This supplement issue of The Journal of Infectious Diseases highlights the continuing problem of rotavirus gastroenteritis, with a focused look at the burden of rotavirus disease in Asia and the prospects for prevention of the disease through immunization. It is estimated that, each year, rotavirus gastroenteritis causes the deaths of 310,000–590,000 infants and young children worldwide; thus, rotavirus infection is the single greatest cause of diarrhea-related deaths among children [1]. Although >90% of these deaths occur in the poorest countries [1, 2], virtually every child will experience at least one case of rotavirus gastroenteritis during the first few years of life [3]. In both developed and developing countries alike, these cases will lead to several million hospitalizations related to dehydration and diarrhea [1]. The development and implementation of oral rehydration therapy and programs to ensure that drinking water is safe have led to impressive reductions in the number of deaths due to diarrheal disease—from 4.6 million deaths among children in 1982 [4] to an estimated 2.5 million deaths among children in 2003 [5]. Despite these achievements, rotavirus infection continues to be the major cause worldwide of severe, dehydrating gastroenteritis. Primary prevention of this disease through immunization has been promoted as a key tool for the reduction in deaths globally, not just diarrhea-related deaths, because rotavirus infection accounts for as many as ∼15% of potentially vaccine-preventable deaths among children globally [6].

Asia is a prime target of efforts to realize this reduction in the burden of rotavirus disease. Because Asia has large population centers and some of the most-populated countries of low socioeconomic status, >55% of all rotavirus disease-associated deaths have been estimated to occur in this region [1] (figure 1). In fact, of the 10 countries with the highest number of rotavirus disease-associated deaths, 6 are located in Asia. As a result, any substantial progress in the prevention of diarrhea-related deaths in this region will have to address the prevention of rotavirus infection. In addition, because Asia comprises diverse populations and economies, both industry and public health organizations view the region as important and have either advocated for or adopted plans to test rotavirus vaccines in the region. The articles in this supplement will highlight each of the candidate vaccine development programs currently under way in Asia and the future plans of these programs.

Figure 1

Top, Distribution of rotavirus disease-associated deaths worldwide, by region. Bottom, Distribution of rotavirus disease-associated deaths in Asia, by country. Figure is adapted from Parashar et al. [1].

Figure 1

Top, Distribution of rotavirus disease-associated deaths worldwide, by region. Bottom, Distribution of rotavirus disease-associated deaths in Asia, by country. Figure is adapted from Parashar et al. [1].

The Asian Rotavirus Surveillance Network (ARSN), a collaboration of a variety of institutions, health ministries, and scientists that represents 36 cities in 9 countries and regions throughout Asia, was formed in 2001 [7]. The ARSN has established a foundation of data and expertise in the region that will facilitate further work. The articles in this supplement represent the work of the ARSN members and selected other investigators in the region during the past few years. Most of these data were presented at the third meeting of the members of the ARSN in Manila, The Philippines, in October 2003. The articles in this supplement offer state-of-the-art updates on most of the principal vaccine candidates, presentations of the newest data on disease burden and the prevalence of rotavirus strains circulating in the region, and overviews of issues critical to decisions regarding the introduction of a rotavirus vaccine (e.g., an analysis of the cost-effectiveness of rotavirus vaccines). The articles in this supplement provide compelling arguments for the need for and the viability of safe and effective vaccines against rotavirus in Asia.

Rotavirus Gastroenteritis: A Significant Health Problem in Asia

The studies presented here support the utility of new surveillance information, rather than past data, in reassessing the role of rotavirus infection as a cause of morbidity and mortality among children in countries where the introduction of a rotavirus vaccine may soon be considered. These studies allow the discussion to move beyond modeled estimates of the disease burden to actual rotavirus-specific data collected in each country. The 2003 estimates of rotavirus disease-associated mortality and morbidity, which indicate that >230,000 deaths occur among children in Asian countries, were extrapolated from older hospital-based studies conducted between 1986 and 1996 and were combined with estimates of the rates of diarrheal disease collected by national public health officials. In general, in the older model, the proportion of diarrhea-related hospitalizations for which severe disease was attributed to rotavirus infection was 20%–25%, which is consistent with data from the 1980s and early 1990s. However, newer data indicate that this proportion underestimates the current rates of detection of rotavirus among children hospitalized for diarrhea. In a preliminary report of the work of the ARSN, 55% of all diarrhea-related hospitalizations among children <5 years old in participating hospitals were attributable to rotavirus infection [7]. This finding was consistent with recently published data from Latin America [8] and Africa [9]. The articles in this supplement demonstrate that these unexpectedly high rates occur throughout Asia and have persisted during both years of surveillance (figure 2). The studies conducted by the ARSN during the past 2 years and presented here indicate that the median prevalence of rotavirus infection among children hospitalized with diarrhea is 43%, which is almost twice as high as the rate used to calculate global estimates of disease. Clearly, new data may well alter the perception among global and national health leaders regarding the effect of rotavirus disease. The development by the World Health Organization (WHO) of a simple, generic protocol for conducting surveillance for rotavirus infection has made the initiation of new studies easier [10] and has led to >2 dozen separate studies worldwide, with additional studies to begin later this year. As surveillance becomes more widespread, estimates of disease burden will become precise and reliable. Additional new tools will soon be available, and researchers can use this “tool kit” of methods to better prepare countries for decisions regarding the introduction of a rotavirus vaccine. These methods include a generic protocol for laboratory testing of rotavirus strains, for surveillance of intussusception, and for assessing the economic effect of rotavirus disease in developing countries.

