh) RV5 6, 10, 14 weeks 51%
(13%, 73%)		 46%
(1%, 71%)		 48%
(22%, 66%)		 [22]
Vietnam RV5 6, 10, 14 weeks 72%
(−45%, 97%)		 65%
(−48%, 94%)		 64%
(8%, 91%)		 [22]
Bangladesh RV5 6, 10, 14 weeks 46%
(−1%, 72%)		 39%
(−18%, 70%)		 43%
(10%, 64%)		 [22]
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Because live oral vaccines, including earlier candidate rotavirus vaccines, have a history of performing less well in developing countries,[10–17] WHO specifically recommended that efficacy trials of both RV1 and RV5 be conducted in low income countries of Africa and Asia before issuing a global recommendation for rotavirus vaccine use. Vaccine efficacy was modest in these trials. In Africa (South Africa and Malawi), two doses of RV1 administered at 10 and 14 weeks of age had 59% (95% CI: 36–74%) efficacy against severe rotavirus diarrhea during the first year of life and three doses at 6, 10, and 14 weeks of age had 64% (95% CI: 42–78%) efficacy.[18] Efficacy appeared to decline during the second year of life, particularly among 2 dose recipients.

In Malawi, efficacy was similar for two and three dose recipients during the first year of life (49% (95% CI: 11%−72%) and 50% (95% CI: 11%−72%), respectively).[18, 19] However, in the second year of life, efficacy disappeared in two dose recipients (3% (95% CI: −101%−53%)) while declining to 33% (95% CI: −49%−71%) among three dose recipients.[18, 19] In South Africa, efficacy was similar in the three dose recipients during the first year of life (82% (95% CI: 55%−94%)) and overall during the first two years of life (85% (95% CI: 35%−98%)).[18, 20] However, among two dose recipients, the study observed a notable decline from 72% (95% CI: 40%−88%) during the first year to 32% (95% CI: −71%−75%) over the first two years of life. .[18, 20]

For RV1, the two dose schedule was given at 10 and 14 weeks of age. No efficacy data for RV1 with the recommended 6 and 10 week schedule is available, and it is possible that the efficacy may be lower than that observed with the 10 and 14 week schedule due to higher maternal antibody and potential interference by first oral polio vaccine dose. The efficacy of three doses of RV5 administered at 6, 10, and 14 weeks of age in Africa (Ghana, Kenya, and Mali) was 64% (95% CI: 40–79%) and in Asia (Bangladesh and Vietnam) was 51% (95% CI: 13–73%) against severe rotavirus disease during the first year of life.[21, 22] As seen for RV1, RV5 efficacy appeared to decline during the second year of life and was 20% (95% CI: −16–44%) in Africa and 46% (95% CI: 1–71%) in Asia.[21, 22]

Despite lower efficacy in low income countries, the significant disease burden in these settings results in a greater absolute number of rotavirus cases prevented per 100 vaccinated children compared with higher income countries with lower disease burden. In clinical trials, RV1 efficacy during the first year of life in South Africa (77%) was higher than in Malawi (49%) but the vaccine prevented seven episodes of severe rotavirus gastroenteritis per 100 vaccinated infants in Malawi compared with four episodes prevented per 100 vaccinated infants in South Africa due to the higher disease burden in Malawi compared with South Africa.[18]

Post-Licensure Effectiveness and Impact of Rotavirus Vaccines

Rotavirus vaccines have had a notable impact on mortality, hospitalizations and outpatient visits in countries that have introduced the vaccine into their national immunization programme, including some evidence suggesting that rotavirus vaccines may offer indirect protection to older, unvaccinated age groups. Perhaps the most exciting post-licensure data pertains to the effect of rotavirus vaccination in reducing deaths from childhood diarrhea in some countries in Latin America, as the mortality benefits of vaccination were not assessed in pre-licensure trials. In Mexico, following RV1 introduction into the national immunization programme in 2007, the diarrhea mortality rate declined to 35% (95% CI: 29–39%) in 2008 compared with the pre-vaccine baseline (2003–2006): the decline in mortality has been sustained for three years from 2008–2010.[23, 24]

Brazil saw a similar decline of 22%−41% in diarrhea mortality rates among children <5 years of age following the introduction of RV1 into the national immunization program in 2006.[25, 26] (Figure 2). While these were ecological analyses that could be affected by secular trends and failed to measure the specific reason for decline in rotavirus deaths (because the cause of diarrhea is rarely diagnosed for deaths), the dramatic decline in mortality seen after vaccine introduction, particularly during the winter seasonal months when rotavirus circulates, support the role of the vaccine. .

Figure 2.

Figure 2.

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Reductions in all-cause diarrhea mortality rates among children <5 years of age pre- and post-rotavirus vaccine introduction in Mexico and Brazil.

Many middle and high income countries have observed substantial declines of 17%−55% in all-cause gastroenteritis hospitalization and even larger declines of 49%−89% in rotavirus gastroenteritis hospitalizations among children <5 years of age within the first two years following rotavirus vaccine introduction..[25, 27–42] Due to the large rotavirus disease burden among hospitalized children, these declines translate into large numbers of hospitalizations prevented. For example, studies show that in the USA following the introduction of rotavirus vaccine in 2006 an estimated 40,000–60,000 acute gastroenteritis hospitalizations, or approximately 4%−5% of all hospitalizations among US children <5 years of age, were prevented in 2008..[33] (Table 3).

Table 3.

