Abstract

Two new vaccines against severe rotavirus gastroenteritis that have high efficacy in middle- and high-income countries have recently been licensed in many countries worldwide. Clinical trials in low-income countries in Africa and Asia are ongoing. Experience gained through studies of natural rotavirus infection and the clinical trials for the current and previous rotavirus vaccines indicate that, as countries begin to introduce these newly approved vaccines into routine childhood immunization programs, monitoring their performance in real world settings should be a high priority. Key epidemiological considerations in the postlicensure period include (1) how the vaccine will perform against severe rotavirus disease under routine public health use; (2) how routine vaccination will impact the epidemiology of disease with regard to the burden of severe disease and death, age distribution of cases, seasonality, and serotype distribution; (3) whether vaccination will have a sufficient impact on transmission to reduce disease burden in unvaccinated age groups; and (4) whether vaccine will confer protection through the first 3 years of life, when most severe disease and mortality associated with rotavirus occur. Monitoring of impact with focus on these public health considerations will allow parents, health care providers, and decision makers to appreciate the health benefits of vaccination in reducing the burden of severe rotavirus disease. It will also allow assessment of the effectiveness of rotavirus vaccines in programmatic use and the need for modifying vaccination schedules or vaccine formulations to enhance the performance of immunization. In this article, we review data for the protective efficacy of the 2 new rotavirus vaccines, with emphasis on issues particularly important for consideration as these vaccines are introduced in routine infant immunization programs

With the licensure and introduction of 2 new rotavirus vaccines (RotaTeq [Merck Vaccines] and Rotarix [GlaxoSmithKline Biologicals]) in routine immunization programs, monitoring their impact on rotavirus-associated morbidity and mortality and demonstrating public health benefits of vaccination are high priorities in many countries worldwide. Prelicensure clinical trials of these vaccines have demonstrated excellent efficacy (85%–98%) against severe rotavirus disease in middle- and high-income countries [1–9]. In developing countries, many factors, such as interference by maternal antibodies, breastfeeding, prevalent viral and bacterial gut infections, and malnutrition, might adversely affect the performance of these vaccines, and trials to evaluate efficacy in these settings are underway [10, 11]. In middle- and high-income countries, variations in use of the vaccine in routine public health practice, compared with clinical trials, could also lead to efficacy that is different from that in clinical trials. In addition, efficacy could vary in areas where the prevalence of strains is different from that in clinical trials [12]. In this article, we review key issues that remain to be fully addressed regarding the effectiveness and public health impact of rotavirus vaccines and outline a framework to address these issues as rotavirus vaccines become a component of routine infant immunization programs globally

Key Issues

Impact on health care use for diarrhea, including herd immunityIn addition to their high demonstrated efficacy against severe rotavirus disease, both Rotarix and RotaTeq substantially reduced overall health care use for diarrhea in clinical trials (Table 1). In the trials, Rotarix reduced the rate of hospitalizations for all-cause gastroenteritis by 42% in Latin America and by 72% in Europe [1, 2]. Similarly, RotaTeq reduced the rate of hospital admissions for all-cause gastroenteritis by 59% in studies conducted primarily in Finland and the United States [3]. These reductions should have a noticeable impact on decreasing childhood morbidity if field effectiveness is similar to efficacy in trials [2]

Table 1

Review of Efficacy Data from Clinical Trials of Rotarix and RotaTeq

Table 1

Review of Efficacy Data from Clinical Trials of Rotarix and RotaTeq

In addition to the direct benefits for vaccinated infants, it is possible that vaccination of a proportion of the population could reduce overall transmission of rotavirus in the community and, thus, also could lead to a reduction in disease risk among unvaccinated persons who are part of the community (ie, herd immunity). Indeed, early postlicensure data from the United States indicate that the decrease in the prevalence of rotavirus disease after vaccine introduction appears to be greater than that expected based on levels of vaccine coverage, and reductions have also been noted among older infants who are age-ineligible for vaccination, raising the possibility of herd immunity [13]

