Vaccine 30S (2012) A3A6

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Vaccine
journal homepage: www.elsevier.com/locate/vaccine

Rotavirus vaccines in developing countries: The potential impact,

implementation challenges, and remaining questions
Thomas Cherian , Susan Wang, Carsten Mantel
Expanded Programme on Immunization, Department of Immunization, Vaccines and Biologicals, World Health Organization, 1211 Geneva 27, Switzerland

a r t i c l e

i n f o

Article history:
Received 17 August 2011
Received in revised form
27 September 2011
Accepted 3 October 2011

Keywords:
Rotavirus vaccine
Developing countries

a b s t r a c t
Diarrhoeal disease is one of the commonest causes of death in children, especially in developing countries
in Africa and Asia. Rotavirus has been consistently identied as the commonest pathogen associated with
severe diarrhoea. Hence, the availability of vaccines against this organism provides the opportunity to
reduce child mortality. Data from efcacy trials in developing countries in Africa and Asia showed that the
vaccine efcacy was lower than that observed in other countries. Nevertheless, the vaccines are expected
to be of signicant benet in high mortality countries in these regions. While the reports published
in this supplement add to our understanding about the performance of these vaccines in developing
countries in these regions, questions remain over the overall impact of these vaccines when used in
national programmes of developing countries in Africa and Asia, the optimal vaccination schedules and
the impact of age restrictions for vaccine use on immunization coverage. Additional research is required
to improve understanding on the performance of these vaccines in developing countries in Africa and
Asia and measures that may improve performance. Data that will assist in the denition of the optimal
immunization schedule and possibly allow relaxation of the age restrictions for vaccine use may help
in enhancing the impact of the vaccines in these countries. Finally, disease surveillance and studies are
required to document the impact of vaccination and monitor changes in disease epidemiology.
2011 World Health Organization. Published by Elsevier Ltd. All rights reserved.

Diarrhoeal disease remains one of the commonest causes of

death in children worldwide. In 2008, an estimated 1.336 million
children under the age of 5 years died as a consequence of diarrhoea, accounting for 15% of all child deaths, and these occurred
mainly in developing countries in Africa and Asia [1]. Rotavirus
accounts for over a third of severe diarrhoea in children in all
regions of the world. However, due to the higher incidence of severe
diarrhoea and lack of timely access to care, most rotavirus deaths
occur in developing countries [2].
Since most developing countries have been able to deliver
vaccines with high coverage to infants [3], safe and effective vaccines against rotavirus are considered to be important tools for
reducing diarrhoea deaths and, thereby, facilitating the achievement of the Millennium Development Goal 4 (MDG-4) to reduce
child mortality. Therefore, the licensure of two effective vaccines against rotavirus, a single-strain attenuated human rotavirus

The authors are staff members of the World Health Organization. The authors
alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions, policy or views of the World Health Organization.
Corresponding author at: Expanded Programme on Immunization, Department
of Immunization, Vaccines and Biologicals, World Health Organization, 20 Avenue
Appia, 1211 Geneva 27, Switzerland. Tel.: +41 22 791 4460; fax: +41 22 791 4193.
E-mail address: cheriant@who.int (T. Cherian).

vaccine (RotarixTM , GlaxoSmithKline Biologicals) and a pentavalent bovine-human reassortant vaccine (RotaTeq , Merck & Co.,
Inc.) was welcome news. Both vaccines showed high efcacy
against severe rotavirus diarrhoea in industrialized countries, as
well as middle-income countries in Latin America. Following the
introduction of the vaccines, impressive declines in rotavirus
and all-cause diarrhoea hospitalizations were observed in many
countries [4]. In Mexico and Brazil 35% and 22% reductions in
diarrhoea-related mortality, respectively, were observed in children under 5 years, following the introduction of rotavirus vaccine
[5,6].
Despite the high efcacy demonstrated by the vaccines in studies in industrialized countries and in Latin America, the World
Health Organizations (WHO) Strategic Advisory Group of Experts
(SAGE) on immunization, deferred making a recommendation for
global use in 2006, pending the availability of efcacy data from
developing countries in Africa and Asia. This was based on the fact
that the efcacy of other live oral vaccines has varied between
different population groups, with efcacy being lower in developing country populations with the highest burden of disease
[7].
The rst results of the efcacy of rotavirus vaccines in developing countries in Africa and Asia were published in 2010
[810]. While these studies showed that the efcacy of both
RotarixTM and RotaTeq were lower in the populations in these