Impact of national rotavirus vaccine introduction on all-cause and rotavirus diarrhea hospitalizations in children <5 years of age

Country Vaccine (Year Introduced) Post-Vaccine Years Studied Percent reduction in specified hospitalizations among children <5 years of age Impact Ref
All-Cause Diarrhea Hospitalizations Rotavirus Hospitalizations
Brazil RV1 (2006) 2007–2009 17% -- 40,000 diarrheal hospital admissions in children <5 years age averted annually [25]
El Salvador RV1 (2006) 2008–2009 28%−37%* 69%−81% Annual healthcare visits for diarrhea (inpatient and outpatient) among children <5 years of age decreased by 61,000 in 2008 and 46,000 in 2009 [28]
Mexico RV1 (2006) 2008–2009 11%−40%† -- 16,000 diarrhea hospitalizations in children <5 years of age averted annually; 1 hospitalization prevented per 125 vaccinated infants by 5 years of age [80]
USA RV5 (2006)
RV1(2008)		 2008–2009 31%−33% 62%−71%° 38,000 diarrheal hospitalizations in children <5 years age averted annually [76]
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*

Includes inpatient and outpatient visits for diarrhea;

†

During peak rotavirus season;

‡

Study period July 2007-June 2009;

°

Rotavirus-coded hospitalizations

In some settings, researchers have observed the indirect effects of rotavirus vaccines among children age-eligible but missed by the vaccination program, and among older children and adults . The USA observed declines of 6%−46% in rotavirus gastroenteritis hospitalizations among age-eligible unvaccinated children although these declines were smaller than the 88%−93% decline observed among age-eligible vaccinated children.[42] Many countries including the USA and Belgium have observed declines in rotavirus disease during the first few years of vaccine introduction that exceed the coverage levels of rotavirus vaccine in the population.[43–46] Furthermore, the declines in rotavirus hospitalizations among children <5 years of age that were age-ineligible during the first few years after vaccine introduction saw declines in rotavirus gastroenteritis hospitalizations (24%−81%) that were similar to or slightly lower than those declines observed among vaccine-eligible age groups (50%−96%).[27–29, 31, 32, 34, 35, 38, 40, 43, 47] Additionally, studies in the USA observed declines in acute gastroenteritis hospitalizations of 8%−29% among older children and adults 5 to 24 years of age during the rotavirus season following rotavirus vaccine introduction suggesting an unappreciated burden of rotavirus disease in these older populations.[48]

Strain Diversity

Rotavirus strains are characterized by two surface proteins, VP7, the glycoprotein (G protein) and VP4, the protease-cleaved protein (P protein), that evoke antibody response. At least 10 G and 11 P antigen types have been identified among human rotavirus strains with five strains (G1P[8], G2P[4], G3P[8], G4P[8], and G9P[8]) found to be responsible for the majority of severe rotavirus infections worldwide.[49–51] However, there are extensive differences in the predominant circulating strains between geographic regions and change over time.[51] G1 strains predominated globally from 1996 to 2007 although the relative frequency decreased over time.[51] Conversely, in Southeast Asia, G2 strains were predominant during 1996–1999, G9 strains dramatically emerged in 2000–2003, and G1 and G2 strains predominated from 2004–2007 accompanied by the emergence of G12 strains.[51]

Clinical trials of RV1 in Latin America found high efficacy (91%; 95% CI: 71%−98%) against severe (Vesikari score ≥11) rotavirus gastroenteritis due to G1P[8] but lower, non-significant efficacy (45%; 95% CI: −82%−86%) against G2P[4].[1] However, a subsequent trial in Europe with a larger sample size showed high levels of protection against severe rotavirus gastroenteritis due to G1 (96%; 95% CI: 90%−99%) and G2 strains (86%; 95% CI: 24%−99%) as well as G3 (94%; 95% CI: 53%−100%), G4 (95%; 95% CI: 68%−100%), and G9 strains (85%; 95% CI: 72%−93%).[8] The RV1 clinical trials in Africa showed similar efficacy against G1 strains (64%; 95% CI: 30%−82%) and non-G1 strains (60%; 95% CI: 37%−74%).[18] The clinical trial of RV5 in the USA and Finland observed a 95% (95% CI: 92%−97%) rate reduction in the number of hospitalizations and emergency department visits due to G1 strains and rate reductions of 93% (95% CI: 49%−99%), 89% (95% CI: 52%−98%), and 100% (95% CI: 67%−100%) in the number of hospitalizations and emergency department visits due to G3, G4, and G9 strains, respectively..[2] The RV5 clinical trial in Africa provided significant protection against severe gastroenteritis due to G8 strains (88%; 95% CI: 7%−100%), P1A[8] strains (36%; 95% CI: 4%−58%), and P2A[6] strains (48%; 95% CI: 10%−70%).[21] In the RV5 clinical trial in Asia, strain-specific vaccine efficacy estimates were imprecise due to small numbers and the trial observed significant protection only against P1A[8] strains (50%; 95% CI: 19%−69%).[22]

Strain-specific vaccine efficacy estimates from the clinical trials are limited to the predominately circulating strains at the time of the trials. However, post-licensure vaccine effectiveness data from countries that have introduced rotavirus vaccine into their routine immunization programs have enabled vaccine performance against a variety of strains in a variety of settings to be evaluated. Of particular interest has been the apparent emergence of G2P[4] in Brazil and Australia following the introduction of RV1 in these countries.[52, 53] G2P[4] is fully heterotypic compared to the RV1 strain and there was some concern that the selective pressure of the vaccine may have led to its predominance. However, vaccine effectiveness studies in Brazil found that RV1 was 39%−89% effective against severe disease caused by G2P[4] strains although the effectiveness may wane in children >12 months of age.[36, 54, 55] RV1 was 83%−85% effective against rotavirus gastroenteritis due to G2P[4] in children 6–11 months of age in Brazil but only 5%−41% effective in children ≥12 months of age.[54] Similarly, a study among indigenous children <3 years of age in Australia noted waning vaccine effectiveness, where RV1 was 19% (95% CI: −105%−68%) effective in preventing rotavirus hospitalizations among children <3 years of age during an outbreak of G2P[4] with higher vaccine effectiveness in children <1 year of age (51%; 95% CI: −92%−88%) than in children 1–2 years of age (9%; 95% CI: −283%−79%).[56] An earlier study in the same indigenous population found that RV1 was 85% (95% CI: 23%−97%) effective against rotavirus hospitalization when G9P[8] was the predominantly circulating strain.[57] RV1 has also been shown to be effective in El Salvador (76%; 95% CI: 64%−84%) when G1P[8] was the predominantly circulating strain and in Mexico (94%; 95% CI: 16%−100%) against G9P[4].[58, 59]

