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Implementing rotavirus vaccination in Asia
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Vaccine 25 (2007) 7711–7716
Implementing rotavirus vaccination in Asia夽 Mathuram Santosham a,∗ , E. Anthony S. Nelson b , Joseph S. Bresee c a
c
Department of International Health, Johns Hopkins University Bloomberg School of Public Health, 615 N. Wolfe Street, E8132, 621 N. Washington Street, Baltimore, MD 21205, USA b Department of Paediatrics, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Special Administrative Region, People’s Republic of China Respiratory and Enteric Virus Branch, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA Received 19 July 2007; accepted 26 July 2007 Available online 22 August 2007
Abstract At the 2006 meeting of the Asian Pacific Pediatric Association (APPA), the Asia Pacific regional rotavirus community and international experts strongly recommended that rotavirus vaccines be used in National Immunization Programmes (NIP) in countries in Asia. Two rotavirus vaccine candidates are currently licensed and have been demonstrated to be safe, well tolerated and highly efficacious. Several additional vaccines are in the late stages of development. The conference participants agreed that decisions on the introduction of rotavirus vaccines may require additional disease burden data in some countries and that economic evaluations will help policymakers reach decisions on nationwide rotavirus vaccine implementation. Other potential issues that arise with vaccine implementation, for example, the concomitant use of rotavirus vaccines with other vaccines, were also discussed. Rotavirus vaccines have the potential to substantially reduce morbidity and mortality from rotavirus disease and impact children’s health in Asia. © 2007 Elsevier Ltd. All rights reserved. Keywords: Rotavirus vaccine; Asia; Vaccine implementation
1. Introduction 1.1. Rotavirus in Asia Around the globe, diarrhoeal disease remains the second most common cause of death among children under the age of 5 years [1]. Rotavirus is the single most common aetiological agent of severe diarrhoea [2]. Each year, rotavirus causes more than 125 million episodes of infantile gastroenteritis and over 600,000 deaths in children younger than 5 years of age, with the highest mortality occurring in the poorest 夽 This article was prepared from the presentations at the meeting “Vaccinology 2006: Focus on Rotavirus and Poliovirus in Asia” organized by The Pediatric Society of Thailand, The Royal College of Pediatricians of Thailand and The Asian Pacific Pediatric Association, Pattaya, Thailand, 20–22 July 2006. ∗ Corresponding author. Tel.: +1 410 955 3952; fax: +1 410 614 1419. E-mail address: [email protected] (M. Santosham).
0264-410X/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2007.07.064
countries [3,4]. Rotavirus infects almost every child before its fifth birthday [3]. Of the rotavirus-associated deaths worldwide, more than 55% are estimated to occur in Asia [5]; the death toll in India and China alone account for more than 135,000 children annually (Fig. 1) [2,3]. Nosocomial rotavirus infections further impact on the healthcare system. Nosocomial cases were responsible for 14–51% of the total rotavirus infections and the proportion was similar in developed (27%) and developing countries (32%) [6]. Continuing epidemiological surveillance within Asia will help define the magnitude of the disease burden (Fig. 2) [5] and track the serotype distributions (Table 1) [7–12]. Efforts to improve sanitation and hygiene have dramatically lowered the overall incidence of diarrhoeal diseases; however, the rates of rotavirus diarrhoea have remained relatively stable over time [2]. In fact, the incidence of rotavirus diarrhoea is similar in developed and developing countries
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Fig. 1. Distribution of estimated rotavirus disease-associated deaths in Asia, by country [3]. DPR, Democratic People’s Republic.