Impact on the prevalence of rotavirus strains and strain-specific vaccine effectivenessIn the Latin American and Finnish trials of Rotarix, a monovalent P[8]G1 vaccine, cross-protection was observed against the most common circulating strains (G1, G3, G4, and G9) that share P[8] serotype specificity, with efficacy ranging from 82% to 96% against severe rotavirus disease caused by these strains (Table 2) [1, 2, 6, 9]. In Latin America, Rotarix was less effective against G2 strains (vaccine effectiveness, 44%; 95% confidence interval [CI], <0% to 88%), which belong to a different G serotype, P subtype, and genogroup than do the vaccine strain and other globally common strains [1]. In Finland, however, Rotarix did confer good protection against severe disease caused by P[4]G2 strains (vaccine effectiveness, 86%; 95% CI, 24%–98%)

Table 2

Strain-Specific Efficacy of Rotarix and RotaTeq against Severe Rotavirus Gastroenteritis or Hospitalizations and Emergency Department Visits

Table 2

Strain-Specific Efficacy of Rotarix and RotaTeq against Severe Rotavirus Gastroenteritis or Hospitalizations and Emergency Department Visits

These findings have prompted debate over whether Rotarix vaccine will provide sufficient protection against P[4]G2 strains [14]. The small number of P[4]G2 strains detected among placebo recipients (n=7) with severe disease in the Latin American trials indicates that P[4]G2 was not circulating during the trial period, and thus, the study did not attain power to conclusively assess protection against this strain [6]. In a meta-analysis of phase II and III studies, the efficacy of Rotarix against severe diarrhea caused by the P[4]G2 strain was estimated to be 71% (95% CI, 20%–91%) [15]. More recently, 2 surveillance studies from Brazil, one of the first countries to implement routine childhood vaccination with Rotarix vaccine, have identified P[4]G2 strains in a large proportion of children with severe diarrhea [16, 17]. Although the observed predominance of P[4]G2 strains in this Brazilian community with Rotarix vaccination coverage of ∼50% is intriguing, it could represent a natural shift in strains that is unrelated to vaccination. For example, in ongoing hospital-based surveillance in El Salvador, where routine Rotarix vaccination was introduced in 2006, P[4]G2 was also predominant (∼80% of total cases were caused by the strain) in 2005–2006, before vaccine introduction [18]. However, P[8]G1 strains became predominant (∼90% of total cases were caused by the strains) during the first rotavirus season after vaccine implementation; only 2% of strains were P[4]G2. Similar findings of periodic strain emergence in the absence of vaccination have been extensively documented in other settings and will likely continue to occur during the postlicensure period. Determination of whether emerging strains are related to vaccination will require caution and careful consideration for employing longitudinal surveillance and epidemiologic studies to better assess interaction of the vaccine with strain ecology

In the Rotavirus Efficacy and Safety Trial (REST) of the pentavalent RotaTeq vaccine, a high level of efficacy was observed against all G1–G4 and G9 serotypes (range, 88%–100%) [2, 3]. Of note, during the study period, relatively few (14%) non-G1 rotavirus strains were in circulation; thus, estimates had wide confidence intervals, and efficacy against non-G1 strains warrants closer attention during the postlicensure period. The pentavalent vaccine conferred 88% (95% CI, <0% to 98%) protection against P[4]G2 strains in Finland and the United States, but data should be cautiously interpreted, because only 8 children in the placebo group were infected with the strain [2, 3]. A recently reported 3-year follow-up of Finnish infants who were part of REST revealed that efficacy against severe rotavirus diarrhea caused by P[4]G2 strains was 82%, compared with >93% efficacy against other strains [19]

Effectiveness of partial vaccinationBecause trials of the currently licensed vaccines were designed to evaluate the full series, few children in the trial received less than a full series of the vaccines. However, some of the burden of severe rotavirus disease may occur among children <6 months of age, before completion of the full series of the vaccine, thus highlighting the importance of evaluating the effectiveness of partial vaccination

With regard to Rotarix, evidence from the recent European trial suggests that the first dose conferred protection of 90% against rotavirus disease of any severity for cases that occurred between receipt of doses (Table 3) [2]. Few cases of severe rotavirus disease precluded firm assessment of efficacy against this outcome

Table 3

Review of Efficacy Data on Subpopulations from Clinical Trials of Rotarix and RotaTeq