0264-410X/$ see front matter 2011 World Health Organization. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.vaccine.2011.10.007

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T. Cherian et al. / Vaccine 30S (2012) A3A6

regions, because of the higher incidence of severe disease, the

observed incidence rate reductions of severe rotavirus diarrhoea was higher than that observed in the developed countries.
The preliminary results of these trials were presented to WHO
SAGE and formed the basis of the revised WHO recommendations [11]. While the SAGE noted the inverse relationship
between child mortality rates and rotavirus vaccine efcacy, the
recommendation for the use of the vaccines was extended to
include all countries, especially those where diarrhoea disease
accounts for 10% of child deaths [11]. This recommendation
was made on the basis that despite the lower efcacy, the vaccines would still prevent a large amount of severe disease and
deaths in the high mortality developing countries in Africa and
Asia.
Several papers in this supplement provide additional information that improves our understanding of the efcacy and
safety of rotavirus vaccines in populations with high child mortality. The pooled analysis of data from the Asian and African
trials with RotaTeq provided greater precision around the
efcacy estimates against very severe rotavirus gastroenteritis
(Vesikari scale 14), which were higher than the efcacy estimates against severe rotavirus gastroenteritis (Vesikari scale 11),
and against non-vaccine type rotavirus diarrhoea (Breiman et al.).
The report of the efcacy of RotaTeq in Kenya published in
this supplement also showed that while the vaccine was not
efcacious in preventing severe gastroenteritis from any cause
in children attending a health care facility, it showed statistically signicant efcacy against severe gastroenteritis of any
cause in children visited at home (Feikin et al.). These analyses and other data published in this supplement (Madhi et al.)
that showed that the efcacy of RotarixTM in the rst year
of life was higher than in the full follow up period, suggesting the possibility of a waning immunity in the second year of
life.
Despite the increasing amount of data on rotavirus diarrhoea
and vaccines, there are a number of issues that remain to be fully
addressed.

1. The impact of rotavirus vaccines in high child mortality

populations
It is assumed that despite the lower observed efcacy of the
current vaccines, they are likely to prevent more cases of severe
disease and deaths in populations with high child mortality rates.
However, the magnitude of the impact of these vaccines in these
populations still needs to be fully documented. The trend towards
greater efcacy against the more severe forms of rotavirus disease
observed in several studies, including those published in this supplement (Breiman et al. and Tapia et al.), suggests that the mortality
reductions due to vaccination may be higher than what may be
estimated using the estimates of efcacy against severe diarrhoea,
which was the primary end point of most clinical trials.
The observed reductions in diarrhoea hospitalizations and
deaths in countries that have introduced rotavirus vaccines were
greater than expected, with reductions in rotavirus diarrhoea also
observed in children too young or too old to be vaccinated [4],
suggesting that infants with rst infection with rotavirus are the
primary transmitters of disease. It has also been suggested that
this indirect effect may be more evident in populations where the
vaccine efcacy and vaccination coverage levels are lower [4]. However, it still needs to be seen whether the vaccines will have a
similar effect on transmission in populations where the immunogenicity and efcacy against rotavirus infection is lower and the
transmission pressure probably greater.

Irrespective of the indirect effect that may occur in high child

mortality populations in developing countries, studies to improve
the understanding of mechanisms that lead to the lower immunogenicity and possible interventions that may enhance the immune
responses to these vaccines are required [12]. Studies that use probiotics or zinc supplementation to improve vaccine performance
are planned or under way (Duncan Steele, personal communication). However, to be successful, the delivery of such adjuncts
would need to be programmatically feasible in resource constrained situations.