make it a difficult problem to eradicate. In addition, the ensuing burden of the disease on healthcare and society imposes an immense strain on the economy. In Hong Kong, the annual total social cost and total direct medical cost for rotavirusassociated admissions were estimated at US$ 4.3 and US$ 4 million, respectively [14]. In Vietnam, the economic burden of the disease is estimated at US$ 3.1 million in medical direct costs, US$ 685,000 in non-medical direct costs, and US$ 1.5 million in indirect costs, with total societal costs of US$ 5.3 million per year [15]. Prevention of rotavirus disease through immunization has been recommended as the best strategy for reducing rotavirus-associated illness and deaths [2,16]. The World Health Organization’s (WHO) Steering Committee on Diarrhoeal Disease Vaccines recognizes vaccination as the answer to avert the devastating consequences of rotavirus and therefore maintains rotavirus vaccine development as a high priority [13]. Preliminary estimates indicate that a universal rotavirus vaccination programme in Asia could potentially save the lives of 109,000 children and prevent 1.4 million hospitalizations and 7.7 million outpatient visits [17]. Such a universal immunization programme in Asia could reduce healthcare costs by US$ 191 million but the economic impact in individual countries would depend on the country’s income level, the cost of the vaccine and the assumptions used [17]. 1.2. Rotavirus vaccines
Fig. 2. Proportion of rotavirus-attributable hospitalizations in Asia, by country, as collated from surveillance efforts by the Asian Rotavirus Surveillance Network (ARSN). Adapted from [5]; © 2005 by the Infectious Diseases Society of America.
with very different levels of sanitation. Despite the efficacy of oral rehydration therapy for treatment of diarrhoea of all aetiologies including rotavirus [13], many children with rotavirus diarrhoea die because of poor access or inadequate use of oral rehydration salts. The resilience and ubiquity of rotavirus Table 1 Serotype distributions in Asia, by country during the period 2001–2003 Country
Most prevalent serotype
Reference
China India Korea Taiwan Thailand Vietnam
G3P[8] G1 G9P[8] G9P[8] G9 G1P[8]
[7] [8] [9] [10] [11] [12]
Adapted from [7–12].
In the past two decades, several rotavirus candidate vaccines have been evaluated. A tetravalent reassortant vaccine, RotaShield® by Wyeth Laboratories Inc. [18,19], was licensed in the United States but withdrawn from the market within a year due to an increased risk for intussusception among vaccine recipients [20,21]. Two new rotavirus vaccines have recently been licensed in a number of countries globally, including several Asian countries (such as Hong Kong and Taiwan), and there are other vaccine candidates in the pipeline (Table 2) [2]. This provides the opportunity to include rotavirus vaccines into NIP. To facilitate this process, there is a need for countries within the Asian region to coherently assess the current circumstances and reach agreement on the basic guidelines and principles for safe and effective use of rotavirus vaccines. Such information will help policy makers assess the applicability of current information on rotavirus vaccines and disease burden to healthcare infrastructures within the local context. This manuscript presents the conclusions from the Asian Pacific Pediatric Association (APPA) “Vaccinology 2006: Focus on Rotavirus and Poliovirus in Asia” meeting held in Pattaya, Thailand, 20–22 July 2006.
2. Discussion Jointly hosted by the Paediatric Society of Thailand, the Royal College of Pediatricians of Thailand and APPA, the
M. Santosham et al. / Vaccine 25 (2007) 7711–7716
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Table 2 An overview of current and emerging rotavirus vaccines Vaccine
Manufacturer
Rotavirus strains (genotype)
RotarixTM
GlaxoSmithKline Merck
Monovalent, attenuated human strain 89-12 (P[8], G1) Pentavalent human-bovine reassortants WC3 × WI79 (P7[5], G1), WC3 × SC2 (P7[5], G2), WC3 × W178 (P7[5],G3), WC3 × BrB (P7[5], G4) and WC3 × WI79 (P1A[8], G1) LLR strain (P[12], G10)
RotaTeq® LLR RV3 UK reassortant Indian neonatal vaccines Rhesus tetravalent
Lanzhou Institute of Biological Products University of Melbourne and Bio Farma National Institutes of Health Bharat Biotech International Ltd. BIOVIRx Inc.
Monovalent neonatal human strain (P2A[6], G3) Tetravalent human-bovine reassortant UK × Wa (P7[5], G1), UK × DS1 (P7[5], G2), UK × P (P7[5], G3) and UK × ST3 (P7[5], G4) Neonatal strains 116E (P[11], G9) and I321 (P[11], G10) Tetravalent human-rhesus reassortants RRV × D (P5[3], G1), RRV × DS1 (P5[3], G2), RRV (P5[3], G3) and RRV × ST3 (P5[3], G4)
Adapted from [2]. LLR, Lanzhou lamb rotavirus; WC3, bovine rotavirus strain.
