Malawi Medical Journal 28 (3): September 2016
College of Medicine Silver Jubilee Special Issue Effect of human rotavirus vaccine on severe diarrhea in African infants 108
N Engl J Med. 2010 Jan 28;362(4):289-98
Research Article (New England Journal of Medicine)
Eect of human rotavirus vaccine on severe diarrhea
in African infants
Shabir A. Madhi
1
, Nigel A. Cunlie
2
, Duncan Steele
3
, Desirée Witte
2,4
, Mari Kirsten
5
,
Cheryl Louw
6,7
, Bagrey Ngwira
4
, John C. Victor
8
, Paul H. Gillard
9
, Brigitte B. Cheuvart
9
, Htay H. Han
9
,
Kathleen M. Neuzil
8
1. Vaccine Preventable Diseases, University of the Witwatersrand, Johannesburg, South Africa
2. Division of Medical Microbiology, University of Liverpool, Liverpool, United Kingdom
3. Initiative for Vaccine Research, World Health Organization, Geneva
4. College of Medicine, University of Malawi, Blantyre, Malawi
5. Department of Paediatric Surgery, University of Pretoria, Pretoria, South Africa
6. Madibeng Center for Research, Brits, South Africa
7. Medical Research Council Diarrhoeal Pathogens Research Unit, University of Limpopo, Limpopo, South Africa
8. Rotavirus Vaccine Program, PATH, Seattle, Washington, U.S.A.
9. GlaxoSmithKline Biologicals, Rixensart, Belgium
Correspondence to: Nigel A. Cunliffe (n.a.cunliffe@liv.ac.uk)
Abstract
Backgr ound
Rotavirus is the most common cause of severe gastroenteritis among young children worldwide. Data are needed to assess the efcacy
of the rotavirus vaccine in African children.
Methods
We conducted a randomized, placebo-controlled, multicenter trial in South Africa (3166 infants; 64.1% of the total) and Malawi (1773
infants; 35.9% of the total) to evaluate the efcacy of a live, oral rotavirus vaccine in preventing severe rotavirus gastroenteritis. Healthy
infants were randomly assigned in a 1:1:1 ratio to receive two doses of vaccine (in addition to one dose of placebo) or three doses of
vaccine — the pooled vaccine group — or three doses of placebo at 6, 10, and 14 weeks of age. Episodes of gastroenteritis caused by
wild-type rotavirus during the rst year of life were assessed through active follow-up surveillance and were graded with the use of the
Vesikari scale.
Results
A total of 4939 infants were enrolled and randomly assigned to one of the three groups; 1647 infants received two doses of the vaccine,
1651 infants received three doses of the vaccine, and 1641 received placebo. Of the 4417 infants included in the per-protocol efcacy
analysis, severe rotavirus gastroenteritis occurred in 4.9% of the infants in the placebo group and in 1.9% of those in the pooled vaccine
group (vaccine efcacy, 61.2%; 95% condence interval, 44.0 to 73.2). Vaccine efcacy was lower in Malawi than in South Africa (49.4%
vs. 76.9%); however, the number of episodes of severe rotavirus gastroenteritis that were prevented was greater in Malawi than in South
Africa (6.7 vs. 4.2 cases prevented per 100 infants vaccinated per year). Efcacy against all-cause severe gastroenteritis was 30.2%. At least
one serious adverse event was reported in 9.7% of the infants in the pooled vaccine group and in 11.5% of the infants in the placebo
group.
Conclusions
Human rotavirus vaccine signicantly reduced the incidence of severe rotavirus gastroenteritis among African infants during the rst
year of life. (ClinicalTrials.gov number, NCT00241644.)
Introduction
Rotavirus is the most important cause of severe gastroenteritis
among children worldwide. The World Health Organization
(WHO) estimates that globally 527,000 deaths occur each year
among children as a result of rotavirus infection
1;
more than
230,000 of the deaths occur in sub-Saharan Africa. Six of the
seven countries with the highest mortality due to rotavirus
diarrhea are located in Africa.