Post-licensure vaccine effectiveness studies have also shown RV5 to offer protection against several different strains. A study in the USA showed RV5 was 95% (95% CI: 57%−99%) effective against hospitalizations and emergency department visits due to G3P[8].[60] Another study in USA found that RV5 was 83%−96% effective against G1, G3, G9, and G12 strains and 72%−77% effective against G2 strains.[61] In Nicaragua, RV5 was 51% (95% CI: 23%−69%) effective against G2P[4] rotavirus disease resulting in hospitalization or intravenous rehydration, 65% (95% CI: 39%−80%) against severe (Vesikari score ≥11) G2P[4] rotavirus disease, and 82% (95% CI: 47%−94%) against very severe (Vesikari score ≥15) G2P[4] rotavirus disease.[62]

Vaccine Safety

A previous quadrivalent rhesus-reassortant rotavirus vaccine, RotaShield® manufactured by Wyeth and licensed in 1998, was withdrawn from use in the USA in 1999 after it was associated with an increased risk of intussusception, a rare adverse event in which one portion of the bowel telescopes into another.[63–65] Researchers in the USA observed an excess risk of one case of intussusception per 10,000 infants vaccinated with RotaShield. [66] Subsequently the USA conducted large clinical trials of for RV1 and RV5 among60,000–70,000 infants to detect a risk of intussusception similar to that observed with RotaShield.[1, 2] Trials failed to detect an increased risk of intussusception following rotavirus vaccination within 30 days of either dose of RV1 or 42 days after any of the RV5 doses.[1, 2] However, post-marketing surveillance has detected a small increased risk of intussusception (1–2 excess cases per 100,000 infants vaccinated) in the first week following the first dose of vaccine in some populations but not in others. .[67–72]

Assessment analyses have found favorable benefit-risk ratios in countries with inconclusive rotavirus vaccine efficacy. (Table 4). A self-controlled case series analysis observed a short term risk of intussusception of one excess case of intussusception per 51,000 to 68,000 infants vaccinated in the 1–7 days following rotavirus vaccination in Mexico and Brazil.[67] Both of these countries documented significant declines in all-cause diarrhea deaths in children following the introduction of rotavirus vaccine.[23–26] For example, each year in Mexico, the rotavirus vaccine will avert an estimated 663 deaths and 11,551 hospitalizations due to rotavirus among children <5 years of age and cause 2 excess deaths (approximately 1 for every 1 million vaccinated infants) and 41 excess hospitalizations (approximately 1 for every 51,000 vaccinated infants) for intussusception.[67] Similarly, in Brazil, the rotavirus vaccine will avert an estimated 640 deaths and 69,572 hospitalizations due to rotavirus among children <5 years of age annually and cause 3 excess deaths (approximately 1 for every 1.4 million vaccinated infants) and 55 excess hospitalizations (approximately 1 for every 68,000 vaccinated infants) for intussusception.[67]

Table 4.

Benefit-risk analyses for selected countries with national rotavirus vaccination programs

Rotavirus Hospitalizations (Deaths) Prevented Intussusception (Deaths) Caused Ref
Mexico 11,600 (663) 41 (2) [67]
Brazil 69,600 (640) 55 (3) [67]
Australia 6,500 (0) 14 (0) [68, 81]
United States 53,000 (14) 58 (0.2) [76]
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Cost-Effectiveness of a Rotavirus Vaccination Program

Global, regional, and country-specific studies have found rotavirus vaccine to be a cost effective intervention. Globally, rotavirus vaccine will prevent an estimated 180,000 rotavirus deaths in children <5 years of age annually when introduced into the national immunization programmes of all GAVI-eligible countries.[73] The estimated cost per disability adjusted life year (DALY) averted is $42 for all GAVI-eligible countries and $60 for GAVI-eligible countries located in Southeast Asia.[73] For every 1000 children vaccinated against rotavirus in GAVI-eligible countries in Southeast Asia, an estimated 52 DALYs will be averted, 87 health care visits due to rotavirus diarrhea will be prevented, and $1360 in medical costs will be saved.[73] Two independent analyses in India concluded that the introduction of rotavirus vaccines into the routine, national immunization program in India would be cost-effective.[74, 75] At a price of $7.00 per dose, the initial price per dose of vaccine, these models estimated an incremental cost effectiveness ratio (ICER) of $174 per life years saved and $134-$200 per DALY averted, which satisfies the WHO criterion for a cost effective intervention where the incremental cost-effectiveness ratio is less than the country’s per capita gross domestic product.[74, 75] At the more likely cost of $1.00 per dose in India, the ICER is $21 per DALY averted.[74] At current immunization levels a national rotavirus vaccination programme in India would prevent 41,000–44,000 deaths and 203,000–293,000 hospitalizations due to rotavirus among children <5 years of age.[74, 75]

Studies have observed that following the introduction of rotavirus vaccine into national immunization programs, there are declines in annual costs to treat rotavirus disease associated with declines in medical visits.. After rotavirus vaccine was introduced into the national immunization program in the USA in 2006, one study found that almost 65,000 hospitalizations due to rotavirus among children <5 years of age over the following two years from July 2007 to June 2009 were prevented which saved approximately $278 million in treatment costs.[42] Another USA study estimated that the vaccine could prevent 53,000 hospitalizations due to rotavirus among children <5 years of age.[76] Additionally, a study examining the indirect benefits of rotavirus vaccine in older children and young adults, a study in the USA estimated that approximately 8,800 gastroenteritis hospitalizations were prevented among individuals 5–24 years of age in 2008 saving $42 million in treatment costs.[48]

Lessons for India

The dramatic declines in rotavirus disease documented in middle and high income countries following vaccine introduction, coupled with the high disease burden in low income countries like India suggest that large declines in the number of deaths, hospitalizations, and outpatient visits due to rotavirus gastroenteritis may be observed following vaccine introduction into the national immunization programs despite modest vaccine efficacy. [5] Thus, with the high rotavirus disease burden in India, rotavirus vaccines have substantial potential to prevent a large number of deaths, hospitalizations, and outpatient visits due to rotavirus even with the modest efficacy. Data on rotavirus vaccine impact in developing countries are sparse due to limited use of rotavirus vaccines in these countries. This will change in the coming years with GAVI support and increased use of vaccines in developing countries. But it is important that Indian policy makers consider available data as early as possible.