meeting provided a venue for experts to reach agreements on the importance of rotavirus disease prevention and vaccine implementation in Asia. The current status of rotavirus disease burden, together with available data on rotavirus vaccine candidates, was evaluated. Rotavirus is estimated to claim the lives of 230,000 children in Asia each year [5]. Six of the 10 countries with the highest number of rotavirus disease-associated deaths are in Asia [5]. The disease also causes significant morbidity resulting in hospitalization and outpatient visits, and the ensuing heavy economic burden is apparent. Therefore, prevention of rotavirus diarrhoea in Asia is of high priority [5]. Presentations from international and regional experts provided information to help participants assess the role of rotavirus vaccines in NIP in their countries. 2.1. Current perspectives It was agreed that although many public health officials recognize diarrhoea as a major health problem, they do not recognize rotavirus as a leading cause of diarrhoea. Further, many healthcare workers and public health officials believe that improvements in quality of water and sanitation will reduce the rates of rotavirus diarrhoea despite the evidence to the contrary. Although paediatricians may appreciate rotavirus as a significant cause of acute diarrhoea in children, they may not consider that vaccination is the optimal control strategy, especially in more developed countries where rotavirus mortality is rare. 2.2. Call for further surveillance Even with licensed rotavirus vaccines becoming available in Asia, a lack of knowledge on the incidence and burden of the disease will limit the use of these vaccines, particularly to those poorer sections of the population who could benefit most. Therefore, effort is needed to educate policy makers, healthcare providers and the public and increase advocacy to ensure that these vaccines can be introduced into NIP at an early stage.
To address this gap in knowledge, collection and dissemination of reliable and accurate data to define the existing disease burden will be very important [2]. In Asia, the Asian Rotavirus Surveillance Network (ARSN) has been instrumental in collecting and presenting epidemiological data on rotavirus disease and serotype characterization in the region (Fig. 2) [5]. Wide variation in rates of mortality due to rotavirus can be explained by the differences in healthcare access and quality of care. On the other hand, morbidity rates are relatively consistent between countries. However, despite the significant amount of data that have been collected by ARSN to date, there is still a paucity of disease burden data in certain countries, often in countries where rotavirus mortality is estimated to be high. The poorest of these countries will be eligible for vaccine funding support from the Global Alliance for Vaccines and Immunization (GAVI). The ARSN is currently collecting rotavirus disease burden data for a number of GAVI-eligible countries. 2.3. Addressing vaccine cost-effectiveness For rotavirus vaccination to become a routine practice in Asia, one of the biggest challenges faced is the anticipated high cost of vaccine and the consequent concern of vaccine funding. Comprehensive disease surveillance will supply clear and critical information on the medical and economic burden of the disease. In turn, local economic evaluations will be one of the influencing factors for key stakeholders in deciding on the value of rotavirus vaccination in each country in relation to other health priorities. 2.4. Assessing the adequacy of vaccine-related data 2.4.1. Vaccine efficacy Past experiences with several live oral rotavirus vaccines have demonstrated poor immunogenicity and efficacy responses in developing countries [2,22–25]. Since children in Asia represent close to half of the world’s children [26], this region is of special importance to public health
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workers, prospective donors and vaccine manufacturers. Disease surveillance data have shed light on the existence of distinct geographical serotype differences within the region (Table 1) [7–12]. Multiple factors may explain the low efficacy observed in previous vaccine trials including host factors that might decrease vaccine take (such as nutritional deficiencies, differences in intestinal flora, and high levels of maternally derived antibodies), virological mismatch between circulating strains and vaccine strains used in earlier vaccines, study designs used in early trials, and other factors [27]. To attest the success or failure of these rotavirus vaccines, it is paramount that additional efficacy studies be conducted in poorer developing countries. 2.4.2. Vaccine safety With the withdrawal of the first rotavirus vaccine licensed in the United States (RotaShield® ) due to an observed association with intussusception [20,21], the issue of safety of rotavirus vaccines has been a foremost concern among the medical community and the vaccine manufacturers. Large scale (over 60,000 subjects per study) pre-licensure studies conducted with RotarixTM (GlaxoSmithKline) and RotaTeq® (Merck) has found no evidence of increased rates of intussusception or any other serious adverse events with either vaccine [28,29]. Post-licensure studies will be required to fully evaluate the safety of these new vaccines. 