2
Similarly, data generated from
global rotavirus surveillance networks highlight the burden
of hospitalizations for rotavirus
3
; among young children
hospitalized for acute diarrhea, the median detection rate for
rotavirus was 40% globally and 41% in Africa. Therefore,
measures to prevent rotavirus diarrhea in African children
are urgently needed.
Vaccines represent the best hope for preventing the
severe consequences of rotavirus infection, especially in
impoverished regions where resources and access to care
may be limited. Two oral, live attenuated rotavirus vaccines,
Rotarix (GlaxoSmithKline Biologicals) and RotaTeq
(Merck), have shown excellent protective efcacy against
severe rotavirus gastroenteritis in trials conducted mainly
in Latin America, Europe, and the United States.
4-6
The
WHO’s Strategic Advisory Group of Experts (SAGE)
rst reviewed data on these vaccines in 2005 and strongly
recommended the inclusion of rotavirus vaccination in the
national immunization programs of countries and regions
in which, according to available data, severe rotavirus
gastroenteritis has a substantial public health impact.
7
But
SAGE noted that live oral vaccines may not be as effective
in protecting the poorest children in developing countries
as they are in protecting children in industrialized countries
and therefore recommended that efcacy trials be conducted
in representative populations in Africa and Asia before the
recommendation is extended.
1,7
In response to this mandate,
we conducted a clinical trial to determine whether Rotarix,
This article originally appeared in the New England Journal of Medicine
Citation: Madhi SA, Cunliffe NA, Steele D, Witte D, Kirsten M, Louw C,
Ngwira B, Victor JC, Gillard PH, Cheuvart BB, Han HH, Neuzil KM. Effect of
human rotavirus vaccine on severe diarrhea in African infants. N Engl J Med.
2010 Jan 28;362(4):289-98.
doi: 10.1056/NEJMoa0904797
(Published 28 January 2010)
© 2010 Massachusetts Medical Society
Republished with permission from the Massachusetts Medical Society
http://dx.doi.org/10.1056/NEJMoa0904797
Malawi Medical Journal 28 (3): September 2016
College of Medicine Silver Jubilee Special Issue
N Engl J Med. 2010 Jan 28;362(4):289-98
Effect of human rotavirus vaccine on severe diarrhea in African infants 109
an attenuated human rotavirus vaccine containing a G1P[8]
strain, could protect African children against severe rotavirus
gastroenteritis.
Methods
Study design and participants
We conducted a double-blind, randomized, placebo-
controlled multicenter study in South Africa and Malawi to
assess the efcacy, safety, and immunogenicity of Rotarix.
A placebo-controlled design was chosen because the
vaccine was not licensed or available in these countries at
the time the study was initiated, and data were needed to
inform policy decisions in low-resource countries. Children
who were infected with human immunodeciency virus
(HIV) and children who had been exposed to HIV were
included in the trial on the basis of the absence of serious
immunosuppression in infants at the age at which these
vaccines are rst given (6 weeks), the experience with other
live vaccines in HIV-infected children, and the need to inform
decisions on the introduction of vaccine in settings with high
prevalences of HIV. The study protocol and the informed
consent form were approved by the ethics committee at
the WHO and by the ethics committees at all study centers.
The trial was conducted in accordance with Good Clinical
Practice guidelines. The parents or legal representatives
of the infants participating in the study provided written
informed consent before the initiation of any study-related
procedures. All the investigators shared responsibility for
the design of the study and the accrual and analysis of the
data. All the authors participated in the preparation of the
manuscript and made the decision to submit the manuscript
for publication.
In South Africa, healthy infants, 5 to 10 weeks of age, were
enrolled from October 2005 through January 2006 and from
November 2006 through early February 2007, before the
anticipated rotavirus seasons of 2006 and 2007, respectively.