Table 3

Review of Efficacy Data on Subpopulations from Clinical Trials of Rotarix and RotaTeq

With regard to RotaTeq, an initial subanalysis of REST suggested that a partial vaccine series was unlikely to protect against severe rotavirus gastroenteritis, with an efficacy of 29% after dose 1 and 80% after dose 2 (Table 3) [20]. However, because this analysis included children immediately after vaccination and because not all children in the cohort were included in the follow-up analysis, the authors recently reanalyzed the data for partial dose efficacy. In this reanalysis, they included the entire study cohort that was monitored for hospitalizations and emergency department visits to assess for breakthrough rotavirus events leading to a hospital visit between doses (ie, from 14 days after the administered dose to the following dose). In this analysis, the first dose conferred 82% protection against rotavirus hospitalization and emergency department visits, and the second dose conferred 84% protection [21]

Duration of protectionTo have an optimal public health impact, rotavirus vaccines would need to provide protection against severe disease in children ⩽2 years of age in developing countries and in children ⩽3 years of age in industrialized countries. With regard to Rotarix, recently published data on efficacy in the large clinical cohorts suggest that, although efficacy decreased slightly in Latin America (from 83% to 79%) and Europe (from 96% to 86%) during the second season of follow-up, overall vaccine protection was sustained at a reasonable level in children ⩽2 years of age (Table 1) [2, 6]

With regard to RotaTeq, a subset of the cohort involved in the clinical efficacy analysis and the cohort involved in health care use in REST were followed up through the second rotavirus season after vaccination. In the cohort involved in the clinical efficacy analysis, overall efficacy was high during both years; however, protection was decreased by 10% during the second season (88%), compared with the first season (98%), which suggests that a waning effect with time may occur [3]. From the cohort involved in the health care use analysis in REST, a smaller cohort of 2502 children were followed up for 2 years, and although data on efficacy against hospitalization during the second season have not been published, overall efficacy in this cohort (97%; 95% CI, 82%–100%) was similar to that in the cohort with 1 year of follow-up (94%; 95% CI, 91%–97%); this finding indicates that there was a sustained level of protection [8]. A recently completed extension of REST demonstrated a sustained reduction in the number of hospitalizations for rotavirus disease for 3 years after vaccination [19]

Coadministration with oral poliovirus vaccine (OPV)The concern of gut interference between OPV and oral rotavirus vaccine was initially evaluated in a Rotarix trial involving 450 South African infants [22]. In this trial, no impact on seroconversion against rotavirus was noted at 6 months of age among infants who received Rotarix concomitantly with either OPV or inactivated poliovirus vaccine at 6 and 10 weeks or 10 and 14 weeks of age, respectively. After the first dose at 6 weeks of age, rotavirus IgA seroconversion rates were ∼60% lower among infants who received Rotarix concomitantly with OPV than among infants who did not receive OPV; however, after the second dose at 10 weeks of age, seroconversion (anti-rotavirus IgA antibodies) rates were similar in both groups. In a phase III clinical trial in 6 Latin American countries in which 2 doses of Rotarix were administered concomitantly with OPV, Rotarix conferred 88% protection against hospitalization for rotavirus gastroenteritis (Table 3) [23]. This finding was comparable to the efficacy in the large trial in 11 Latin American countries in which OPV and rotavirus vaccines were administered sequentially with a 2-week interval

Concomitant administration of RotaTeq with OPV did not interfere with titers against polioviruses 1, 2, or 3. The geometric mean titers for anti-rotavirus IgA were 50% lower in the group that received RotaTeq and OPV concomitantly than in the group that received OPV 2 weeks after receipt of RotaTeq [24]. However, the seroconversion rates were high in both groups (93% and 98%, respectively). Trials on the efficacy of RotaTeq coadministered with OPV have not been conducted; however, when administered with other parenteral vaccines, efficacy was 90% against severe rotavirus disease [25]