The benefits of rotavirus vaccination may extend beyond those which are expected among children <5 years of age. Indirect benefits of rotavirus vaccination have been observed in the early years of the rotavirus vaccination program in early adopter countries suggesting that rotavirus vaccine may offer some protection to those populations not directly covered by the immunization program. Little information is available about the incidence of rotavirus disease among older children and adults in most countries, including in India, but even if a small unrecognized disease burden exists in these populations, the impact of rotavirus vaccines at the population level could be greater than anticipated. Further studies of disease burden among all ages and data from clinical trials or demonstration projects in India will help to determine the performance and project the impact of rotavirus vaccine introduction.

India, like other developing countries, has documented tremendous diversity in circulating rotavirus strains.[77–79] (Figure 3). Fortunately, substantial evidence suggests that rotavirus vaccines provide heterotypic protection against a wide range of genotypes. Secular trends in circulating strains continue to occur in countries that have introduced rotavirus vaccine. While it may be too soon to determine if vaccine pressure will result in the emergence of escape strains, both globally available vaccines have demonstrated effectiveness against multiple rotavirus strains. Countries that have introduced rotavirus vaccine, such as Brazil, Mexico, Australia, and the USA, have documented large declines in hospitalizations due to rotavirus disease further suggesting that these vaccines are having an impact on rotavirus disease burden due to a variety of strains. However, small differences in effectiveness against individual strains may lead to the emergence of escape strains over time making continued monitoring of circulating strains important following vaccine introduction.

Figure 3.

Figure 3.

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Distribution of G Types Globally and in India*

*Adapted from [51] and [79].

Note: NT indicates non-typable strains and Mix indicated mixed infections.

Risk-benefit analyses in several countries that have introduced rotavirus vaccine into their national immunization programs have found that the benefits of rotavirus vaccination greatly outweigh the risk. While the analyses are country-specific and vaccine-specific , countries like India with high rotavirus mortality burden will likely benefit from the introduction of rotavirus vaccine even if there is a low level risk of intussusception. However, each country must weigh its own benefit-risk scenario prior to vaccine introduction.

Summary

India has its own rotavirus vaccines in the pipeline with phase 3 trials of the 116E vaccine currently ongoing. Once this vaccine is available for use in India, many of these issues including performance and impact under conditions of routine use, effectiveness against currently circulating strains, safety, and cost-effectiveness will need to be examined. However, the experience of the international community with the two currently available oral rotavirus vaccines does provide insight into the likely performance and impact of the Indian 116E vaccine. Due to the high rotavirus mortality burden, the introduction of a vaccine will likely have a notable impact on disease burden, protect against a wide variety of circulating strains, and result in a decrease in the economic burden of rotavirus in India. Studies to examine rotavirus vaccine impact and safety using many of the study designs employed by international researchers can help answer many of these questions and provide support for sustained use of rotavirus vaccine in India.

HIGHLIGHTS:

  • India has the highest disease burden of mortality and morbidity and needs to consider whether to introduce rotavirus vaccine in the national immunization programme

  • An effective affordable vaccine has been developed in India and is expected to be available shortly, and other candidates are in the pipeline

  • Rotavirus vaccines are being rapidly introduced in several countries and both developed and developing countries have demonstrated an impact on rotavirus disease

Acknowledgements:

The Working Group meeting on March 20, 2012 was convened and supported by the Department of Biotechnology.

The Working Group consisted of Rashmi Arora, Deputy Director, Epidemiology and Communicable Diseases, Indian Council for Medical Research, Ministry of Health and Family Welfare

Ajay Khera, Deputy Commissioner (Immunization), Ministry of Health and Family Welfare, Government of India

T. S. Rao, Advisor, Department of Biotechnology, Ministry of Science and Technology, Government of India

M.K. Bhan, Secretary, Department of Biotechnology, Ministry of Science and Technology, Government of India

Ashish Bavdekar, Associate Professor of Paediatrics, KEM Hospital, Pune

Temsunaro R. Chandola, Centre for Health Research and Development, Society for Applied Studies, Delhi

Nita Bhandari, Director, Centre for Health Research and Development, Society for Applied Studies, Delhi

Sunita Taneja, Centre for Health Research and Development, Society for Applied Studies, Delhi

Tivendra Kumar, Centre for Health Research and Development, Society for Applied Studies, Delhi

Vinohar Balraj, Professor of Community Health, Christian Medical College, Vellore

Jayaprakash Muliyil, Academic Officer, Christian Medical College, Vellore

Gagandeep Kang, The Wellcome Trust Research Laboratory, Christian Medical Medical College, Vellore

Jacob John, Associate Professor of Community Health, Christian Medical College, Vellore

Mohan V. Raghava, Associate Professor of Community Health, Christian Medical College, Vellore

Rajiv Sarkar, Department of Gastrointestinal Sciences, Christian Medical College, Vellore

Umesh D. Parashar, Head, Viral Gastroenteritis Section, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta

Nicholas C. Grassly, Professor of Infectious Disease & Vaccine Epidemiology, Imperial College, London

Mathuram Santosham, Professor of International Health and Pediatrics, Johns Hopkins Bloomberg, School of Public Health, Baltimore

Footnotes

Conflict of interest: None of the authors have a conflict of interest

Disclaimer: The findings and conclusions of this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention (CDC).

