de Oliveira, Lucia Helena RN, MSc*; Danovaro-Holliday, M. Carolina MD, MSc*; Sanwogou, N. Jennifer MPH*; Ruiz-Matus, Cuauhtemoc MD, MPH*; Tambini, Gina MD, MPH†; Andrus, Jon Kim MD‡
Rotavirus infects virtually all children <5 years of age with severe gastroenteritis in both developing and developed countries, causing an estimated 610,000 deaths, 2.4 million hospitalizations, and 25 million clinic visits annually worldwide.1,2 However, 80% of rotavirus-related deaths occur in developing countries. In Latin America and the Caribbean (LAC), rotavirus causes an estimated 15,000 deaths, 75,000 hospitalizations, and 2 million clinic visits annually.3,4
In 1998, a rotavirus vaccine was first licensed and made available in the market in the United States. However, in 1999, less than a year after introduction, the license was withdrawn from the market due to documented increased risk of intussusception.5,6 In 2006, 2 new human, live-attenuated oral vaccines, Rotateq (Merck and Co.) and Rotarix (GSK Biologicals, Rixensart, Belgium), were licensed and made available commercially. Rotateq is an oral pentavalent vaccine G1, G2, G3, G4 [P8] that is administered in a 3-dose schedule. Rotarix is an oral monovalent vaccine G1 [P8] that is administered in a 2-dose schedule. These vaccines have proven to be safe and efficacious in clinical trials and in the surveillance of adverse events conducted in developed countries and in Latin American countries.7,8 Furthermore, recent effectiveness studies conducted in El Salvador and Nicaragua found that the vaccine was associated with a decreased risk of severe rotavirus diarrhea in young children.9,10
In 2006, the Directing Council of the Pan American Health Organization (PAHO), an annual meeting of the ministers of health in the Americas, passed a resolution calling upon Member States to mobilize additional funding to introduce new vaccines in national immunization programs; rotavirus was considered one of the priority new vaccines.11 In November 2007, a consultation of experts convened by the World Health Organization (WHO) to evaluate data from clinical trials of rotavirus vaccines concluded that vaccine efficacy data could be extrapolated to populations that fell into similar child-mortality strata. On the basis of their review of the evidence, the WHO's Strategic Advisory Group of Experts on Immunization recommends the inclusion of rotavirus vaccination of infants into all national immunization programs. In countries where diarrheal deaths account for ≥10% of mortality among children aged <5 years, the introduction of the vaccine is strongly recommended.12
The objective of this article is to provide an update including lessons learned on the status of rotavirus vaccine introduction in LAC. This update should serve as a useful reference to ministries of health (MOH) and other policy-makers faced with the challenge of introducing the rotavirus vaccine or other new vaccines into their Expanded Program on Immunization (EPI).
MATERIALS AND METHODS
Data examined to assess rotavirus vaccine introduction included country reports to PAHO, data from the rotavirus sentinel surveillance network, published cost-effectiveness studies, rotavirus vaccine purchase records from PAHO's Revolving Fund, and reports from international evaluations in Ecuador and El Salvador. The data were collected from 2004 to May 2010.
PAHO is an international public health agency with more than 100 years of experience in working to improve health and living standards of the countries of the Americas. PAHO serves as the Regional Office for the Americas of the WHO, and provides technical assistance to all countries and territories in the Western Hemisphere. Most of PAHO's technical cooperation is targeted to the poorer countries in LAC.13
Since the 1980s, PAHO's Member States submit annual immunization reports, using the standardized PAHO-WHO/UNICEF Joint Reporting Form on Immunization (previously known as EPI tables).14 Data used from this source include vaccines recommended in the countries' immunization schedule, rotavirus vaccine presentation, annual administrative coverage rates (number of vaccine doses administered divided by the number of children aged <1 year), vaccine stock-outs, and financial information, such as the percentage of all routine vaccine expenditures financed with government funds and other sources such as donations. Government funds may include bank loans to improve national immunization budgets. Data on vaccine safety were obtained from a regional network for monitoring events supposedly attributable to vaccination or immunization, which was created concomitantly with vaccine introduction,3,15 country ad hoc reports to PAHO, and presentations from LAC countries in selected international meetings.