Studies involving vulnerable groupsRotarix has also been demonstrated to have equal efficacy against severe rotavirus gastroenteritis in Venezuelan and Brazilian infants considered to be well nourished (vaccine effectiveness, 73%), compared with malnourished infants (vaccine effectiveness, 74%), when using World Health Organization (WHO) growth charts for weight-for-age to assess nutritional status (Table 3) [26]. Studies are currently ongoing in Africa to assess the safety and efficacy of Rotarix in human immunodeficiency virus (HIV)–infected infants

In a subset of REST, RotaTeq reduced rates of hospitalization for rotavirus gastroenteritis by 96% among premature infants (born at 25–36 gestational weeks of age) [27]. No published data exist on efficacy in malnourished infants. Studies to assess the safety and efficacy of RotaTeq that include HIV-infected infants are ongoing in Africa

Vaccine performance in developing countriesThe first study to assess the efficacy of Rotarix in Africa (South Africa and Malawi) has been completed. An interim analysis of data for the South African cohort indicates a potentially promising future for this vaccine if similar results are obtained in other developing countries in Asia and Africa. In South Africa, 2 doses of the vaccine offered 77% protection against severe rotavirus gastroenteritis during the first year of life [28]. P[8]G1 comprised 54%–56% of the circulating strains in the study population. In contrast, efficacy was only 49% in the low-income country of Malawi [28]. The efficacy of RotaTeq in low socioeconomic settings in Asia and Africa is currently being assessed in clinical trials, and completion is anticipated in 2009

Monitoring the Impact and Effectiveness of Rotavirus Vaccines after Introduction

With the licensure and introduction of the 2 new rotavirus vaccines in routine immunization programs, the WHO has highlighted the need for monitoring the impact of these vaccines on rotavirus-associated morbidity and mortality and for assessing the public health benefits of vaccination (Table 4). In this section, we summarize a framework for monitoring the impact of rotavirus vaccines once they are introduced in routine immunization schedules. Additional details are outlined in a recently published WHO generic protocol for monitoring the impact of rotavirus vaccination [29]

Table 4

Objectives and Rationale for Assessing Postlicensure Performance of Rotavirus Vaccines

Table 4

Objectives and Rationale for Assessing Postlicensure Performance of Rotavirus Vaccines

Assessment of vaccine impact by monitoring trends in gastroenteritis and rotavirus disease burdenVaccine impact can be monitored by assessing trends in gastroenteritis and rotavirus disease burden and correlating decreases in disease incidence with vaccination coverage rates. Because the efficacy of rotavirus vaccines is greatest against severe rotavirus disease, the impact of vaccination will be greatest on severe outcomes, such as hospitalization. Furthermore, because rotavirus disease accounts for 30%–50% of all hospitalizations of young children with acute gastroenteritis, the impact of vaccination might be visible even if only data on hospitalization for all-cause gastroenteritis are available, especially in settings where rotavirus disease is seasonal. Depending on the availability of data, in addition to assessment of hospitalizations, countries may want to assess visits to outpatient clinics and emergency departments for gastroenteritis

Consideration of how the epidemiology of rotavirus disease might change in the era after initiation of vaccination will also be crucial when monitoring disease trends. The reduction in the prevalence of severe disease should be proportional to the vaccination coverage rates in the region and will be seen primarily in infants <1 year of age during the first year of vaccine introduction, in infants <2 years of age during the second year of the program, and in incrementally increasing age groups during successive years. However, the possibility exists that rotavirus vaccines may interrupt transmission and, thus, protect not only children <5 years of age, the age group targeted for vaccine (direct effects), but also other age groups (indirect effects or herd immunity), such as school-age children and adults, in whom rotavirus disease has been reported to occur but remains to be well studied [30–33]

Two general sources of data would meet the objectives of monitoring disease trends in the context of assessing vaccine impact: (1) primary data sources, such as an active gastroenteritis surveillance system, or (2) secondary data sources, such as national data on hospitalizations for gastroenteritis. Although these data are often incomplete and nonspecific, consideration of factors, such as monitoring data from several years before and after vaccine introduction, comparing rates in vaccinated age groups with those in unvaccinated age groups, assessing changes in seasonal patterns (eg, delays in onset of rotavirus season), and monitoring for changing age patterns of illness, may allow for a reasonable assessment of potential vaccine impact