2.5. Choosing the vaccine A number of rotavirus vaccines are anticipated (Table 2) [2], with two rotavirus vaccines currently available in the market—RotarixTM and RotaTeq® . One vaccine is based on an attenuated monovalent human rotavirus strain and the other is a pentavalent human-bovine reassortant vaccine. Studies have demonstrated significant differences in their rate of viral shedding (>50% for RotarixTM versus <10% for RotaTeq® ) [29–33]. However, it should be recognized that these data are not directly comparable because the method of rotavirus detection differed in the two studies. In the trials with RotaTeq® , potential faecal shedding of vaccine was monitored by viral culture with use of a plaque assay and RNA electropherotyping [29], while trials with RotarixTM employed the enzyme-linked immunosorbent assay [30,31]. Some experts in the field believe that high viral shedding is beneficial because it may provide a higher possibility of herd immunity or herd protection. On the other hand, other experts argue that a vaccine with low shedding is preferable since it reduces the chances of transmission to immunocompromised individuals. Provided these and future rotavirus vaccines have equivalent safety and efficacy, it is unlikely that differences in shedding will have any material impact. 2.6. Vaccine implementation Among the other issues that concern vaccine implementation, the subject of potential interference of rotavirus vaccine
in breastfed infants was discussed. The presence of antibodies to different rotavirus serotypes in breast milk is postulated to influence the take rate of rotavirus vaccines [34]. Research has demonstrated that although these affect serum immune responses, it is usually statistically insignificant [35]. More importantly, no decrease in the protective efficacy of rotavirus vaccine in breastfed and non-breastfed infants has been observed. In light of the immense burden of rotavirus disease, the greater benefits for using a rotavirus vaccine far outweigh this concern of potential interference. Hence, it is recommended that the vaccine should be administered to breastfed infants and this recommendation should be reviewed when more data becomes available. For rotavirus vaccines to be administered to infants with other routine childhood immunizations, potential interference with concomitant administration needs to be considered. Some participants felt that co-administration of rotavirus vaccine with oral polio vaccine (OPV) could result in interference. Therefore, rotavirus vaccination should be administered at least 2 weeks apart when feasible. Participants agreed that more data was required to assess possible interference of OPV on rotavirus vaccine efficacy. In choosing a rotavirus vaccine for a particular country, several factors should be taken into account—the cost of the vaccine, the ease of administration and the number of doses needed. Both RotarixTM and RotaTeq® are expected to have significant impact in disease reduction in all countries and it is likely that vaccine cost will be the main driver of decisions on the recommended vaccine for NIP.
3. Conclusion 3.1. The challenges ahead The implementation of rotavirus vaccination brings hope that prevention of this disease could potentially save the lives of millions of children worldwide. The summary of the concerns and recommendations of the regional medical community at the APPA meeting regarding rotavirus disease burden and the implementation of rotavirus vaccination are as follows: • It is recommended that individual countries assess existing disease burden, vaccine efficacy data and the estimated cost-effectiveness of vaccination in the local country context. Tools to facilitate the estimation of disease burden and cost-effectiveness of vaccination are available from the WHO, along with technical resources [36]. • Countries with limited data are encouraged to conduct surveillance that will produce reliable data to estimate the local disease burden. • More data on the co-administration of rotavirus vaccine with OPV and breastfeeding are required. However, pending further updates, it is recommended that rotavirus
M. Santosham et al. / Vaccine 25 (2007) 7711–7716
vaccine should be administered to breastfed infants. Some participants felt that OPV should be administered at least 2 weeks apart from rotavirus vaccination until more data are available. The conference participants recommended that additional studies needs to be conducted in order to assess the impact of co-administration of OPV and rotavirus vaccines on the immune responses to rotavirus vaccine. • Post-marketing surveillance is strongly encouraged to monitor adverse events including incidence of intussusception, evaluate the impact on total diarrhoeal and rotavirus-specific disease burdens, and to conduct serotype surveillance. • As multiple rotavirus vaccines could become available in a single country, the likely scenario of a mixed schedule of vaccination using different vaccine candidates should be investigated.
3.2. Moving ahead Rotavirus vaccines are now recommended for routine immunization of children in a number of South American countries and the United States [37,38]. Both vaccines are already licensed in several Asian countries. Given the high disease burden in Asia, the use of rotavirus vaccines was strongly recommended by the APPA conference participants.
Acknowledgements This article is supported by The Pediatric Society of Thailand and by an educational grant from GlaxoSmithKline, Sanofi Pasteur and Merck.
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Vaccine 25 (2007) 7711–7716
Implementing rotavirus vaccination in Asia夽 Mathuram Santosham a,∗ , E. Anthony S. Nelson b , Joseph S. Bresee c a
c
Department of International Health, Johns Hopkins University Bloomberg School of Public Health, 615 N. Wolfe Street, E8132, 621 N. Washington Street, Baltimore, MD 21205, USA b Department of Paediatrics, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Special Administrative Region, People’s Republic of China Respiratory and Enteric Virus Branch, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA Received 19 July 2007; accepted 26 July 2007 Available online 22 August 2007
Abstract At the 2006 meeting of the Asian Pacific Pediatric Association (APPA), the Asia Pacific regional rotavirus community and international experts strongly recommended that rotavirus vaccines be used in National Immunization Programmes (NIP) in countries in Asia. Two rotavirus vaccine candidates are currently licensed and have been demonstrated to be safe, well tolerated and highly efficacious. Several additional vaccines are in the late stages of development. The conference participants agreed that decisions on the introduction of rotavirus vaccines may require additional disease burden data in some countries and that economic evaluations will help policymakers reach decisions on nationwide rotavirus vaccine implementation. Other potential issues that arise with vaccine implementation, for example, the concomitant use of rotavirus vaccines with other vaccines, were also discussed. Rotavirus vaccines have the potential to substantially reduce morbidity and mortality from rotavirus disease and impact children’s health in Asia. © 2007 Elsevier Ltd. All rights reserved. Keywords: Rotavirus vaccine; Asia; Vaccine implementation
1. Introduction 1.1. Rotavirus in Asia Around the globe, diarrhoeal disease remains the second most common cause of death among children under the age of 5 years [1]. Rotavirus is the single most common aetiological agent of severe diarrhoea [2]. Each year, rotavirus causes more than 125 million episodes of infantile gastroenteritis and over 600,000 deaths in children younger than 5 years of age, with the highest mortality occurring in the poorest 夽 This article was prepared from the presentations at the meeting “Vaccinology 2006: Focus on Rotavirus and Poliovirus in Asia” organized by The Pediatric Society of Thailand, The Royal College of Pediatricians of Thailand and The Asian Pacific Pediatric Association, Pattaya, Thailand, 20–22 July 2006. ∗ Corresponding author. Tel.: +1 410 955 3952; fax: +1 410 614 1419. E-mail address: [email protected] (M. Santosham).
0264-410X/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2007.07.064
countries [3,4]. Rotavirus infects almost every child before its fifth birthday [3]. Of the rotavirus-associated deaths worldwide, more than 55% are estimated to occur in Asia [5]; the death toll in India and China alone account for more than 135,000 children annually (Fig. 1) [2,3]. Nosocomial rotavirus infections further impact on the healthcare system. Nosocomial cases were responsible for 14–51% of the total rotavirus infections and the proportion was similar in developed (27%) and developing countries (32%) [6]. Continuing epidemiological surveillance within Asia will help define the magnitude of the disease burden (Fig. 2) [5] and track the serotype distributions (Table 1) [7–12]. Efforts to improve sanitation and hygiene have dramatically lowered the overall incidence of diarrhoeal diseases; however, the rates of rotavirus diarrhoea have remained relatively stable over time [2]. In fact, the incidence of rotavirus diarrhoea is similar in developed and developing countries
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Fig. 1. Distribution of estimated rotavirus disease-associated deaths in Asia, by country [3]. DPR, Democratic People’s Republic.
make it a difficult problem to eradicate. In addition, the ensuing burden of the disease on healthcare and society imposes an immense strain on the economy. In Hong Kong, the annual total social cost and total direct medical cost for rotavirusassociated admissions were estimated at US$ 4.3 and US$ 4 million, respectively [14]. In Vietnam, the economic burden of the disease is estimated at US$ 3.1 million in medical direct costs, US$ 685,000 in non-medical direct costs, and US$ 1.5 million in indirect costs, with total societal costs of US$ 5.3 million per year [15]. Prevention of rotavirus disease through immunization has been recommended as the best strategy for reducing rotavirus-associated illness and deaths [2,16]. The World Health Organization’s (WHO) Steering Committee on Diarrhoeal Disease Vaccines recognizes vaccination as the answer to avert the devastating consequences of rotavirus and therefore maintains rotavirus vaccine development as a high priority [13]. Preliminary estimates indicate that a universal rotavirus vaccination programme in Asia could potentially save the lives of 109,000 children and prevent 1.4 million hospitalizations and 7.7 million outpatient visits [17]. Such a universal immunization programme in Asia could reduce healthcare costs by US$ 191 million but the economic impact in individual countries would depend on the country’s income level, the cost of the vaccine and the assumptions used [17]. 1.2. Rotavirus vaccines
Fig. 2. Proportion of rotavirus-attributable hospitalizations in Asia, by country, as collated from surveillance efforts by the Asian Rotavirus Surveillance Network (ARSN). Adapted from [5]; © 2005 by the Infectious Diseases Society of America.
with very different levels of sanitation. Despite the efficacy of oral rehydration therapy for treatment of diarrhoea of all aetiologies including rotavirus [13], many children with rotavirus diarrhoea die because of poor access or inadequate use of oral rehydration salts. The resilience and ubiquity of rotavirus Table 1 Serotype distributions in Asia, by country during the period 2001–2003 Country
Most prevalent serotype
Reference
China India Korea Taiwan Thailand Vietnam
G3P[8] G1 G9P[8] G9P[8] G9 G1P[8]
[7] [8] [9] [10] [11] [12]
Adapted from [7–12].
In the past two decades, several rotavirus candidate vaccines have been evaluated. A tetravalent reassortant vaccine, RotaShield® by Wyeth Laboratories Inc. [18,19], was licensed in the United States but withdrawn from the market within a year due to an increased risk for intussusception among vaccine recipients [20,21]. Two new rotavirus vaccines have recently been licensed in a number of countries globally, including several Asian countries (such as Hong Kong and Taiwan), and there are other vaccine candidates in the pipeline (Table 2) [2]. This provides the opportunity to include rotavirus vaccines into NIP. To facilitate this process, there is a need for countries within the Asian region to coherently assess the current circumstances and reach agreement on the basic guidelines and principles for safe and effective use of rotavirus vaccines. Such information will help policy makers assess the applicability of current information on rotavirus vaccines and disease burden to healthcare infrastructures within the local context. This manuscript presents the conclusions from the Asian Pacific Pediatric Association (APPA) “Vaccinology 2006: Focus on Rotavirus and Poliovirus in Asia” meeting held in Pattaya, Thailand, 20–22 July 2006.
2. Discussion Jointly hosted by the Paediatric Society of Thailand, the Royal College of Pediatricians of Thailand and APPA, the
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Table 2 An overview of current and emerging rotavirus vaccines Vaccine
Manufacturer
Rotavirus strains (genotype)
RotarixTM
GlaxoSmithKline Merck
Monovalent, attenuated human strain 89-12 (P[8], G1) Pentavalent human-bovine reassortants WC3 × WI79 (P7[5], G1), WC3 × SC2 (P7[5], G2), WC3 × W178 (P7[5],G3), WC3 × BrB (P7[5], G4) and WC3 × WI79 (P1A[8], G1) LLR strain (P[12], G10)
RotaTeq® LLR RV3 UK reassortant Indian neonatal vaccines Rhesus tetravalent
Lanzhou Institute of Biological Products University of Melbourne and Bio Farma National Institutes of Health Bharat Biotech International Ltd. BIOVIRx Inc.
Monovalent neonatal human strain (P2A[6], G3) Tetravalent human-bovine reassortant UK × Wa (P7[5], G1), UK × DS1 (P7[5], G2), UK × P (P7[5], G3) and UK × ST3 (P7[5], G4) Neonatal strains 116E (P[11], G9) and I321 (P[11], G10) Tetravalent human-rhesus reassortants RRV × D (P5[3], G1), RRV × DS1 (P5[3], G2), RRV (P5[3], G3) and RRV × ST3 (P5[3], G4)
Adapted from [2]. LLR, Lanzhou lamb rotavirus; WC3, bovine rotavirus strain.