2. The optimal vaccination schedule in developing

countries
To be optimally effective and cost-effective, a vaccination schedule should aim to induce immunity with the fewest number of
doses before a sizeable proportion of the target population acquires
natural infection. In developing countries where natural infection
occurs early, completion of the immunization schedule early in
infancy is desirable though programmatically challenging. From a
programmatic perspective, it is easier if the vaccine doses are delivered at the same contact as with other vaccines. Hence, clinical
trials of the two vaccines evaluated efcacy of the vaccine delivered along with other vaccines in the national programme at 6, 10
and 14 weeks. For RotarixTM , two schedules were used. In one arm,
two doses of the vaccines were delivered at 10 and 14 weeks of
age, and in another, three doses at 6, 10 and 14 weeks of age [8].
The choice of age for the two dose schedule in the trial was based
on the fact that the sero response rates to vaccination at 10 and
14 weeks were higher than when the vaccine was administered at
6 and 10 weeks [13].
In framing the recommendations for the use of RotarixTM , SAGE
noted that in the efcacy trials, the vaccine was administered at
either 10 and 14 weeks or at 6, 10 and 14 weeks. However, taking note of the fact that in many developing countries, there are
delays in the administration of the scheduled doses of vaccine at 6,
10 and 14 weeks and the need to deliver the rst dose of vaccine
before 15 weeks, it was recommended that the vaccine be administered with the rst and second doses of DTP containing vaccines
despite the lower sero conversion rate observed by Steele et al.
when the rst dose was administered at 6 weeks. It was also recommended that this schedule be reviewed in the light of new data that
may become available [11]. While available data from developing
countries in Asia and Africa suggest that efcacy of both available
vaccines is lower in the second year of life, data presented by Madhi
et al. and Cunliffe et al., in this supplement now show a lower efcacy of RotarixTM in the second year of life when given in a 10,
14 weeks schedule, as compared to a 6, 10, 14 weeks schedule. A
recent report from a cohort study in India showed that reinfection
with rotavirus is more common than previously believed and that
the rate of protection against subsequent episodes of rotavirus diarrhoea of any severity is lower than has been previously reported
[14]. The authors suggest that these data indicate the need for
increasing the dose or number of doses of vaccine to induce optimal
protection in this setting.
These and other data on efcacy and effectiveness of the vaccine administered in different schedules and ages, new data on
the actual age when vaccines scheduled for delivery at 6, 10 and
14 weeks are delivered, as well as the age of the rst episode and
subsequent episodes of severe rotavirus diarrhoea, would be crucial in dening the optimal age and schedule for immunization in
developing countries in Africa and Asia.
Finally, the decreased efcacy of the two vaccines in the second
year of life, observed in the trials in Africa and Asia, raise a question about the need for a booster dose of the vaccine. However,

T. Cherian et al. / Vaccine 30S (2012) A3A6

the current recommendations restricting the use of the vaccines in

children above 32 weeks would need to be addressed in planning
any such studies to evaluate the benets and risks of a booster dose.

3. Intussusception, age restrictions for vaccination and

related programmatic challenges
In view of the increased risk of intussusception observed with
the older rhesus reassortant rotavirus vaccine (Rotashield ), the
trials with the newer rotavirus vaccines restricted its use to younger
infants in whom the natural risk of intussusception is lower. Since
intussusception was more often associated with the rst dose,
delivery of the rst dose was restricted to children 612 weeks
(RotaTeq ) or 613 weeks (RotarixTM ) [15,16] of age and the
labelled indications restrict the use of the vaccines to children less
than 24 or 32 weeks of age. Consequently, the WHO recommendations were to deliver the rst dose of either vaccine by 15 weeks
of age and the last dose by 32 weeks of age [11]. The age restrictions for the delivery of vaccine are a programmatic challenge in
developing countries in Africa and Asia.
In many developing countries the availability of immunization
cards is low, vaccination registers are often incomplete and mothers often do not remember the exact date of birth of their infants.
This makes it difcult for health workers to decide whether or not
a child is eligible for rotavirus vaccination. Furthermore, in these
countries, a number of programmatic issues may make it difcult
to deliver vaccines in a timely fashion. These include geographical or social factors that make access to xed facilities difcult, the
periodicity of the outreach sessions where this delivery modality is
used, and inability to conduct immunization sessions regularly due
to resource constraints. A review of data from surveys has indeed
shown that in many developing countries, there may be signicant
delays in administering the scheduled vaccinations [17]. Unless
greater efforts are made to train health care workers, improve
record keeping and strengthen immunization systems to facilitate
timely vaccine delivery, the coverage with these vaccines is likely
to be even lower than other EPI vaccines. Together with the lower
efcacy of the vaccine in developing countries, a low coverage could
result in failure to realize the full benet of these vaccines in the
populations that have the highest morbidity and mortality from
rotavirus diarrhoea.
Till recently the risk of intussusception with the newer rotavirus
vaccines was more theoretical and in 2009 the WHO Global
Advisory Committee on Vaccine Safety suggested that the age
restrictions for use of the vaccines may be relaxed to improve
coverage. However, the committee also encouraged national programmes that opted to provide the rst dose >15 weeks and the
last dose >32 weeks of age to monitor the safety and efcacy of the
vaccine. In many developing countries, delivering vaccine doses
beyond recommended ages would probably not be a deliberate
choice but a consequence of systemic weakness. Such countries
will also nd it difcult to establish systems to monitor safety and
respond adequately to adverse events.
Recently, signals showing an increased risk of intussusception
with the newer rotavirus vaccines were reported from Australia and
Latin America [18,19]. While the observed rates of intussusception
were far lower than what was observed with Rotashield , and the
benets from vaccination far outweighed the risks, the risk of intussusception from the newer vaccines was no longer a theoretical one.
In Australia, when exposure windows associated with all doses of
rotavirus vaccine from 1 to 9 months of age were combined, there
was no evidence of an increased risk of intussusception following
vaccination for either vaccine. However, in infants 1 to <3 months of
age, there was suggestive evidence of excess intussusception cases
17 and 121 days following the rst dose of both vaccines [18]. In