Active surveillance systemsPrimary data sources relevant to the demonstration of rotavirus vaccine impact would involve an active surveillance system at sentinel hospitals where children <5 years of age who have diarrhea are systematically tested for rotavirus disease [34]. Ideally, surveillance would be initiated at least 1–2 years before vaccine introduction to ensure baseline rates of hospitalization for rotavirus disease. Such an active surveillance system would allow monitoring of vaccine impact by assessing the reduction in the rate of hospitalization for rotavirus disease in conjunction with vaccine coverage rates, as demonstrated for other vaccine-preventable diseases [35–37]

Secondary data sourcesRegions and countries may have existing data sources on all-cause gastroenteritis, such as hospital discharge and national mortality data, which could be useful for establishing diarrhea disease burden and trends after vaccine introduction. If interpreted with caution, this approach of using existing data sources to monitor trends in rotavirus and all-cause gastroenteritis disease burden may be useful in assessing vaccine impact in a region with known vaccination coverage

Assessing vaccine effectiveness with use of a case-control designThe ideal measure of vaccine impact is demonstrating a reduction in rotavirus disease incidence in the vaccinated population. However, from an operational perspective, monitoring secular trends in all-cause gastroenteritis– and rotavirus-associated health outcomes to demonstrate the impact of vaccination can be challenging because of the need for baseline data before implementation of vaccination and difficulties in interpretation of trends because of natural year-to-year variation in disease incidence. Furthermore, a high level of vaccine coverage may need to be achieved before impact may be visible through these ecological methods. Therefore, in the early phases of introduction of rotavirus vaccine in a country, the field performance of a vaccine might be better assessed by conducting specialized epidemiological methods, such as case-control studies [38–40]

With use of a case-control method, vaccine effectiveness can be estimated by comparing the prevalence of vaccination among patients with rotavirus disease with that among control subjects without disease. Interpretation of vaccine effectiveness data in conjunction with vaccination coverage rates would also provide indirect estimates of vaccine impact on rotavirus disease burden. Advantages of the case-control design include efficiency in terms of cost and time to conduct the study and the opportunity to address other parameters of interest (eg, efficacy by severity of disease, effectiveness of partial vaccination, effectiveness against specific rotavirus strains, duration of protection, and potential interference from concomitant OPV administration) and to identify potential risk factors for poor vaccine performance (eg, breastfeeding and low socioeconomic status). Case-control studies might also be used to assess the impact of rotavirus vaccination on reduction in mortality, an outcome that will not be addressed in ongoing clinical trials in low-income countries

The study is ideally implemented when coverage is 20%–80%, because the sample size is substantially higher outside this range of coverage and could pose practical challenges for the use of this method [29]. In regions with well-established immunization programs, we have noted that vaccine uptake in the age-eligible group can reach a high, steady state soon after vaccine introduction (1–2 years) [41]. In addition, the logistics of a case-control study can be complex; therefore, it is important to plan the study at the beginning of or before implementation of a vaccination program

Assessment of the impact of vaccination on rotavirus strainsTwo questions with regard to the impact of vaccination on rotavirus strains warrant close scrutiny [12, 14, 18]. Will strain-specific variations in efficacy occur? Will vaccination exert a selective pressure resulting in antigenic shifts or drifts of public health concern? Information on the prevalence of circulating rotavirus strains will be important for assessing the likely impact of vaccine, for understanding reasons for any observed reduction in vaccine effectiveness, and for monitoring possible changes in strains as a result of vaccination. For example, rare human strains and reassortants between wild-type and vaccine strains may become more common in humans after vaccine introduction [12]. In addition to assessing the prevalence of different strains before and after vaccine implementation, evaluating strain-specific disease incidence over several seasons and strain-specific vaccine effectiveness through epidemiological studies will allow full assessment of the public health impact of vaccination. Examination of strains among children who become infected despite receiving vaccination and monitoring for emergence of unusual reassortants of common strains will also help with understanding of mechanisms of immunity against rotavirus and viral evolution

Because of known secular trends and regional differences in strain variation even before vaccine introduction, strain surveillance data should be cautiously interpreted with regard to determining the association between vaccination and any observed changes in the circulating strains in the vaccinated community. Perhaps a better measure of public health impact of vaccination on strain prevalence might be through a case-control evaluation of vaccine effectiveness against specific strains