References

  • [1].Ruiz-Palacios GM, Perez-Schael I, Velazquez FR, Abate H, Breuer T, Clemens SC, et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. The New England journal of medicine. 2006 Jan 5;354(1):11–22. [DOI] [PubMed] [Google Scholar]
  • [2].Vesikari T, Matson DO, Dennehy P, Van Damme P, Santosham M, Rodriguez Z, et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. The New England journal of medicine. 2006 Jan 5;354(1):23–33. [DOI] [PubMed] [Google Scholar]
  • [3].Rotavirus vaccines. WHO position paper. January 2013. Weekly epidemiological record. http://www.who.int/wer/2013/wer8805.pdf [Google Scholar]
  • [4].Tate JE, Burton AH, Boschi-Pinto C, Steele AD, Duque J, Parashar UD, et al. 2008 estimate of worldwide rotavirus-associated mortality in children younger than 5 years before the introduction of universal rotavirus vaccination programmes: a systematic review and meta-analysis. The Lancet infectious diseases. 2012. Feb;12(2):136–41. [DOI] [PubMed] [Google Scholar]
  • [5].Tate JE, Chitambar S, Esposito DH, Sarkar R, Gladstone B, Ramani S, et al. Disease and economic burden of rotavirus diarrhoea in India. Vaccine. 2009 Nov 20;27 Suppl 5:F18–24. [DOI] [PubMed] [Google Scholar]
  • [6].Bhandari N, Rongsen-Chandola T, Bavdekar A, John J, Antony K, Taneja S, et al. Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: A randomized double blind placebo controlled trial. Lancet (accepted for publication) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [7].Linhares AC, Velazquez FR, Perez-Schael I, Saez-Llorens X, Abate H, Espinoza F, et al. Efficacy and safety of an oral live attenuated human rotavirus vaccine against rotavirus gastroenteritis during the first 2 years of life in Latin American infants: a randomised, double-blind, placebo-controlled phase III study. Lancet. 2008. Apr 5;371(9619):1181–9. [DOI] [PubMed] [Google Scholar]
  • [8].Vesikari T, Karvonen A, Prymula R, Schuster V, Tejedor JC, Cohen R, et al. Efficacy of human rotavirus vaccine against rotavirus gastroenteritis during the first 2 years of life in European infants: randomised, double-blind controlled study. Lancet. 2007 Nov 24;370(9601):1757–63. [DOI] [PubMed] [Google Scholar]
  • [9].Phua KB, Lim FS, Lau YL, Nelson EA, Huang LM, Quak SH, et al. Safety and efficacy of human rotavirus vaccine during the first 2 years of life in Asian infants: randomised, double-blind, controlled study. Vaccine. 2009 Oct 9;27(43):5936–41. [DOI] [PubMed] [Google Scholar]
  • [10].De Mol P, Zissis G, Butzler JP, Mutwewingabo A, Andre FE. Failure of live, attenuated oral rotavirus vaccine. Lancet. 1986 Jul 12;2(8498):108. [DOI] [PubMed] [Google Scholar]
  • [11].Georges-Courbot MC, Monges J, Siopathis MR, Roungou JB, Gresenguet G, Bellec L, et al. Evaluation of the efficacy of a low-passage bovine rotavirus (strain WC3) vaccine in children in Central Africa. Research in virology. 1991. Sep-Oct;142(5):405–11. [DOI] [PubMed] [Google Scholar]
  • [12].Hanlon P, Hanlon L, Marsh V, Byass P, Shenton F, Hassan-King M, et al. Trial of an attenuated bovine rotavirus vaccine (RIT 4237) in Gambian infants. Lancet. 1987 Jun 13;1(8546):1342–5. [DOI] [PubMed] [Google Scholar]
  • [13].John TJ. Antibody response of infants in tropics to five doses of oral polio vaccine. British medical journal. 1976 Apr 3;1(6013):812. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [14].John TJ, Jayabal P. Oral polio vaccination of children in the tropics. I. The poor seroconversion rates and the absence of viral interference. American journal of epidemiology. 1972. Oct;96(4):263–9. [DOI] [PubMed] [Google Scholar]
  • [15].Lanata CF, Black RE, del Aguila R, Gil A, Verastegui H, Gerna G, et al. Protection of Peruvian children against rotavirus diarrhea of specific serotypes by one, two, or three doses of the RIT 4237 attenuated bovine rotavirus vaccine. The Journal of infectious diseases. 1989. Mar;159(3):452–9. [DOI] [PubMed] [Google Scholar]
  • [16].Linhares AC, Gabbay YB, Mascarenhas JD, de Freitas RB, Oliveira CS, Bellesi N, et al. Immunogenicity, safety and efficacy of tetravalent rhesus-human, reassortant rotavirus vaccine in Belem, Brazil. Bulletin of the World Health Organization. 1996;74(5):491–500. [PMC free article] [PubMed] [Google Scholar]
  • [17].Patriarca PA, Wright PF, John TJ. Factors affecting the immunogenicity of oral poliovirus vaccine in developing countries: review. Reviews of infectious diseases. 1991. Sep-Oct;13(5):926–39. [DOI] [PubMed] [Google Scholar]
  • [18].Madhi SA, Cunliffe NA, Steele D, Witte D, Kirsten M, Louw C, et al. Effect of human rotavirus vaccine on severe diarrhea in African infants. The New England journal of medicine. 2010 Jan 28;362(4):289–98. [DOI] [PubMed] [Google Scholar]
  • [19].Cunliffe NA, Witte D, Ngwira BM, Todd S, Bostock NJ, Turner AM, et al. Efficacy of human rotavirus vaccine against severe gastroenteritis in Malawian children in the first two years of life: A randomized, double-blind, placebo controlled trial. Vaccine. 2012 Apr 27;30 Suppl 1:A36–43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [20].Madhi SA, Kirsten M, Louw C, Bos P, Aspinall S, Bouckenooghe A, et al. Efficacy and immunogenicity of two or three dose rotavirus-vaccine regimen in South African children over two consecutive rotavirus-seasons: A randomized, double-blind, placebo-controlled trial. Vaccine. 2012 Apr 27;30 Suppl 1:A44–51. [DOI] [PubMed] [Google Scholar]
  • [21].Armah GE, Sow SO, Breiman RF, Dallas MJ, Tapia MD, Feikin DR, et al. Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in sub-Saharan Africa: a randomised, double-blind, placebo-controlled trial. Lancet. 2010 Aug 21;376(9741):606–14. [DOI] [PubMed] [Google Scholar]
  • [22].Zaman K, Dang DA, Victor JC, Shin S, Yunus M, Dallas MJ, et al. Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in Asia: a randomised, double-blind, placebo-controlled trial. Lancet. 2010 Aug 21;376(9741):615–23. [DOI] [PubMed] [Google Scholar]
  • [23].Richardson V, Hernandez-Pichardo J, Quintanar-Solares M, Esparza-Aguilar M, Johnson B, Gomez-Altamirano CM, et al. Effect of rotavirus vaccination on death from childhood diarrhea in Mexico. The New England journal of medicine. 2010 Jan 28;362(4):299–305. [DOI] [PubMed] [Google Scholar]
  • [24].Richardson V, Parashar U, Patel M. Childhood diarrhea deaths after rotavirus vaccination in Mexico. The New England journal of medicine. 2011 Aug 25;365(8):772–3. [DOI] [PubMed] [Google Scholar]
  • [25].do Carmo GM, Yen C, Cortes J, Siqueira AA, de Oliveira WK, Cortez-Escalante JJ, et al. Decline in diarrhea mortality and admissions after routine childhood rotavirus immunization in Brazil: a time-series analysis. PLoS medicine. 2011. Apr;8(4):e1001024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [26].Lanzieri TM, Linhares AC, Costa I, Kolhe DA, Cunha MH, Ortega-Barria E, et al. Impact of rotavirus vaccination on childhood deaths from diarrhea in Brazil. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases. 2011. Mar;15(3):e206–10. [DOI] [PubMed] [Google Scholar]
  • [27].Safadi MA, Berezin EN, Munford V, Almeida FJ, de Moraes JC, Pinheiro CF, et al. Hospital-based surveillance to evaluate the impact of rotavirus vaccination in Sao Paulo, Brazil. The Pediatric infectious disease journal. 2010. Nov;29(11):1019–22. [DOI] [PubMed] [Google Scholar]
  • [28].Yen C, Armero Guardado JA, Alberto P, Rodriguez Araujo DS, Mena C, Cuellar E, et al. Decline in rotavirus hospitalizations and health care visits for childhood diarrhea following rotavirus vaccination in El Salvador. The Pediatric infectious disease journal. 2011. Jan;30(1 Suppl):S6–S10. [DOI] [PubMed] [Google Scholar]
  • [29].Chang HG, Smith PF, Tserenpuntsag B, Markey K, Parashar U, Morse DL. Reduction in hospitalizations for diarrhea and rotavirus infections in New York state following introduction of rotavirus vaccine. Vaccine. 2010 Jan 8;28(3):754–8. [DOI] [PubMed] [Google Scholar]
  • [30].Molto Y, Cortes JE, De Oliveira LH, Mike A, Solis I, Suman O, et al. Reduction of diarrhea-associated hospitalizations among children aged < 5 Years in Panama following the introduction of rotavirus vaccine. The Pediatric infectious disease journal. 2011. Jan;30(1 Suppl):S16–20. [DOI] [PubMed] [Google Scholar]
  • [31].Field EJ, Vally H, Grimwood K, Lambert SB. Pentavalent rotavirus vaccine and prevention of gastroenteritis hospitalizations in Australia. Pediatrics. 2010. Sep;126(3):e506–12. [DOI] [PubMed] [Google Scholar]
  • [32].Yen C, Tate JE, Wenk JD, Harris JM, 2nd, Parashar UD. Diarrhea-associated hospitalizations among US children over 2 rotavirus seasons after vaccine introduction. Pediatrics. 2011. Jan;127(1):e9–e15. [DOI] [PubMed] [Google Scholar]
  • [33].Curns AT, Steiner CA, Barrett M, Hunter K, Wilson E, Parashar UD. Reduction in acute gastroenteritis hospitalizations among US children after introduction of rotavirus vaccine: analysis of hospital discharge data from 18 US states. The Journal of infectious diseases. 2010 Jun 1;201(11):1617–24. [DOI] [PubMed] [Google Scholar]
  • [34].Cortese MM, Tate JE, Simonsen L, Edelman L, Parashar UD. Reduction in gastroenteritis in United States children and correlation with early rotavirus vaccine uptake from national medical claims databases. The Pediatric infectious disease journal. 2010. Jun;29(6):489–94. [DOI] [PubMed] [Google Scholar]
  • [35].Begue RE, Perrin K. Reduction in gastroenteritis with the use of pentavalent rotavirus vaccine in a primary practice. Pediatrics. 2010. Jul;126(1):e40–5. [DOI] [PubMed] [Google Scholar]
  • [36].Gurgel RG, Bohland AK, Vieira SC, Oliveira DM, Fontes PB, Barros VF, et al. Incidence of rotavirus and all-cause diarrhea in northeast Brazil following the introduction of a national vaccination program. Gastroenterology. 2009. Dec;137(6):1970–5. [DOI] [PubMed] [Google Scholar]
  • [37].Braeckman T, Van Herck K, Raes M, Vergison A, Sabbe M, Van Damme P. Rotavirus vaccines in Belgium: policy and impact. The Pediatric infectious disease journal. 2011. Jan;30(1 Suppl):S21–4. [DOI] [PubMed] [Google Scholar]
  • [38].Raes M, Strens D, Vergison A, Verghote M, Standaert B. Reduction in pediatric rotavirus-related hospitalizations after universal rotavirus vaccination in Belgium. The Pediatric infectious disease journal. 2011. Jul;30(7):e120–5. [DOI] [PubMed] [Google Scholar]
  • [39].Anderson EJ, Rupp A, Shulman ST, Wang D, Zheng X, Noskin GA. Impact of rotavirus vaccination on hospital-acquired rotavirus gastroenteritis in children. Pediatrics. 2011. Feb;127(2):e264–70. [DOI] [PubMed] [Google Scholar]
  • [40].Eberly MD, Gorman GH, Eide MB, Olsen CH, Rajnik M. The effect of rotavirus immunization on rotavirus gastroenteritis hospitalization rates in military dependents. Vaccine. 2011 Jan 17;29(4):650–9. [DOI] [PubMed] [Google Scholar]
  • [41].Buttery JP, Lambert SB, Grimwood K, Nissen MD, Field EJ, Macartney KK, et al. Reduction in rotavirus-associated acute gastroenteritis following introduction of rotavirus vaccine into Australia’s National Childhood vaccine schedule. The Pediatric infectious disease journal. 2011. Jan;30(1 Suppl):S25–9. [DOI] [PubMed] [Google Scholar]