Figure 2

Sites in the current and future Asian Rotavirus Surveillance Network. Percentages denote the proportion of diarrhea-related hospitalizations attributable to rotavirus infection, by country.

Figure 2

Sites in the current and future Asian Rotavirus Surveillance Network. Percentages denote the proportion of diarrhea-related hospitalizations attributable to rotavirus infection, by country.

Another value of new or ongoing data from these and other studies is the ability to monitor the changing prevalences of rotavirus strains. The data from the articles in this supplement indicate that the diversity of rotavirus strains in the region is greater than previously was appreciated. Of the 2875 strains collected in 7 ARSN member countries during the past 2 years, only 57% (n = 1651) were of the 4 globally common serotypes. The newly emergent serotype 9 (G9) strains have become common in Asia and accounted for ∼30% of all strains detected during the past 2 years. Because G9 rotaviruses were detected in all countries in the regions where strain characterization has been completed, and because they accounted for more than one-half of all strains in Thailand, ongoing monitoring of the emergence of the G9 strain will be a critical component of vaccine introduction in the region. One clear result of these studies is that strains of serotypes other than G1–G4 and G9 appear to be relatively scarce. It would appear that Asia may have less strain diversity than Africa or Latin America, providing some assurance that current vaccine approaches are likely to be effective in this region. Extending virologic surveillance to additional Asian countries of low income levels will be helpful for monitoring the emergence of unusual strains in areas where vaccine are most needed.

Prospects for Safe and Effective Vaccines

A growing body of evidence supports the hypothesis that improvements in hygiene and provision of a safe water supply will not be as effective in the prevention of rotavirus diarrhea as they are to the prevention of are bacterial enteric infections [11]. As a result, international health agencies have promoted the development of rotavirus vaccines as the best method for the prevention of morbidity and mortality associated with rotavirus infection and as a cornerstone of efforts to further reduce global rates of diarrhea-related deaths. In 1997 and, again, in 2000 [12], the WHO recommended that all new rotavirus vaccines should be tested in Asia and Africa and that this testing should be performed concurrently with trials conducted in the United States and Europe. By doing this, the safety and efficacy of vaccines might be demonstrated in poor, developing countries early during development, thereby accelerating the availability of new vaccines to the children who are most in need of them.

The articles in this supplement provide not only a primer on leading rotavirus vaccine candidates but, also, a sample of the variety of approaches toward the goal of expediting the introduction of new rotavirus vaccines into the poorest countries. Two articles review the progress in the development of vaccines by multinational vaccine producers. The study by Phua et al. [13] of the monovalent serotype 1 strain vaccine (Rotarix; GlaxoSmithKline) is the first evaluation of a rotavirus vaccine in Asia since 1998. More important, trials involving this vaccine are under way in Bangladesh and South Africa, which represent the populations that could benefit most from rotavirus vaccines. These trials, in parallel with those conducted in North America and Europe, signal a new commitment toward proving that the vaccine will work in diverse settings and recognize that rotavirus disease is a worldwide phenomenon. The article by Heaton et al. [14], in which the leading polyvalent vaccine (Rotateq; Merck) is reviewed, provides an excellent review of the rationale for the strategy of including multiple strains in a single vaccine, in which the parent bovine strain does not itself protect against the full range of disease in children. Finally, 2 reports, one by Glass et al. [15] and the other by Kapikian et al. [16], document programs to develop new vaccines through collaborative relationships between vaccine manufacturers in developing countries and partners in developed countries. The development of the neonatal Indian strains and the pursuit of the polyvalent human-bovine reassortant by investigators at the US National Institutes of Health are promising examples of such partnerships. This approach is also being used in a collaboration between an Indonesian manufacturer and the group in Melbourne, Australia, that first discovered rotavirus; in this collaboration, another neonatal strain is being developed as a vaccine candidate [17]. Each of these candidates in early stages of clinical development may well lead to an expanded capacity to produce reasonably priced vaccines for children in developing countries.