Summary

In summary, clinical trials of rotavirus vaccines in middle- and high-income countries have demonstrated high efficacy against severe rotavirus disease, including a substantial reduction in the incidence of severe gastroenteritis caused by any pathogen. Two important topics will be studied over the next several years: (1) the efficacy of the vaccines in low-income settings and (2) performance of the vaccines under routine field settings. As countries begin to introduce rotavirus vaccines in routine childhood immunization programs, opportunities will exist to address many unanswered scientific questions about vaccine performance in different settings and to demonstrate the real world impact and value of these vaccines to parents, physicians, and policy makers, thereby generating key evidence to sustain vaccine use

References

1
Ruiz-Palacios
GM
Perez-Schael
I
Velazquez
FR
, et al.  . 
Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis
N Engl J Med
 , 
2006
, vol. 
354
 (pg. 
11
-
22
)
2
Vesikari
T
Karvonen
A
Prymula
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
, vol. 
370
 (pg. 
1757
-
63
)
3
Vesikari
T
Matson
DO
Dennehy
P
, et al.  . 
Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine
N Engl J Med
 , 
2006
, vol. 
354
 (pg. 
23
-
33
)
4
Araujo
EC
Clemens
SA
Oliveira
CS
, et al.  . 
Safety, immunogenicity, and protective efficacy of two doses of RIX4414 live attenuated human rotavirus vaccine in healthy infants
J Pediatr
 , 
2007
, vol. 
83
 (pg. 
217
-
24
)
5
Clark
HF
Bernstein
DI
Dennehy
PH
, et al.  . 
Safety, efficacy, and immunogenicity of a live, quadrivalent human-bovine reassortant rotavirus vaccine in healthy infants
J Pediatr
 , 
2004
, vol. 
144
 (pg. 
184
-
90
)
6
Linhares
AC
Velazquez
FR
Perez-Schael
I
, 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
, vol. 
371
 (pg. 
1181
-
9
)
7
Salinas
B
Perez Schael
I
Linhares
AC
, et al.  . 
Evaluation of safety, immunogenicity and efficacy of an attenuated rotavirus vaccine, RIX4414: a randomized, placebo-controlled trial in Latin American infants
Pediatr Infect Dis J
 , 
2005
, vol. 
24
 (pg. 
807
-
16
)
8
Vesikari
T
Itzler
R
Matson
DO
, et al.  . 
Efficacy of a pentavalent rotavirus vaccine in reducing rotavirus-associated health care utilization across three regions (11 countries)
Int J Infect Dis
 , 
2007
, vol. 
11
 
Suppl 2
(pg. 
S29
-
35
)
9
Vesikari
T
Karvonen
A
Puustinen
L
, et al.  . 
Efficacy of RIX4414 live attenuated human rotavirus vaccine in Finnish infants
Pediatr Infect Dis J
 , 
2004
, vol. 
23
 (pg. 
937
-
43
)
10
Steele
AD
Update on rotavirus vaccines
Pediatr Infect Dis J
 , 
2005
, vol. 
24
 (pg. 
947
-
52
)
11
Glass
RI
Parashar
UD
Bresee
JS
, et al.  . 
Rotavirus vaccines: current prospects and future challenges
Lancet
 , 
2006
, vol. 
368
 (pg. 
323
-
32
)
12
Laird
AR
Bielfelt
B
, et al.  . 
Serotype diversity and reassortment between human and animal rotavirus strains: implications for rotavirus vaccine programs
J Infect Dis
 , 
2005
, vol. 
192
 