In 2004, PAHO began implementing sentinel hospital surveillance network for rotavirus in LAC countries. Countries use standardized definitions and diagnostics, in accordance with a generic surveillance protocol, to facilitate comparability.16–18 Countries report the number of suspected and confirmed cases of rotavirus hospitalizations to PAHO on a monthly basis.
The Revolving Fund is the mechanism for bulk purchase of vaccines and immunization supplies that PAHO manages on behalf of its Member States since 1979. Annually, vaccine orders from countries that wish to participate in the Revolving Fund are consolidated and an international bid is then opened to all vaccine manufacturers for products prequalified by the WHO. PAHO procures vaccines with money drawn from the Fund and countries reimburse the Fund for purchases made on their behalf. Larger countries may pay in advance to the Fund.19,20 Data from purchase records on rotavirus vaccine were obtained.
PAHO conducts regular international immunization evaluations in LAC countries. In 2009, PAHO, the Ministry of Health of Ecuador, and the US Centers for Disease Control and Prevention (CDC) conducted a new vaccine postintroduction evaluation (PIE) to assess the introduction of rotavirus vaccine in Ecuador's national immunization program (Ministerio de Salud Pública, unpublished data, 2008). The PIE methodology was developed in 2008 by the WHO, in collaboration with the CDC and the London School of Hygiene and Tropical Medicine to assess the overall effect of the introduction of a new vaccine on a country's national EPI. The methodology focuses on a range of programmatic aspects such as vaccine storage and wastage, logistics of vaccine administration, and community receptiveness to the vaccine.21 In 2009, PAHO also conducted an international EPI evaluation in El Salvador.22 The methodology for this type of evaluation focuses on all technical aspects of a country's EPI. It was developed by PAHO and has been used in LAC for almost 30 years.23
As of May 2010, 14 LAC countries (42%) and 1 territory have introduced the rotavirus vaccine into their universal childhood immunization schedules (Fig. 1). As a result, 83% of the 10.8 million children born annually in LAC live in countries routinely using the rotavirus vaccines. Six LAC countries (Brazil, El Salvador, Mexico, Nicaragua, Panama, and Venezuela) introduced the rotavirus vaccine in 2006, the same year the vaccine was licensed by the United States Food and Drug Administration (FDA) and the European Medicines Agency (Table 2). Ecuador was the next country to introduce the vaccine in 2007, followed by Bolivia in 2008; Colombia, Honduras, Peru, and the United Kingdom's overseas territory of Cayman Islands in 2009; and Guatemala, Guyana, and Paraguay in 2010. Only Mexico introduced the vaccine at the subnational level in 2006, in the poorest municipalities where the disease burden was greatest, but by May 2007 it had expanded its use nationwide.3
Private-sector use of the rotavirus vaccine in LAC has been widespread, but not quantified. All countries, except Guyana and Nicaragua, use the monovalent rotavirus vaccine G1[P8] in a 2-dose schedule at 2 and 4 months of age. Guyana and Nicaragua use the pentavalent rotavirus vaccine G1, G2, G3, G4 [P8] in a 3-dose schedule at 2, 4, and 6 months of age.
Rotavirus vaccine is recommended to be given simultaneously with other vaccines in the routine immunization schedule, including the polio and the DTP-Hib-Hepatitis B vaccines. However, in several instances, coverage levels for the last dose of rotavirus vaccine are lower than those for the third dose of DTP-Hib-Hepatitis B and polio vaccines. Rotavirus coverage was lower than DTP-Hib coverage for all 6 countries in 2007, for 6 of 8 countries in 2008, and for all 11 countries in 2009 (Table 1). However, rotavirus coverage increased in 2009 in 6 of the 8 countries that were using the rotavirus vaccine in 2008. This increase ranged from 1% in Brazil to 15.5% in Ecuador (Table 1). The reported drop-out rates for rotavirus vaccines, defined as the difference between children who receive the first and the last dose of the vaccine, are high, reaching up to 20.2% in Panama in 2008. In 2009, the drop-out rates were reduced for every country, with the largest drop-out rate being 20.1% in Panama (Table 1).
The LAC rotavirus surveillance network was implemented in 2004. In 2005, 7 countries started reporting surveillance data to PAHO.18 By 2009, 15 countries were systematically reporting rotavirus surveillance data to PAHO from 59 sentinel hospitals. These countries included Bolivia, Brazil, Chile, Ecuador, El Salvador, Colombia, Guatemala, Guyana, Honduras, Nicaragua, Panama, Paraguay, Suriname, Saint Vincent & the Grenadines, and Venezuela. Chile, Suriname, and Saint Vincent & the Grenadines have reported surveillance data but have not introduced the vaccine. Of the 14 countries that have introduced the rotavirus vaccine, 7 (Bolivia, El Salvador, Guatemala, Guyana, Honduras, Paraguay, and Venezuela) had sentinel surveillance implemented prior to vaccine introduction; 2 (Ecuador and Panama) implemented surveillance after introducing the vaccine; and 3 (Brazil, Colombia, and Nicaragua) implemented sentinel surveillance in the same year as vaccine introduction (Table 2). Three countries and 1 territory using the vaccine (the United Kingdom's overseas territory of Cayman Islands, Peru, and Mexico) have not become part of the regional LAC sentinel rotavirus surveillance network. Two countries participating in the network, El Salvador and Nicaragua have used their surveillance system as a platform to conduct rotavirus vaccine effectiveness studies.
Countries have reported 58 instances of programmatic errors, where the oral vaccine was given intramuscularly. Of these programmatic errors, 90% were in the private sector and, in most cases, happened early in the introduction process when the vaccine was presented as a syringe. No untoward consequences were observed. To date, the passive events supposedly attributable to vaccination or immunization surveillance system has reported no data to suggest an association between rotavirus vaccine use and intussusception or other serious adverse events. A collaborative multinational safety study—-between MOH, the CDC, the FDA, the Program for Appropriate Technology in Health (PATH), the Global Alliance for Vaccines and Immunisation (GAVI), and PAHO—is being conducted in Brazil and Mexico. This study aims to assess whether an association between oral rotavirus vaccine and intussusception exists under routine public health use of the vaccine.
Rotavirus vaccine cost-effectiveness studies for Brazil, Chile, Colombia, Panama, Peru, Mexico, and Venezuela published in international literature have shown a favorable cost-effectiveness ratio, which is strongly influenced by the price of the vaccine.24–30 PAHO's Revolving Fund offers the vaccine at the lowest price in the market. As of May 2010, 12 countries and 1 territory using the vaccine purchase it through the Fund. The pentavalent rotavirus vaccine is offered through the Revolving Fund at US $5.5 per dose (US $16.5 per child fully vaccinated) and the monovalent rotavirus vaccine is offered at US $7.5 per dose (US $15 per child fully vaccinated); the latter vaccine was priced at US $7.9 in 2008 and 2009. In 2008, all LAC countries using rotavirus vaccine in their national immunization program reported having a budget line for vaccine purchase. All but 1 country financed >95% of their public sector routine vaccine expenses using government funds. Of the 6 GAVI-eligible countries in LAC (countries with a gross national income <US $1000 per capita in 1999), Bolivia, Guyana, Honduras, and Nicaragua currently purchase the rotavirus vaccine using GAVI support. Nicaragua received a donation from the manufacturer between 2006 and 2009.
In the early stages of vaccine use, countries purchasing the vaccine directly from the manufacturers reported vaccine delays leading to stock-outs. Since 2007, no such stock-outs have been reported. However in 2009, 1 country purchasing through the Revolving Fund was late in paying for the vaccine; therefore, the country did not receive rotavirus vaccines for several months, resulting in rotavirus vaccine shortages nationwide.