Importance of Surveillance in Decisions Regarding the Introduction of Vaccines

In 2001, the Global Alliance for Vaccines and Immunization and the WHO convened a meeting to outline steps designed to accelerate the introduction of a rotavirus vaccine into developing countries. As in the previous meeting held in 1997, a central finding from the meeting was the lack of recent, high-quality data on the burden of disease in the poorest countries with which to establish the need for vaccines when they become available. The ARSN was established primarily to address this acknowledged gap [7]. The value of the ARSN has been 2-fold. First, the disease burden documented by the ARSN confirms the global importance of rotavirus disease and provides a foundation for each of the member countries to use their own data to make decisions about the priority of rotavirus disease prevention. Second, data from the ARSN document the regional epidemiological profile of rotavirus, which will inform both international policy makers and vaccine developers alike. For instance, the data from the ARSN indicate that the age distribution of rotavirus disease-associated hospitalizations tends to shift toward younger ages in countries with the lowest income levels, compared with countries with higher income levels (figure 3). For example, in India and Myanmar, ∼80% of hospitalizations occur among children during the first year of life, whereas, in developed countries (e.g., Korea, Hong Kong, and Taiwan), only ∼30% of hospitalizations occur among children in the same age group. This epidemiological feature had been hypothesized previously [18], but the organizational structure of the ARSN allowed this pattern to be documented by use of data collected simultaneously from countries with a variety of income levels and by use of a standard protocol that ensured the comparability of the data. These data reinforce the necessity of timely vaccination programs in these countries and inform the predicted cost-benefit analyses of vaccination. Thus, although data collected by each country will have primary benefit in that particular country, one strength of a regional network is that it provides the opportunity to examine general trends in the region that might better inform international vaccine agencies and decision makers.

Figure 3

Cumulative age distribution of hospitalizations related to rotavirus (RV) infection among children 0–59 months of age in Asia, by country

Figure 3

Cumulative age distribution of hospitalizations related to rotavirus (RV) infection among children 0–59 months of age in Asia, by country

Next Steps and Priorities

Decisions concerning the addition of rotavirus vaccines or any other new vaccines to national immunization programs will be driven by scientific, political, economic, and logistical considerations. Two of the priority activities identified by the WHO in 1997—that is, determining the rotavirus disease burden in developing countries and testing new vaccines in those countries—have been partially accomplished. Although some data are now available, many countries in Asia and other regions still lack high-quality data with which to make decisions about the introduction of rotavirus vaccines. In addition, data confirming the burden of mortality associated with rotavirus infection are still needed, and studies are being planned to address this need. Expansion of the ARSN this year to additional sites in the region (figure 2) and the establishment of new surveillance networks in Africa, Latin America, and the Middle East are under way, such that the global picture of the rotavirus disease burden will come more into focus during the next 2–3 years. Although vaccine trials are either under way or planned in Asia and Africa, a need exists for more-rapid testing of existing vaccine candidates and for accelerating the development of promising candidates by producers in developing countries. This is particularly relevant to live, orally administered vaccines, which have often been found to have lower immunogenicity or efficacy in populations in developing countries than in populations in developed countries. The results of early trials of rotavirus vaccines in Africa provide a powerful reminder of the necessity of ensuring the efficacy of these vaccines in the poorest countries [19, 20]. Finally, economic analyses of the costs and effects of new vaccines have become standard parts of decision packages, not only for developed countries but, also, for developing countries and international donor agencies. The regional analysis included here is a beginning to this important dialogue, but country-specific analyses will certainly be needed to make decisions for the first countries to use the vaccines.

Rotavirus vaccines promise to be important tools in efforts to reduce global mortality among children and to reduce morbidity and associated costs of health care in developed countries. It is to be hoped that this supplement will provide a broad overview of the variety of activities that will serve as the foundation for future vaccine programs.

References

1
Parashar
UD
Hummelman
EG
Bresee
JS
Miller
MA
Glass
RI
Global illness and deaths caused by rotavirus disease in children
Emerg Infect Dis
 , 
2003
, vol. 
9
 (pg. 
565
-
72
)
2
Miller
MA
McCann
L
Policy analysis of the use of hepatitis B, Haemophilus influenzae type B-, Streptococcus pneumoniae-conjugate, and rotavirus vaccines, in national immunization schedules
Health Econ
 , 
2000
, vol. 
9
 (pg. 
19
-
35
)
3
Velazquez
FR
Matson
DO
Calva
JJ
, et al.  . 
Rotavirus infection in infants as protection against subsequent infections
N Engl J Med
 , 
1996
, vol. 
335
 (pg. 
1022
-
8
)
4
Snyder
JD
Merson
MH
The magnitude of the global problem of acute diarrhoeal disease: a review of active surveillance data
Bull World Health Organ
 , 
1982
, vol. 
60
 (pg. 
605
-
13
)
5
Kosek
M
Bern
C
Guerrant
RL
The global burden of diarrhoeal disease, as estimated from studies published between 1992 and 2000
Bull World Health Organ
 , 
2003
, vol. 
81
 (pg. 
197
-
204
)
6
The Global Alliance for Vaccines and Immunization (GAVI)
Annual deaths in 2002 from diseases for which vaccines will be available soon: WHO estimates (January 2005)
 , 
2005
Accessed 15 July 2005
Geneva
GAVI Secretariat
 