  • [42].Cortes JE, Curns AT, Tate JE, Cortese MM, Patel MM, Zhou F, et al. Rotavirus vaccine and health care utilization for diarrhea in U.S. children. The New England journal of medicine. 2011 Sep 22;365(12):1108–17. [DOI] [PubMed] [Google Scholar]
  • [43].Payne DC, Staat MA, Edwards KM, Szilagyi PG, Weinberg GA, Hall CB, et al. Direct and indirect effects of rotavirus vaccination upon childhood hospitalizations in 3 US Counties, 2006–2009. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2011 Aug 1;53(3):245–53. [DOI] [PubMed] [Google Scholar]
  • [44].Tate JE, Mutuc JD, Panozzo CA, Payne DC, Cortese MM, Cortes JE, et al. Sustained decline in rotavirus detections in the United States following the introduction of rotavirus vaccine in 2006. The Pediatric infectious disease journal. 2011. Jan;30(1 Suppl):S30–4. [DOI] [PubMed] [Google Scholar]
  • [45].Tate JE, Panozzo CA, Payne DC, Patel MM, Cortese MM, Fowlkes AL, et al. Decline and change in seasonality of US rotavirus activity after the introduction of rotavirus vaccine. Pediatrics. 2009. Aug;124(2):465–71. [DOI] [PubMed] [Google Scholar]
  • [46].Zeller M, Rahman M, Heylen E, De Coster S, De Vos S, Arijs I, et al. Rotavirus incidence and genotype distribution before and after national rotavirus vaccine introduction in Belgium. Vaccine. 2010 Nov 3;28(47):7507–13. [DOI] [PubMed] [Google Scholar]
  • [47].Paulke-Korinek M, Kundi M, Rendi-Wagner P, de Martin A, Eder G, Schmidle-Loss B, et al. Herd immunity after two years of the universal mass vaccination program against rotavirus gastroenteritis in Austria. Vaccine. 2011 Mar 24;29(15):2791–6. [DOI] [PubMed] [Google Scholar]
  • [48].Lopman BA, Curns AT, Yen C, Parashar UD. Infant rotavirus vaccination may provide indirect protection to older children and adults in the United States. The Journal of infectious diseases. 2011 Oct 1;204(7):980–6. [DOI] [PubMed] [Google Scholar]
  • [49].Gentsch JR, Laird AR, Bielfelt B, Griffin DD, Banyai K, Ramachandran M, et al. Serotype diversity and reassortment between human and animal rotavirus strains: implications for rotavirus vaccine programs. The Journal of infectious diseases. 2005 Sep 1;192 Suppl 1:S146–59. [DOI] [PubMed] [Google Scholar]
  • [50].Santos N, Hoshino Y. Global distribution of rotavirus serotypes/genotypes and its implication for the development and implementation of an effective rotavirus vaccine. Reviews in medical virology. 2005. Jan-Feb;15(1):29–56. [DOI] [PubMed] [Google Scholar]
  • [51].Banyai K, Laszlo B, Duque J, Steele AD, Nelson EA, Gentsch JR, et al. Systematic review of regional and temporal trends in global rotavirus strain diversity in the pre rotavirus vaccine era: Insights for understanding the impact of rotavirus vaccination programs. Vaccine. 2012 Apr 27;30 Suppl 1:A122–30. [DOI] [PubMed] [Google Scholar]
  • [52].Gurgel RQ, Cuevas LE, Vieira SC, Barros VC, Fontes PB, Salustino EF, et al. Predominance of rotavirus P[4]G2 in a vaccinated population, Brazil. Emerging infectious diseases. 2007. Oct;13(10):1571–3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [53].Kirkwood CD, Boniface K, Barnes GL, Bishop RF. Distribution of rotavirus genotypes after introduction of rotavirus vaccines, Rotarix(R) and RotaTeq(R), into the National Immunization Program of Australia. The Pediatric infectious disease journal. 2011. Jan;30(1 Suppl):S48–53. [DOI] [PubMed] [Google Scholar]
  • [54].Correia JB, Patel MM, Nakagomi O, Montenegro FM, Germano EM, Correia NB, et al. Effectiveness of monovalent rotavirus vaccine (Rotarix) against severe diarrhea caused by serotypically unrelated G2P[4] strains in Brazil. The Journal of infectious diseases. 2010 Feb 1;201(3):363–9. [DOI] [PubMed] [Google Scholar]
  • [55].Justino MC, Linhares AC, Lanzieri TM, Miranda Y, Mascarenhas JD, Abreu E, et al. Effectiveness of the monovalent G1P[8] human rotavirus vaccine against hospitalization for severe G2P[4] rotavirus gastroenteritis in Belem, Brazil. The Pediatric infectious disease journal. 2011. May;30(5):396–401. [DOI] [PubMed] [Google Scholar]
  • [56].Snelling TL, Andrews RM, Kirkwood CD, Culvenor S, Carapetis JR. Case-control evaluation of the effectiveness of the G1P[8] human rotavirus vaccine during an outbreak of rotavirus G2P[4] infection in central Australia. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2011 Jan 15;52(2):191–9. [DOI] [PubMed] [Google Scholar]
  • [57].Snelling TL, Schultz R, Graham J, Roseby R, Barnes GL, Andrews RM, et al. Rotavirus and the indigenous children of the Australian outback: monovalent vaccine effective in a high-burden setting. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2009 Aug 1;49(3):428–31. [DOI] [PubMed] [Google Scholar]
  • [58].de Palma O, Cruz L, Ramos H, de Baires A, Villatoro N, Pastor D, et al. Effectiveness of rotavirus vaccination against childhood diarrhoea in El Salvador: case-control study. Bmj. 2010;340:c2825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [59].Yen C, Figueroa JR, Uribe ES, Carmen-Hernandez LD, Tate JE, Parashar UD, et al. Monovalent rotavirus vaccine provides protection against an emerging fully heterotypic G9P[4] rotavirus strain in Mexico. The Journal of infectious diseases. 2011 Sep 1;204(5):783–6. [DOI] [PubMed] [Google Scholar]
  • [60].Boom JA, Tate JE, Sahni LC, Rench MA, Hull JJ, Gentsch JR, et al. Effectiveness of pentavalent rotavirus vaccine in a large urban population in the United States. Pediatrics. 2010. Feb;125(2):e199–207. [DOI] [PubMed] [Google Scholar]
  • [61].Staat MA, Payne DC, Donauer S, Weinberg GA, Edwards KM, Szilagyi PG, et al. Effectiveness of pentavalent rotavirus vaccine against severe disease. Pediatrics. 2011. Aug;128(2):e267–75. [DOI] [PubMed] [Google Scholar]
  • [62].Patel M, Pedreira C, De Oliveira LH, Tate J, Orozco M, Mercado J, et al. Association between pentavalent rotavirus vaccine and severe rotavirus diarrhea among children in Nicaragua. JAMA : the journal of the American Medical Association. 2009 Jun 3;301(21):2243–51. [DOI] [PubMed] [Google Scholar]
  • [63].Murphy TV, Gargiullo PM, Massoudi MS, Nelson DB, Jumaan AO, Okoro CA, et al. Intussusception among infants given an oral rotavirus vaccine. The New England journal of medicine. 2001 Feb 22;344(8):564–72. [DOI] [PubMed] [Google Scholar]
  • [64].Centers for Disease C, Prevention. Withdrawal of rotavirus vaccine recommendation. MMWR Morbidity and mortality weekly report. 1999 Nov 5;48(43):1007. [PubMed] [Google Scholar]
  • [65].Centers for Disease C, Prevention. Intussusception among recipients of rotavirus vaccine--United States, 1998–1999. MMWR Morbidity and mortality weekly report. 1999 Jul 16;48(27):577–81. [PubMed] [Google Scholar]
  • [66].Peter G, Myers MG, National Vaccine Advisory C, National Vaccine Program O. Intussusception, rotavirus, and oral vaccines: summary of a workshop. Pediatrics. 2002. Dec;110(6):e67. [DOI] [PubMed] [Google Scholar]
  • [67].Patel MM, Lopez-Collada VR, Bulhoes MM, De Oliveira LH, Bautista Marquez A, Flannery B, et al. Intussusception risk and health benefits of rotavirus vaccination in Mexico and Brazil. The New England journal of medicine. 2011 Jun 16;364(24):2283–92. [DOI] [PubMed] [Google Scholar]
  • [68].Buttery JP, Danchin MH, Lee KJ, Carlin JB, McIntyre PB, Elliott EJ, et al. Intussusception following rotavirus vaccine administration: post-marketing surveillance in the National Immunization Program in Australia. Vaccine. 2011 Apr 5;29(16):3061–6. [DOI] [PubMed] [Google Scholar]
  • [69].Belongia EA, Irving SA, Shui IM, Kulldorff M, Lewis E, Yin R, et al. Real-time surveillance to assess risk of intussusception and other adverse events after pentavalent, bovine-derived rotavirus vaccine. The Pediatric infectious disease journal. 2010. Jan;29(1):1–5. [DOI] [PubMed] [Google Scholar]
  • [70].Haber P, Patel M, Izurieta HS, Baggs J, Gargiullo P, Weintraub E, et al. Postlicensure monitoring of intussusception after RotaTeq vaccination in the United States, February 1, 2006, to September 25, 2007. Pediatrics. 2008. Jun;121(6):1206–12. [DOI] [PubMed] [Google Scholar]
  • [71].Shui IM, Baggs J, Patel M, Parashar UD, Rett M, Belongia EA, et al. Risk of intussusception following administration of a pentavalent rotavirus vaccine in US infants. JAMA : the journal of the American Medical Association. 2012 Feb 8;307(6):598–604. [DOI] [PubMed] [Google Scholar]
  • [72].Yen C, Tate JE, Steiner CA, Cortese MM, Patel MM, Parashar UD. Trends in Intussusception Hospitalizations among US Infants Before and After Implementation of the Rotavirus Vaccination Program, 2000–2009. The Journal of infectious diseases. 2012 Apr 26. [DOI] [PubMed] [Google Scholar]
  • [73].Atherly DE, Lewis KDC, Tate J, Parashar UD, Rheingans RD. Projected health and economic impact of rotavirus vaccination in GAVI-eligible countries: 2011–2030. Vaccine. 2010;30 (Suppl 1):A7–A14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [74].Esposito DH, Tate JE, Kang G, Parashar UD. Projected impact and cost-effectiveness of a rotavirus vaccination program in India, 2008. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2011 Jan 15;52(2):171–7. [DOI] [PubMed] [Google Scholar]
  • [75].Rose J, Hawthorn RL, Watts B, Singer ME. Public health impact and cost effectiveness of mass vaccination with live attenuated human rotavirus vaccine (RIX4414) in India: model based analysis. Bmj. 2009;339:b3653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [76].Desai R, Cortese MM, Meltzer MI, Shankar M, Tate JE, Yen C, Patel MM, Parashar UD. Potential intussusception risk versus benefits of rotavirus vaccination in the United States. Pediatr Infect Dis J. 2013. Jan;32(1):1–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [77].Kang G, Arora R, Chitambar SD, Deshpande J, Gupte MD, Kulkarni M, et al. Multicenter, hospital-based surveillance of rotavirus disease and strains among indian children aged <5 years. The Journal of infectious diseases. 2009 Nov 1;200 Suppl 1:S147–53. [DOI] [PubMed] [Google Scholar]
  • [78].Miles MG, Lewis KD, Kang G, Parashar UD, Steele AD. A systematic review of rotavirus strain diversity in India, Bangladesh, and Pakistan. Vaccine. 2012 Apr 27;30 Suppl 1:A131–9. [DOI] [PubMed] [Google Scholar]
  • [79].Kahn G, Fitzwater S, Tate J, Kang G, Ganguly N, Nair G, et al. Epidemiology and Prospects for Prevention of Rotavirus Disease in India. Indian Pediatrics. 2012;49(6):467–74. [DOI] [PubMed] [Google Scholar]
  • [80].Quintanar-Solares M, Yen C, Richardson V, Esparza-Aguilar M, Parashar UD, Patel MM. Impact of rotavirus vaccination on diarrhea-related hospitalizations among children < 5 years of age in Mexico. The Pediatric infectious disease journal. 2011. Jan;30(1 Suppl):S11–5. [DOI] [PubMed] [Google Scholar]
  • [81].Carlin JB, Macartney KK, Lee KJ, Quinn HE, Buttery J, Lopert R, Bines J, McIntyre PB. Intussusception risk and disease prevention associated with rotavirus vaccines in Australia’s National Immunization Program. Clin Infect Dis. 2013. Nov;57(10):1427–34. [DOI] [PubMed] [Google Scholar]

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