8,9
Since rotavirus is known to circulate year-round in Malawi,
10
infants in Malawi were enrolled from October 2006 through
July 2007.
Infants were randomly assigned individually, in a 1:1:1 ratio,
into three groups to receive two doses of the rotavirus vaccine
at 10 and 14 weeks of age; three doses of the vaccine at 6,
10, and 14 weeks of age; or three doses of placebo. Infants
in the two-dose vaccine group received a dose of placebo
at 6 weeks of age. Vaccines that are administered routinely
according to the guidelines of the Expanded Program on
Immunization (EPI) were concomitantly administered with
the vaccine or placebo. No restrictions were imposed on the
breast-feeding of infants around the time of vaccination.
Testing for HIV
The parents or legal representatives of the infants were given
the opportunity to have the infants tested for HIV at the
time the rst dose of vaccine or placebo was administered
or 1 month after the last dose, and testing was performed
when consent was given. Detailed information regarding
the testing and treatment of infants is included in the
Supplementary Appendix, available with the full text of this
article at NEJM.org.
Vaccine
The study vaccine, the calcium carbonate buffer, and
the placebo were developed and manufactured by
GlaxoSmithKline Biologicals. The composition of the
vaccine was the same as the commercial formulation, and the
placebo was the same formulation without the viral antigen.
11
Analysis of stool samples during episodes of
gastroenteritis
An episode of gastroenteritis was identied by the occurrence
of diarrhea, whether or not it was accompanied by vomiting;
diarrhea was dened as the passage of three or more stools
that were looser than normal within a 24-hour period. Stool
samples were collected during each episode of gastroenteritis
that occurred between the date the rst dose of vaccine or
placebo was administered and the date the child reached 1
year of age. Stool samples were tested for rotavirus with
the use of an enzyme-linked immunosorbent assay (ELISA)
(Rotaclone, Meridian Bioscience). All stool samples that were
positive for rotavirus were examined further with the use of
a reverse-transcriptase–polymerase-chain-reaction (PCR)
assay, followed by a reverse hybridization assay to determine
the G and P types.
12
Assessment of vaccine ecacy
The efcacy of the vaccine was assessed during the period
from 2 weeks after the last dose of vaccine or placebo was
administered until the child reached 1 year of age. Active
surveillance for all gastroenteritis episodes was conducted by
members of the study staff through weekly visits to parents
or guardians to collect diary cards and through the collection
of data from health clinics that served the study populations.
The severity of each episode of gastroenteritis was evaluated
with the use of the Vesikari scale
13
(on which scores range
from 1 to 20, with higher scores indicating greater severity)
and was categorized as severe if the score was 11 or more.
Assessment of safety
All serious adverse events including deaths were recorded
for the period between the date the rst dose of vaccine
or placebo was administered and the date the child reached
1 year of age. The site investigator, who was unaware of
the group assignments of the children, determined whether
the serious adverse events appeared to have any causal
association with vaccination.
Assessment of immunogenicity
Blood samples were collected from approximately 10% of
the infants immediately before the rst dose of vaccine
or placebo was administered and from all infants 1 month
after the last dose to determine the serum concentrations of
antirotavirus IgA antibody. The blood samples were analyzed
with the use of an ELISA (GlaxoSmithKline Biologicals),
with the assay cutoff point set at 20 U per milliliter.
14
Statistical analysis
The primary study analysis compared ndings from the
pooled vaccine group with those from the placebo group.
The secondary end points were the efcacy of each vaccine
dose (i.e., the two-dose vaccine and the three-dose vaccine)
as compared with placebo. A supplementary analysis was
performed to evaluate the efcacy, immunogenicity, and
safety of the vaccine according to country.
Infants who had received the complete vaccination course
and had entered the efcacy surveillance period, which began
2 weeks after the last dose, were included in the prespecied
primary efcacy analysis (per-protocol efcacy cohort).