Suppl 1
(pg. 
S146
-
59
)
13
Delayed onset and diminished magnitude of rotavirus activity—United States November 2007-May 2008
MMWR Morb Mortal Wkly Rep
 , 
2008
, vol. 
57
 (pg. 
697
-
700
)
14
Grimwood
K
Kirkwood
CD
Human rotavirus vaccines: too early for the strain to tell
Lancet
 , 
2008
, vol. 
371
 (pg. 
1144
-
5
)
15
De Vos
B
Han
HH
Bouckenooghe
A
, et al.  . 
Live attenutated human rotavirus vaccine, RIX4414, provides clinical protection in infants against rotavirus strains with and without shared G and P genotypes: integrated analysis of randomized controlled trials
Pediatr Infect Dis J
 , 
2009
, vol. 
28
 (pg. 
261
-
6
)
16
Gurgel
RQ
Cuevas
LE
Vieira
SC
, et al.  . 
Predominance of rotavirus P[4]G2 in a vaccinated population, Brazil
Emerg Infect Dis
 , 
2007
, vol. 
13
 (pg. 
1571
-
3
)
17
Nakagomi
T
Cuevas
LE
Gurgel
RG
, et al.  . 
Apparent extinction of non-G2 rotavirus strains from circulation in Recife, Brazil, after the introduction of rotavirus vaccine
Arch Virol
 , 
2008
, vol. 
153
 (pg. 
591
-
3
)
18
Patel
MM
de Oliveira
LH
Bispo
AM
Gentsch
J
Parashar
UD
Rotavirus P[4]G2 in a vaccinated population, Brazil
Emerg Infect Dis
 , 
2008
, vol. 
14
 (pg. 
863
-
5
)
19
Vesikari
T
Karvonen
A
Allen
S
Lawrence
J
Ciarlet
M
Serotype-specific efficacy of the pentavalent rotavirus vaccine against hospitalizations and emergency department visits up to three years [abstract G2-3747]
Program and abstracts of the the 48th Interscience Conference on Antimicrobial Agents and Chemotherapy and the 46th Infectious Diseases Society of America Annual Meeting
 , 
2008
20
Vesikari
T
Matson
D
Dennehy
P
, et al.  . 
Efficacy of the pentavalent rotavirus vaccine in subjects after 1 or 2 doses in the Rotavirus Efficacy & Safety Trial (REST) [abstract 145]
Program and abstracts of the 44th Annual Meeting of the Infectious Disease Society of America
 , 
2006
pg. 
58
 
21
Vesikari
T
Dennehy
P
Matson
D
, et al.  . 
Efficacy of pentavalent rotavirus vaccine, RotaTeq, between doses: potential benefits of early protection [abstract P-12]
Program and abstracts of the 8th International Rotavirus Syposium
 , 
2008
pg. 
49
 
22
Steele
AD
De Vos
B
Tumbo
J
, et al.  . 
Co-administration study in South African infants of a live-attenuated oral human rotavirus vaccine (RIX4414) and poliovirus vaccines
Vaccine
 , 
2008
 
(Epub ahead of print)
23
Tregnaghi
M
Lopez
P
De Leon
T
, et al.  . 
Oral human rotavirus vaccine RIX4414 (Rotarix™) co-administered with routine EPI vaccinations including oral polio vaccine (OPV) is highly efficacious in Latin-America]. Program and abstracts of the 13th International Congress on Infectious Diseases (Kuala Lumpur, Malaysia)
Int J Infect Dis
 , 
2008
, vol. 
122
 