meeting provided a venue for experts to reach agreements on the importance of rotavirus disease prevention and vaccine implementation in Asia. The current status of rotavirus disease burden, together with available data on rotavirus vaccine candidates, was evaluated. Rotavirus is estimated to claim the lives of 230,000 children in Asia each year [5]. Six of the 10 countries with the highest number of rotavirus disease-associated deaths are in Asia [5]. The disease also causes significant morbidity resulting in hospitalization and outpatient visits, and the ensuing heavy economic burden is apparent. Therefore, prevention of rotavirus diarrhoea in Asia is of high priority [5]. Presentations from international and regional experts provided information to help participants assess the role of rotavirus vaccines in NIP in their countries. 2.1. Current perspectives It was agreed that although many public health officials recognize diarrhoea as a major health problem, they do not recognize rotavirus as a leading cause of diarrhoea. Further, many healthcare workers and public health officials believe that improvements in quality of water and sanitation will reduce the rates of rotavirus diarrhoea despite the evidence to the contrary. Although paediatricians may appreciate rotavirus as a significant cause of acute diarrhoea in children, they may not consider that vaccination is the optimal control strategy, especially in more developed countries where rotavirus mortality is rare. 2.2. Call for further surveillance Even with licensed rotavirus vaccines becoming available in Asia, a lack of knowledge on the incidence and burden of the disease will limit the use of these vaccines, particularly to those poorer sections of the population who could benefit most. Therefore, effort is needed to educate policy makers, healthcare providers and the public and increase advocacy to ensure that these vaccines can be introduced into NIP at an early stage.
To address this gap in knowledge, collection and dissemination of reliable and accurate data to define the existing disease burden will be very important [2]. In Asia, the Asian Rotavirus Surveillance Network (ARSN) has been instrumental in collecting and presenting epidemiological data on rotavirus disease and serotype characterization in the region (Fig. 2) [5]. Wide variation in rates of mortality due to rotavirus can be explained by the differences in healthcare access and quality of care. On the other hand, morbidity rates are relatively consistent between countries. However, despite the significant amount of data that have been collected by ARSN to date, there is still a paucity of disease burden data in certain countries, often in countries where rotavirus mortality is estimated to be high. The poorest of these countries will be eligible for vaccine funding support from the Global Alliance for Vaccines and Immunization (GAVI). The ARSN is currently collecting rotavirus disease burden data for a number of GAVI-eligible countries. 2.3. Addressing vaccine cost-effectiveness For rotavirus vaccination to become a routine practice in Asia, one of the biggest challenges faced is the anticipated high cost of vaccine and the consequent concern of vaccine funding. Comprehensive disease surveillance will supply clear and critical information on the medical and economic burden of the disease. In turn, local economic evaluations will be one of the influencing factors for key stakeholders in deciding on the value of rotavirus vaccination in each country in relation to other health priorities. 2.4. Assessing the adequacy of vaccine-related data 2.4.1. Vaccine efficacy Past experiences with several live oral rotavirus vaccines have demonstrated poor immunogenicity and efficacy responses in developing countries [2,22–25]. Since children in Asia represent close to half of the world’s children [26], this region is of special importance to public health
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workers, prospective donors and vaccine manufacturers. Disease surveillance data have shed light on the existence of distinct geographical serotype differences within the region (Table 1) [7–12]. Multiple factors may explain the low efficacy observed in previous vaccine trials including host factors that might decrease vaccine take (such as nutritional deficiencies, differences in intestinal flora, and high levels of maternally derived antibodies), virological mismatch between circulating strains and vaccine strains used in earlier vaccines, study designs used in early trials, and other factors [27]. To attest the success or failure of these rotavirus vaccines, it is paramount that additional efficacy studies be conducted in poorer developing countries. 2.4.2. Vaccine safety With the withdrawal of the first rotavirus vaccine licensed in the United States (RotaShield® ) due to an observed association with intussusception [20,21], the issue of safety of rotavirus vaccines has been a foremost concern among the medical community and the vaccine manufacturers. Large scale (over 60,000 subjects per study) pre-licensure studies conducted with RotarixTM (GlaxoSmithKline) and RotaTeq® (Merck) has found no evidence of increased rates of intussusception or any other serious adverse events with either vaccine [28,29]. Post-licensure studies will be required to fully evaluate the safety of these new vaccines. 