7
Bresee
JS
Fang
Z-Y
Wang
B
, et al.  . 
Rotavirus surveillance in Asia: first report from the “Asian Rotavirus Surveillance Network”
Emerg Infect Dis
 , 
2003
, vol. 
10
 (pg. 
95
-
8
)
8
O'Ryan
M
Perez-Schael
I
Mamani
N
, et al.  . 
Rotavirus-associated medical visits and hospitalizations in South America: a prospective study at three large sentinel hospitals
Pediatr Infect Dis J
 , 
2001
, vol. 
20
 (pg. 
685
-
93
)
9
Steele
AD
Peenze
I
de Beer
MC
, et al.  . 
Anticipating rotavirus vaccines: epidemiology and surveillance of rotavirus in South Africa
Vaccine
 , 
2003
, vol. 
21
 (pg. 
354
-
60
)
10
World Health Organization (WHO)
Generic protocols (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. Document WHO/V&B/02.15
 , 
2002
Geneva
WHO
(pg. 
1
-
67
)
11
Villa
S
Guiscafre
H
Martinez
H
Munoz
O
Gutierrez
G
Seasonal diarrhoeal mortality among Mexican children
Bull World Health Organ
 , 
1999
, vol. 
77
 (pg. 
375
-
80
)
12
World Health Organization (WHO)
Report of the meeting on future directions for rotavirus vaccine research in developing countries
 , 
2000
Geneva
WHO
(pg. 
1
-
56
)
13
Phua
KB
Quak
S-H
Lee
B-W
, et al.  . 
Evaluation of RIX4414, a live, attenuated rotavirus vaccine, in a randomized, double-blind, placebo-controlled phase 2 trial involving 2464 Singaporean infants
J Infect Dis
 , 
2005
, vol. 
192
 
Suppl 1
(pg. 
S6
-
16
(in this issue)
14
Heaton
PM
Goveia
MG
Miller
JM
Offit
P
Clark
HF
Development of a pentavalent rotavirus vaccine against prevalent serotypes of rotavirus gastroenteritis
J Infect Dis
 , 
2005
, vol. 
192
 
Suppl 1
(pg. 
S17
-
21
(in this issue)
15
Glass
RI
Bhan
MK
Ray
P
, et al.  . 
Development of candidate rotavirus vaccines derived from neonatal strains in India
J Infect Dis
 , 
2005
, vol. 
192
 
Suppl 1
(pg. 
S30
-
5
)
16
Kapikian
AZ
Simonsen
L
Vesikari
T
, et al.  . 
A hexavalent human rotavirus-bovine rotavirus (UK) reassortant vaccine designed for use in developing countries and delivered in a schedule with the potential to eliminate the risk of intussusception
J Infect Dis
 , 
2005
, vol. 
192
 
Suppl 1
(pg. 
S22
-
9
(in this issue)
17
Barnes
GL
Lund
JS
Mitchell
SV
, et al.  . 
Early phase II trial of human rotavirus vaccine candidate RV3
Vaccine
 , 
2002
, vol. 
20
 (pg. 
2950
-
6
)
18
Bresee
J
Glass
RI
Ivanoff
B
Gentsch
J
Current status and future priorities for rotavirus vaccine development, evaluation, and implementation in developing countries
Vaccine
 , 
1999
, vol. 
17
 (pg. 
2207
-
22
)
19
Del Mol
P
Zissis
G
Butlzler
JP
Mutwewingabo
A
Andre
FE
Failure of live, attenuated oral rotavirus vaccine
Lancet
 , 
1980
, vol. 
2
 pg. 
108
 
20
Hanlon
P
Marsh
V
Shenton
F
, et al.  . 
Trial of an attenuated bovine rotavirus vaccine (RIT 4237) in Gambian infants [letter]
Lancet
 , 
1987
, vol. 
1
 (pg. 
1342
-
5
)

Author notes

Potential conflicts of interest: E.A.S.N. has received funding and support from Merck for rotavirus surveillance studies and is currently principal investigator of a phase 3 rotavirus vaccine study funded by GlaxoSmithKline; he has also received lecture fees and travel support from GlaxoSmithKline. All other authors: no potential conflicts reported.