(Suppl 1)
(pg. 
:e147
-
8
)
24
Ciarlet
M
Sani-Grosso
R
Yuan
G
, et al.  . 
Concomitant use of the oral pentavalent human-bovine reassortant rotavirus vaccine and oral poliovirus vaccine
Pediatr Infect Dis J
 , 
2008
, vol. 
27
 (pg. 
874
-
80
)
25
Rodriguez
ZM
Goveia
MG
Stek
JE
, et al.  . 
Concomitant use of an oral live pentavalent human-bovine reassortant rotavirus vaccine with licensed parenteral pediatric vaccines in the United States
Pediatr Infect Dis J
 , 
2007
, vol. 
26
 (pg. 
221
-
7
)
26
Perez-Schael
I
Salinas
B
Tomat
M
, et al.  . 
Efficacy of the human rotavirus vaccine RIX4414 in malnourished children
J Infect Dis
 , 
2007
, vol. 
196
 (pg. 
537
-
40
)
27
Goveia
MG
Rodriguez
ZM
Dallas
MJ
, et al.  . 
Safety and efficacy of the pentavalent human-bovine (WC3) reassortant rotavirus vaccine in healthy premature infants
Pediatr Infect Dis J
 , 
2007
, vol. 
26
 (pg. 
1099
-
104
)
28
Cunliffe
NA
Kirsten
M
Madhi
S
, et al.  . 
Efficacy of human rotavirus vaccine RIx4414 in Africa during the first year of life [abstract 572]
Program and abstracts of the 26th Meeting of the European Society of Pediatric Infectious Diseases
 , 
2009
29
World Health Organization
Generic protocol for monitoring impact of rotavirus vaccination on rotavirus disease burden and viral strains
2009
Geneva
World Health Organization
(pg. 
1
-
73
)
30
Anderson
EJ
Weber
SG
Rotavirus infection in adults
Lancet Infect Dis
 , 
2004
, vol. 
4
 (pg. 
91
-
9
)
31
Griffin
DD
Fletcher
M
Levy
ME
, et al.  . 
Outbreaks of adult gastroenteritis traced to a single genotype of rotavirus
J Infect Dis
 , 
2002
, vol. 
185
 (pg. 
1502
-
5
)
32
Hrdy
DB
Epidemiology of rotaviral infection in adults
Rev Infect Dis
 , 
1987
, vol. 
9
 (pg. 
461
-
9
)
33
Mikami
T
Nakagomi
T
Tsutsui
R
, et al.  . 
An outbreak of gastroenteritis during school trip caused by serotype G2 group A rotavirus
J Med Virol
 , 
2004
, vol. 
73
 (pg. 
460
-
4
)
34
World Health Organization
Generic protocols for (i) hospital-based surveillance to estimate the burden of rotavirus gastroenteritis in children and (ii) a community-based survey on utilization of health care services for gastroenteritis in children
2002
Geneva
World Health Organization
(pg. 
1
-
67
)
35
Farhoudi
D
Lofdahl
M
Giesecke
J
Invasive Haemophilus influenzae type b disease in Sweden 1997–2003: epidemiological trends and patterns in the post-vaccine era
Scand J Infect Dis
 , 
2005
, vol. 
37
 (pg. 
717
-
22
)
36
Grijalva
CG
Nuorti
JP
Arbogast
PG
Martin
SW
Edwards
KM
Decline in pneumonia admissions after routine childhood immunisation with pneumococcal conjugate vaccine in the USA: a time-series analysis
Lancet
 , 
2007
, vol. 
369
 (pg. 
1179
-
86
)
37
von Gottberg
A
de Gouveia
L
Madhi
SA
, et al.  . 
Impact of conjugate Haemophilus influenzae type b (Hib) vaccine introduction in South Africa
Bull World Health Organ
 , 
2006
, vol. 
84
 (pg. 
811
-
8
)
38
Clemens
J
Brenner
R
Rao
M
Tafari
N
Lowe
C
Evaluating new vaccines for developing countries: efficacy or effectiveness
JAMA
 , 
1996
, vol. 
275
 (pg. 
390
-
7
)
39
Orenstein
WA
Bernier
RH
Dondero
TJ
, et al.  . 
Field evaluation of vaccine efficacy
Bull World Health Organ
 , 
1985
, vol. 
63
 (pg. 
1055
-
68
)
40
Smith
PG
Retrospective assessment of the effectiveness of BCG vaccination against tuberculosis using the case-control method
Tubercle
 , 
1982
, vol. 
63
 (pg. 
23
-
35
)
41
de Oliveira
LH
Danovaro-Holliday
MC
Matus
CR
Andrus
JK
Rotavirus vaccine introduction in the Americas: progress and lessons learned
Expert Rev Vaccines
 , 
2008
, vol. 
7
 (pg. 
345
-
53
)
Potential conflicts of interest: none reported
Financial support: none reported
Supplement sponsorship: This article was published as part of a supplement entitled “Global Rotavirus Surveillance: Preparing for the Introduction of Rotavirus Vaccines,” which was prepared as a project of the Rotavirus Vaccine Program, a partnership between PATH, the World Health Organization, and the US Centers for Disease Control and Prevention, and was funded in full or in part by the GAVI Alliance
The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention