Health Impact of Rotavirus Vaccination in Developing Countries: Progress and Way Forward
Health Impact of Rotavirus Vaccination in Developing Countries: Progress and Way Forward
Umesh D. Parashar 2
Hope Johnson 1
A. Duncan Steele 0
Jacqueline E. Tate 2
0 Bill & Melinda Gates Foundation, Seattle , Washington
1 Gavi, the Vaccine Alliance , Geneva , Switzerland
2 Division of Viral Diseases, Centers for Disease Control and Prevention , Atlanta , Georgia
Two rotavirus vaccines have been licensed in >100 countries worldwide since 2006. As of October 2105, these vaccines have been implemented in the national immunization programs of 79 countries, including 36 low-income countries that are eligible for support for vaccine purchase from Gavi, the Vaccine Alliance. Rotavirus vaccines were initially introduced in Australia and countries of the Americas and Europe after completion of successful clinical trials in these regions, and the impact of routine vaccination in reducing the health burden of severe childhood gastroenteritis in these regions has been well documented. Because of concerns around the performance of orally administered rotavirus vaccines in developing countries, vaccine implementation in these settings only began after additional clinical trials were completed and the World Health Organization issued a global recommendation for use of rotavirus vaccines in 2009. This supplementary issue of Clinical Infectious Diseases includes a collection of articles describing the impact and effectiveness of routine rotavirus vaccination in developing countries that were among the early adopters of rotavirus vaccine. The data highlight the benefits of vaccination and should provide valuable evidence to sustain vaccine use in these countries and encourage other countries to adopt routine rotavirus vaccination to reduce the health burden of severe childhood gastroenteritis.
In 2006, pivotal clinical trials of 2 live oral rotavirus vaccines—a
pentavalent bovine-human reassortant vaccine (RV5) given in a
3-dose schedule (RotaTeq, Merck & Co), and a monovalent
human vaccine (RV1) given in a 2-dose schedule (Rotarix,
GSK Biologicals)—demonstrated good efficacy (85%–98%) in
preventing severe rotavirus gastroenteritis [
]. In addition,
these large trials of 60 000–70 000 infants each were specifically
designed to evaluate the risk of intussusception, an uncommon
adverse event that had led to the withdrawal of an earlier
rotavirus vaccine (RotaShield, Wyeth Lederle) from the United
States in 1999; reassuringly, no risk was found with either
]. The World Health Organization’s (WHO) Strategic
Advisory Group of Experts reviewed these data from trials
conducted in Europe and the Americas and recommended that
rotavirus vaccines be included in the national immunization
programs of countries in these regions where vaccine efficacy
had been demonstrated [
Beginning with the United States in February 2006, many
countries in the Americas and Europe, as well as Australia,
soon adopted rotavirus vaccines as part of their routine childhood
vaccination programs. In many of these countries, the remarkable
impact of these vaccines in reducing the burden of severe
childhood gastroenteritis has been unequivocally demonstrated.
A systematic review of data from 8 countries reported a 49%–
89% decline in laboratory-confirmed rotavirus hospitalizations
and 17%–55% decline in all-cause gastroenteritis hospitalizations
among children aged <5 years within 2 years of vaccine
]. As an unanticipated benefit, in some countries, rotavirus
vaccination of young infants has also resulted in the declines in
rotavirus disease among children who missed vaccination and
among older children and even adults who were not vaccine
]. This phenomenon, known as herd protection, is
likely related to reduction in community transmission of
rotavirus because vaccination limits the number of children susceptible
to rotavirus disease. Most notably, studies from Mexico, Brazil,
and Panama showed a reduction in childhood deaths from
allcause diarrhea following vaccine implementation, a key outcome
that was not evaluated in clinical trials [
Despite this impressive success in developed countries, the
full impact of rotavirus vaccines remained to be realized in
developing countries of Asia and Africa where morbidity and
mortality due to rotavirus are greatest. Because of concerns
that the performance of orally administered rotavirus vaccines
may be diminished in developing countries of Africa and Asia
due to possible interference by concurrent enteric infections,
greater levels of maternal antibodies, and higher rates of
malnutrition and comorbidities, WHO recommended further efficacy
testing in these settings prior to issuing a global
recommendation for vaccine use [
]. As expected, efficacy trials of both RV5
and RV1 in developing countries showed lower vaccine efficacy
(50%–64%) against severe rotavirus gastroenteritis compared
with developed countries [
]. Notably, despite the
diminished efficacy, the public health benefits of vaccination in terms
of the numbers of severe rotavirus gastroenteritis episodes
prevented for every 100 vaccinated infants were greater in developing
compared with developed countries because of the substantially
greater baseline rate of severe rotavirus gastroenteritis in
developing countries [
]. These considerations led WHO to issue a
recommendation for global use of rotavirus vaccines in 2009,
particularly in developing countries with high mortality from
childhood diarrhea [
As of September 2015, 79 countries worldwide have
implemented rotavirus vaccines in their national immunization
programs, including 36 low-income, developing countries that are
eligible for support for vaccine purchase from Gavi, the Vaccine
Alliance (Figure 1). The global rollout of rotavirus vaccines
provides an opportunity to assess the real-world impact of rotavirus
vaccination in preventing and reducing the health burden of
severe childhood diarrhea in developing countries. Such post–
vaccine introduction data are particularly important to generate
as (1) vaccine performance in routine programmatic use could
differ from the ideal conditions of a clinical trial; (2) widespread
vaccine use may result in changes in rotavirus epidemiology (eg,
changes in average age of infection and seasonality) that may not be
detected in trials; and (3) vaccination may have effects on disease
transmission in the community and, thus, may provide indirect
benefits to unvaccinated individuals as well (ie, herd immunity).
The articles in this supplement describe the effects of rotavirus
vaccination in many developing countries in Africa, Eastern
Europe/Central Asia, and Latin America that were early adopters of
vaccination. The evidence and lessons learned, summarized in this
report, will be valuable for these countries to sustain their
vaccination programs and will also inform decision making in countries
that are considering implementing rotavirus vaccination.
IMPACT OF ROTAVIRUS VACCINATION IN
REDUCING MORBIDITY AND MORTALITY FROM
Perhaps the most convincing and readily interpretable evidence
of vaccine impact is the documentation of a decline in the
burden of the target disease following vaccine introduction.
However, assessing trends in disease before and after vaccine
introduction requires cautious interpretation to account for
secular trends and other possible factors (eg, changes in
surveillance practices or healthcare-seeking behavior) that might be
associated with the decline. Several articles in this supplement
from African (Botswana, South Africa, Ghana, Togo, Zambia)
and East European/Central Asian (Armenia and Moldova)
countries show evidence of rapid and substantial declines in
severe diarrhea and/or rotavirus disease following vaccine
]. In these evaluations, a role for vaccine in
disease reduction is supported by observations such as (1)
sharp declines coinciding temporally with the timing of vaccine
introduction; (2) greater declines during the months of the year
with seasonal peaks of rotavirus disease; and (3) greater initial
declines in younger age groups that receive vaccination in the
initial years of the vaccination, followed by a progressive decline
in older age groups in later years after introduction. Of note, data
from Botswana and Zambia showed a decline in in-hospital
mortality from diarrhea at sentinel hospitals conducting
]. Although some caution in interpretation is
warranted given the relatively small number of deaths observed
in these studies, these promising data on life-saving benefits of
rotavirus vaccination were indicated by findings from Latin
American countries that have convincingly shown a decline in
diarrhea mortality after rotavirus vaccine implementation. In
fact, a report in this supplement found that nationwide diarrhea
mortality in Mexican children has been reduced by almost half
following rotavirus vaccine implementation, and these declines
have been sustained for 7 years after vaccine introduction .
VACCINE EFFECTIVENESS IN ROUTINE USE
Observational studies such as those using a case-control design
can measure field effectiveness of vaccination in routine
programmatic use, proving a measure of vaccine performance
under “real world” conditions. These data expand the evidence
from clinical trials, as they include groups that may have been
excluded from clinical trials (eg, malnourished or
immunocompromised children) and children with less rigidly adhered to
vaccination schedules (eg, age at administration, interval between
doses, the number of doses). Several reports in this supplement
provide reassuring evidence that the real-world effectiveness of
rotavirus vaccination in developing countries is similar to the
vaccine efficacy in prelicensure trials, with a gradient of lower
efficacy in countries with greater levels of child mortality [
]. Some observations are noteworthy. First, evidence of a
decline in effectiveness in the second year of life compared
with the first year was seen in some studies but not in others;
furthermore, it was encouraging that effectiveness against the most
severe rotavirus disease that is likely to be associated with the
worst clinical outcomes was well sustained over the first 2 years
of life when the vast majority of rotavirus cases occur. Second,
evidence of some protection from a partial series of rotavirus
vaccine was seen, which is particularly relevant regarding protection
against severe rotavirus disease that occurs at a very young age
before a child is fully immunized. Finally, both RV5 and RV1
provided protection against a range of circulating rotavirus
strains, supporting observations from clinical trials and other
postlicensure data that both rotavirus vaccines provide good
cross-protection against non-vaccine-type strains.
INDIRECT PROTECTION FROM ROTAVIRUS
Indirect protection (ie, herd immunity) occurs as a result of
decreased transmission of the infectious pathogen in the
community because of vaccination of a proportion of the
population, thereby amplifying the benefits of vaccination among
both vaccinated and unvaccinated persons. Indirect protection
from rotavirus vaccination has been well documented in
developed countries in the Americas and Europe, and in Australia,
evident from substantial reductions in disease in age groups
who were too old to be vaccinated, including young adults in
some settings. However, it was unclear if these observations
would extend to developing countries, given differences in
population age-group structure and intensity of viral transmission.
The reports from Armenia and Moldova in this supplement
both demonstrate a decline in severe rotavirus disease among
older age groups that were not vaccinated and also greater
declines in vaccinated age groups than that expected based on
vaccine coverage and effectiveness, indicating evidence of indirect
]. However, data from Zambia and South Africa
do not indicate any evidence of indirect protection, and thus
further evidence is required to understand the extent of herd
protection across a range of geographic and socioeconomically diverse
THE WAY FORWARD
The early evidence on the real-world impact and effectiveness of
rotavirus vaccination in developing countries from the articles
in this supplement is encouraging, and provides powerful
information to encourage countries to sustain rotavirus vaccine use
and to help inform decision making regarding vaccine use in
countries that have not yet recommended rotavirus vaccination.
However, further monitoring and evidence generation are
required to address several key issues (Table 1). First, given the
observed variability in vaccine effectiveness across countries,
additional evidence should be generated to improve the
generalizability of the findings, particularly from challenging settings in
the most impoverished countries with the weakest healthcare and
immunization programs. Additionally, a better understanding of
the extent of herd protection across a range of geographic settings
will help to quantify the full impact of a rotavirus vaccination
program. Data on the impact and effectiveness of rotavirus
vaccines in developing countries can also help drive the research
agenda to improve the performance of existing vaccines or
develop new vaccines. Second, as the experiences described in
these reports are limited to the first 2–3 years after vaccine
implementation for most countries, continued monitoring is
desirable to assess whether over the long term the observed
disease reductions and vaccine effectiveness are sustained and
to examine if any changes in disease epidemiology occur,
such as shifts in the age distribution of rotavirus cases or the
emergence of unusual rotavirus strains due to possible
vaccine-driven selection pressure. Third, while changes in the
proportion of severe diarrhea attributable to nonrotavirus
pathogens are expected to occur with the decline in incidence of
rotavirus disease following vaccine implementation, monitoring
the incidence of severe diarrheal disease caused by nonrotavirus
pathogens before and after rotavirus vaccine implementation
would help to assess if vaccination leads to changes in the
overall ecology of diarrheal disease. Fourth, to date, no developing
country in Asia has implemented routine rotavirus vaccination
with either RV5 or RV1; thus, generating evidence from Asian
countries as they introduce vaccines is a high priority. Of note,
India recently recommended inclusion of an indigenously
manufactured rotavirus vaccine (Rotavac) in its national
immunization program [
], and Vietnam has also licensed its
own rotavirus vaccine (Rotavin), providing initial opportunities
to examine the effect of rotavirus vaccination in low-income
Asian countries. Fifth, because only 6 of the 36 Gavi-eligible
countries that have implemented rotavirus vaccination to date
have selected RV5, generation of additional postlicensure data
from developing countries for this vaccine in particular should
be prioritized. Finally, postlicensure evaluations in developed
countries have identified a low risk of intussusception with both
RV5 and RV1; however, this risk is exceeded by the marked
health benefits of vaccination seen in these countries and has
not led to any change in vaccination recommendations from
WHO and many national health authorities that have reviewed
the evidence . Although the benefits of vaccination are likely
to be even more substantial in low-income countries given the
greater health burden of rotavirus, efforts should be made to
generate information on any intussusception risk associated
with vaccination in these settings to allow informed risk-benefit
assessments and provide additional confidence in the
Disclaimer. The findings and conclusions in this report are those of the
authors and do not necessarily represent the official position of Centers for
Disease Control and Prevention (CDC). The views expressed by the authors
do not necessarily reflect the views of PATH, the CDC Foundation, the Bill
and Melinda Gates Foundation, or GAVI, the Vaccine Alliance.
Supplement sponsorship. This article appears as part of the supplement
“Health Benefits of Rotavirus Vaccination in Developing Countries,”
sponsored by PATH and the CDC Foundation through grants from the
Bill and Melinda Gates Foundation and GAVI, the Vaccine Alliance.
Potential conflicts of interest. All authors: No reported conflicts. All
authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the content
of the manuscript have been disclosed.
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