Infants in the pooled vaccine and placebo groups who
had at least one episode of severe rotavirus gastroenteritis
caused by wild-type rotavirus strains during the period from
2 weeks after the last dose was administered until the infants
reached 1 year of age were considered as having achieved the
Malawi Medical Journal 28 (3): September 2016
College of Medicine Silver Jubilee Special Issue
N Engl J Med. 2010 Jan 28;362(4):289-98http://dx.doi.org/10.1056/NEJMoa0904797
Effect of human rotavirus vaccine on severe diarrhea in African infants 110
Ecacy
Severe gastroenteritis caused by circulating rotavirus was
detected in 70 of 1443 infants in the placebo group (4.9%)
as compared with 56 of 2974 infants in the pooled vaccine
group (1.9%), resulting in a vaccine efcacy against the
primary outcome of severe rotavirus gastroenteritis of
61.2% (95% condence interval [CI], 44.0 to 73.2; P<0.001)
(Table 1). Vaccination with the rotavirus vaccine prevented
5.0 episodes of severe rotavirus gastroenteritis per 100
infant-years (Table 2). The vaccine showed efcacy against
severe rotavirus gastroenteritis both in infants who received
two doses of vaccine (58.7% efcacy; 95% CI, 35.7 to 74.0)
and in those who received three doses (63.7% efcacy;
95% CI, 42.4 to 77.8). In South Africa, the efcacy of the
vaccine was 76.9% (95% CI, 56.0 to 88.4), and in Malawi
the vaccine efcacy was 49.4% (95% CI, 19.2 to 68.3); 4.2
and 6.7 episodes of severe rotavirus gastroenteritis per 100
infant-years were prevented by vaccination in South Africa
and Malawi, respectively (Table 1 and Table 2). The efcacy
of the rotavirus vaccine against rotavirus gastroenteritis of
any severity is presented in Table 2 in the Supplementary
Appendix.
The distribution of rotavirus G and P types differed between
South Africa and Malawi (Figure 1 in the Supplementary
Appendix). The G1P[8] strain was detected in 57.0% of the
primary outcome. The efcacy analysis was also performed
on data from the total cohort, which included infants who
received at least one dose of vaccine or placebo. The safety
analysis was performed on data from the total cohort. The
immunogenicity analysis was performed on data from infants
in the per-protocol efcacy cohort for whom immunogenicity
data were available. The method used to calculate the sample
size and specic information about the statistical analysis are
shown in the Supplementary Appendix.
Results
Study population
A total of 4939 infants were enrolled and randomly assigned
to one of three groups (Figure 1); 1647 infants were assigned
to the two-dose group, 1651 to the three-dose group (for
a total of 3298 in pooled vaccine group), and 1641 to the
placebo group. A total of 4417 infants were included in the
primary efcacy analysis — 2974 in the pooled vaccine group
and 1443 in the placebo group. The reasons for withdrawal
from the study are listed in Figure 1. The demographic
characteristics of the infants and the proportion of children
who were infected with HIV were similar across the study
groups. Almost all infants (≥99%) received oral poliovirus
vaccine concomitantly with each dose of rotavirus vaccine
or placebo (Table 1 in the Supplementary Appendix).
The
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of
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n engl j med 362;4 nejm.org january 28, 2010
292
the sample size and specific information about
the statistical analysis are shown in the Supple-
mentary Appendix.
Results
Study Population
A total of 4939 infants were enrolled and ran-
domly assigned to one of three groups (Fig. 1);
1647 infants were assigned to the two-dose
group, 1651 to the three-dose group (for a total
of 3298 in pooled vaccine group), and 1641 to
the placebo group. A total of 4417 infants were
included in the primary efficacy analysis — 2974
in the pooled vaccine group and 1443 in t he pla-
cebo group. The reasons for withdrawal from
the study are listed in Figure 1. The demograph-
ic characteristics of the infants and the propor-
tion of children who were infected wit h HIV were
similar across the study groups. Almost all in-
fants (≥99%) received oral poliovirus vaccine
concomitantly with each dose of rotavirus vac-
cine or placebo (
Table 1
in the Supplementary
Appendix).