In September 2009, a PIE of the rotavirus vaccine was conducted in Ecuador by the MOH, PAHO, WHO, and CDC. This is the only such evaluation conducted in LAC. The objective of the evaluation was to identify the problematic areas within the EPI related to the new vaccine introduction. The main strengths identified include the study of disease burden prior to the decision of using the rotavirus vaccine and the careful planning of the vaccine introduction, including the assessment, the needs, and expansion of the cold chain capacity; the creation and dissemination of guidelines on vaccine use; and the training of health care workers using videos and other adult-focused educational methods. Persons interviewed indicated that the new vaccine introduction processes contributed to the strengthening of the routine EPI, as it allowed for the logistics and other aspects of the program to be reviewed. Similar to most LAC countries, Ecuador purchases the vaccine using government funds. The main weakness identified was the lack of rotavirus surveillance before the vaccine introduction, which limits the ability to evaluate its effect. Other weaknesses identified were common to the general functioning of the EPI and not related to the introduction of the new vaccine.
The experience of the rotavirus vaccine into LAC countries stands out because this is the first time that a new vaccine is introduced in developing countries at the same time as it is licensed and introduced in developed ones. Because improvements in water, food, and sanitation are unlikely to reduce rotavirus disease incidence, vaccination appears to be the best intervention to control the disease.31
The efficacy of the rotavirus vaccines in prelicensure clinical trials was 98% (95% confidence interval [CI], 88.3%–100%) and 85% (95% CI, 71.7%–92.4%) against severe rotavirus gastroenteritis for the pentavalent rotavirus vaccine and the monovalent rotavirus vaccine, respectively.7,8 These measured clinical trial efficacies depended on the administration schedule and the population evaluated. Vaccine efficacy and effectiveness studies conducted in several regions of the world have shown varied levels of performance, some lower than the initial clinical efficacy trials. The efficacy studies have demonstrated the vaccine to have an effect in reducing severe rotavirus gastroenteritis in Africa and Asia.32 Therefore, rotavirus vaccination has the potential to significantly reduce rotavirus disease morbidity, especially severe cases, and mortality. In Nicaragua, the pentavalent vaccine, using a 3-dose schedule, showed an effectiveness of 46% (95% CI, 18%–64%) against rotavirus hospitalization, 58% (95% CI, 30%–74%) against severe rotavirus diarrhea, and 77% (95% CI, 39%–92%) against very severe rotavirus diarrhea.9 In El Salvador, the monovalent vaccine, using a 2-dose schedule, showed an effectiveness of 76% (95% CI, 64%–84%). Protection was significantly lower (P = 0.046) among children who were 12 months or older (59%, 27%–77%) compared with children aged 6 to 11 months (83%, 68%–91%). One dose of vaccine was 51% (26%–67%) effective. All children under 5 years of age who were admitted to sentinel hospitals for diarrhea declined by 40% in 2008 and by 51% in 2009 from the prevaccine year 2006.10 In both studies, based on the results mentioned, the effectiveness was lower than in vaccine efficacy trials.
Maximum vaccination effect will require high-coverage levels. Rotavirus vaccine coverage is lower than the coverage for other vaccines recommended at the same age, even lower than another oral vaccine such as the oral polio vaccine. In countries with less than 50% rotavirus coverage for children with a vaccine effectiveness of approximately 70% against severe diarrhea gastroenteritis, the intervention would have a limited effect. Populations with low coverage are less likely to have access to healthcare services and are, therefore, more at risk for dying of the disease.
One factor that may in part explain the lower coverage rates achieved with rotavirus vaccine, compared with the coverage rates of other childhood vaccines, is the age restriction for rotavirus vaccination, a consideration that was emphasized in LAC countries using the vaccine. Due to concerns about the risk of intussusception, the manufacturers recommended starting vaccination no later than 12 weeks of age for both vaccines and completing the schedule no later than 24 weeks of age for monovalent vaccine and no later than 32 weeks of age for the pentavalent rotavirus vaccine.33 In 2009, following the results of safety phase III studies and considering postmarketing data not showing an increased risk of intussusception for either vaccine, the Global Advisory Committee on Vaccine Safety concluded that both vaccines are safe and the first dose can be administered between 6 to 15 weeks and the last dose up to 32 weeks of age for either vaccine.34 Other possible factors to explain the lower coverage rates may be vaccine stock-outs in some countries and the logistical problems presented when the rotavirus vaccine is transported for outreach sessions, as the vaccine volume requires an additional thermos.3 As countries gain more experience with the use of the rotavirus vaccine, immunization programs are implementing strategies to deal with these issues, such as improving the timely tracking of defaulters, to increase coverage rates to levels comparable with those achieved for other vaccines.