2.5. Choosing the vaccine A number of rotavirus vaccines are anticipated (Table 2) [2], with two rotavirus vaccines currently available in the market—RotarixTM and RotaTeq® . One vaccine is based on an attenuated monovalent human rotavirus strain and the other is a pentavalent human-bovine reassortant vaccine. Studies have demonstrated significant differences in their rate of viral shedding (>50% for RotarixTM versus <10% for RotaTeq® ) [29–33]. However, it should be recognized that these data are not directly comparable because the method of rotavirus detection differed in the two studies. In the trials with RotaTeq® , potential faecal shedding of vaccine was monitored by viral culture with use of a plaque assay and RNA electropherotyping [29], while trials with RotarixTM employed the enzyme-linked immunosorbent assay [30,31]. Some experts in the field believe that high viral shedding is beneficial because it may provide a higher possibility of herd immunity or herd protection. On the other hand, other experts argue that a vaccine with low shedding is preferable since it reduces the chances of transmission to immunocompromised individuals. Provided these and future rotavirus vaccines have equivalent safety and efficacy, it is unlikely that differences in shedding will have any material impact. 2.6. Vaccine implementation Among the other issues that concern vaccine implementation, the subject of potential interference of rotavirus vaccine
in breastfed infants was discussed. The presence of antibodies to different rotavirus serotypes in breast milk is postulated to influence the take rate of rotavirus vaccines [34]. Research has demonstrated that although these affect serum immune responses, it is usually statistically insignificant [35]. More importantly, no decrease in the protective efficacy of rotavirus vaccine in breastfed and non-breastfed infants has been observed. In light of the immense burden of rotavirus disease, the greater benefits for using a rotavirus vaccine far outweigh this concern of potential interference. Hence, it is recommended that the vaccine should be administered to breastfed infants and this recommendation should be reviewed when more data becomes available. For rotavirus vaccines to be administered to infants with other routine childhood immunizations, potential interference with concomitant administration needs to be considered. Some participants felt that co-administration of rotavirus vaccine with oral polio vaccine (OPV) could result in interference. Therefore, rotavirus vaccination should be administered at least 2 weeks apart when feasible. Participants agreed that more data was required to assess possible interference of OPV on rotavirus vaccine efficacy. In choosing a rotavirus vaccine for a particular country, several factors should be taken into account—the cost of the vaccine, the ease of administration and the number of doses needed. Both RotarixTM and RotaTeq® are expected to have significant impact in disease reduction in all countries and it is likely that vaccine cost will be the main driver of decisions on the recommended vaccine for NIP.
3. Conclusion 3.1. The challenges ahead The implementation of rotavirus vaccination brings hope that prevention of this disease could potentially save the lives of millions of children worldwide. The summary of the concerns and recommendations of the regional medical community at the APPA meeting regarding rotavirus disease burden and the implementation of rotavirus vaccination are as follows: • It is recommended that individual countries assess existing disease burden, vaccine efficacy data and the estimated cost-effectiveness of vaccination in the local country context. Tools to facilitate the estimation of disease burden and cost-effectiveness of vaccination are available from the WHO, along with technical resources [36]. • Countries with limited data are encouraged to conduct surveillance that will produce reliable data to estimate the local disease burden. • More data on the co-administration of rotavirus vaccine with OPV and breastfeeding are required. However, pending further updates, it is recommended that rotavirus
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vaccine should be administered to breastfed infants. Some participants felt that OPV should be administered at least 2 weeks apart from rotavirus vaccination until more data are available. The conference participants recommended that additional studies needs to be conducted in order to assess the impact of co-administration of OPV and rotavirus vaccines on the immune responses to rotavirus vaccine. • Post-marketing surveillance is strongly encouraged to monitor adverse events including incidence of intussusception, evaluate the impact on total diarrhoeal and rotavirus-specific disease burdens, and to conduct serotype surveillance. • As multiple rotavirus vaccines could become available in a single country, the likely scenario of a mixed schedule of vaccination using different vaccine candidates should be investigated.
3.2. Moving ahead Rotavirus vaccines are now recommended for routine immunization of children in a number of South American countries and the United States [37,38]. Both vaccines are already licensed in several Asian countries. Given the high disease burden in Asia, the use of rotavirus vaccines was strongly recommended by the APPA conference participants.
Acknowledgements This article is supported by The Pediatric Society of Thailand and by an educational grant from GlaxoSmithKline, Sanofi Pasteur and Merck.
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