A5

Mexico, an increased risk of intussusception was observed after the

rst dose of RotarixTM , but no such increase was observed in Brazil,
though an increased risk following the second dose of vaccine was
observed, albeit lower than in Mexico [19]. The authors of the Latin
American study noted that in Brazil, unlike in Mexico, rotavirus vaccine was co-administered with oral polio vaccine (OPV) and since
co-administration of the rst dose of rotavirus vaccine with OPV
has been shown to reduce the immunogenicity of the former, speculated whether this might be a possible explanation of the observed
difference in intussusception risk in the two countries. This raises
the possibility that in developing countries where the vaccine will
generally be co-administered with OPV and where the immunogenicity of the vaccine is lower, the risk of intussusception would
be even lower than that observed in Latin America. If this is conrmed through careful post-marketing surveillance in select early
introducer countries, global advisory committees might be more
inclined to relax the age restrictions for vaccine use, thus making it
easier to deliver vaccine and achieve high coverage in developing
countries in Africa and Asia.

4. Monitoring changes in rotavirus strains and interpreting

the results
Data from developing countries in Asia and Africa show greater
strain diversity than has been described in industrialized countries
[20]. A review paper in this supplement (Miles et al.) describes the
strain diversity of rotavirus in Bangladesh, India and Pakistan and
also refers to the reports of the emergence of reassortant zoonotic
strains in the region. The implications of strain diversity on vaccine
efcacy are not fully understood, since available data show that
the current vaccines induce cross-protections against the prevalent
strains encountered in the clinical trials. However, there is a need
to have surveillance in place to monitor for strain changes following vaccination in African and Asian countries, to detect any newly
emergent strains, and importantly, be able to interpret the data and
attribute it to vaccine use, since natural changes in prevalence of
rotavirus strains are common [21].

5. Conclusions
Rotavirus diarrhoea is an important cause of childhood morbidity and mortality world wide and particularly so in developing
countries with high child mortality. Data on rotavirus diarrhoea
and the efcacy of vaccination in developing countries is rapidly
increasing, and there is increasing evidence to suggest that the
vaccines will have a signicant effect on childhood morbidity and
mortality, despite the lower efcacy of the vaccines, in developing
country populations in Asia and Africa. However, further data are
required to fully understand and document the impact of rotavirus
vaccines in these populations. There are programmatic challenges
related to the age restrictions for delivering vaccines that might
affect the overall impact of vaccines in populations where timely
delivery of the vaccine is difcult. Data that would allow relaxation
of the age restrictions and adjuncts that might improve vaccine
performance would certainly contribute to improving the impact
of these vaccines. On the other hand, the challenges raised by
rotavirus vaccine might represent an opportunity to innovate and
improve immunization systems to improve timely delivery of vaccines, that would not only improve the impact of rotavirus vaccines,
but all childhood vaccines, in general. Continued surveillance is
required to monitor for strain changes that may alter vaccine effectiveness or that may be a result of vaccination. However, data on
strain changes need to be very carefully evaluated before attributing them to vaccination.

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T. Cherian et al. / Vaccine 30S (2012) A3A6

Conict of interest statement: The authors declare no conicts of

interest.

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