Rotavirus vaccine was introduced in LAC much faster than other new vaccines such as Hepatitis B.35 Factors that may have contributed to the rapid uptake include the 2006 Directing Council Resolution, which called upon PAHO Member States to mobilize additional funding to enable the introduction of new vaccines including rotavirus.11 Member States resolved to support the mortality reduction targets consistent with WHO's Global immunization Vision and Strategy 2006–2015,36 and the MDGs.37 The same year as the Directing Council Resolution was approved, PAHO launched the ProVac Initiative. ProVac assist countries in strengthening national capacity to make evidence-based decisions for new and underutilized vaccine introduction.38
In LAC, vaccines are considered a public good; therefore, governments assume the responsibility of purchasing vaccines for their national immunization programs. In several cases, the funds for vaccine purchase are secured through national legislation and other budgetary mechanisms, which enable sustainability.39 The cost-effectiveness studies in LAC countries have provided data to support the decision to invest in introducing the rotavirus vaccine into the EPI.24–30 PAHO's Revolving Fund has substantially contributed to the sustainable provision of the rotavirus vaccines to Member States, by ensuring that the countries receive an uninterrupted supply of WHO prequalified vaccines at the lowest market price available.40,41
Surveillance data are important to understand the burden of rotavirus.18,33,42,43 Since 2004, PAHO's Technical Advisory Group on Vaccine-Preventable Diseases has recommended the implementation of rotavirus surveillance in LAC countries.44 The standardized hospital-based rotavirus surveillance network in children aged <5 years in LAC was implemented in 2004 and was instrumental in providing evidence of the high burden of rotavirus disease in the Region (31.5% of diarrhea hospitalization were attributable to rotavirus infection in selected countries in 2006–2007). The surveillance has also provided a better understanding of the disease seasonality in this Region, as well as the profile of circulating serotypes.18 In 2010, Guatemala detected a rotavirus outbreak through its sentinel surveillance system that has led the government to recommend rotavirus vaccine introduction.45 The challenge will be to continue to improve data quality and increase the number of countries conducting standardized surveillance.18,46
Surveillance of events supposedly associated with vaccination and immunization after vaccine introduction is also critical to detect rare adverse events. In March 2010, there was a temporary concern regarding the discovery of circovirus 1 (PCV1) in the monovalent vaccine and fragments of PCV1 and PCV2 in the pentavalent vaccine. WHO and PAHO concluded that these findings did not present a threat to public health and recommended to continue the use of the vaccine.47 In May 2010, the majority of an advisory committee for the US FDA supported the continued use of the rotavirus vaccine which was under FDA suspension, arguing that the benefits of the vaccine far outweigh the theoretical risks of the contaminant.48
Our review of the progress of rotavirus vaccine in LAC countries has several limitations. The information presented comes from routine data reporting from countries to PAHO; incompleteness and data quality issues are of concern. The main conclusions stand: LAC countries are rapidly introducing the rotavirus vaccine into their immunization programs and dealing with particular challenges related to this vaccine, and are contributing to better understand the effectiveness and safety of rotavirus vaccine as a public health intervention.
Rotavirus vaccine introduction in LAC has been successful, but many questions remain to be answered. Constant monitoring of the following epidemiologic issues will be fundamental to better assess the effect of rotavirus vaccine introduction in developing countries: vaccine performance against severe disease during routine use, vaccine effect on rotavirus disease epidemiology, changes in burden of severe disease and death, age distribution of cases, seasonality and serotype distribution, indirect protection for unvaccinated children, and duration of protection.32,49 To that end, LAC countries will continue to provide useful data to monitor rotavirus trends and vaccine effect.
The authors thank the immunization programs of all LAC countries for sharing their immunization data, particularly regarding rotavirus data; the Pan American Health Organization immunization focal points in LAC countries for their support with the introduction of rotavirus vaccine; and Ms. Beatrice Carpano for her editorial assistance. The authors also acknowledge the unwavering dedication of the health care workers providing immunization services to the people of the Americas.
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