7 col
39p6
4939 (99.9%) Underwent randomization
and were included in the safety analysis
4941 Infants were assessed for eligibility
2 Withdrew consent
3298 Were assigned to receive
rotavirus vaccine
1641 Were assigned to receive
placebo
495 Were withdrawn
90 Had a serious adverse event
1 Had a nonserious adverse event
8 Had a protocol violation
133 Withdrew consent (not owing to
adverse event)
115 Relocated
143 Were lost to follow-up
62 Had incomplete vaccination course
81 Had complete vaccination course
5 Had other reasons
249 Were withdrawn
44 Had a serious adverse event
1 Had a nonserious adverse event
4 Had a protocol violation
79 Withdrew consent (not owing to
adverse event)
53 Relocated
63 Were lost to follow-up
29 Had incomplete vaccination course
34 Had complete vaccination course
5 Had other reasons
324 Were excluded from the efficacy analysis
264 Were not administered at least one
dose
23 Contracted concomitant infection by
rotavirus strain other than the vaccine
strain up to 2 wk after dose 3 (which
may influence efficacy response)
21 Were not administered study vaccine
dose as per protocol
11 Were not entered into the follow-up
surveillance period
5 Had broken randomization code
198 Were excluded from the efficacy analysis
140 Were not administered at least one
dose
39 Contracted concomitant infection by
rotavirus strain other than the vaccine
strain up to 2 wk after dose 3 (which
may influence efficacy response)
8 Were not administered study vaccine
dose as per protocol
10 Were not entered into the follow-up
surveillance period
1 Had broken randomization code
2974 (90.1%) Were included in the
efficacy analysis
1443 (87.9%) Were included in the
efficacy analysis
AUTHOR:
FIGURE:
RETAKE:
SIZE
4-C H/TLine Combo
Revised
AUTHOR, PLEASE NOTE:
Figure has been redrawn and type has been reset.
Please check carefully.
1st
2nd
3rd
Madhi
1 of 1
ARTIST:
TYPE:
MRL
1-28-10JOB: 361xx ISSUE:
Figure 1. Study Assignment and Follow-up.
The New England Journal of Medicine
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http://dx.doi.org/10.1056/NEJMoa0904797
Malawi Medical Journal 28 (3): September 2016
College of Medicine Silver Jubilee Special Issue
N Engl J Med. 2010 Jan 28;362(4):289-98
Effect of human rotavirus vaccine on severe diarrhea in African infants 111
episodes among recipients of the placebo in South Africa
and in 12.9% of the episodes among recipients of the
placebo in Malawi. The type-specic efcacy against severe
rotavirus gastroenteritis and the difference in incidence
rates between the vaccine groups and the placebo group are
shown in Table 1 and Table 2, respectively.
The incidence rate of severe gastroenteritis from any cause
was 8.6% in the pooled vaccine group as compared with
12.3% in the placebo group, corresponding to a reduction
in the rate with vaccination of 30.2% (95% CI, 15.0 to 42.6;
P<0.001) (Table 3). The reductions in all-cause severe
gastroenteritis were statistically signicant in both countries.
The efcacy of the vaccine in the total vaccinated cohort
was similar to that in the per-protocol efcacy cohort (Tables
3 to 6 in the Supplementary Appendix).
Safety
At least one serious adverse event occurred during the study
period in 319 of the 3298 infants in the pooled vaccine group
(9.7%; 95% CI, 8.7 to 10.7) and in 189 of the 1641 infants
in the placebo group (11.5%; 95% CI, 10.0 to 13.2) (Table
7 in the Supplementary Appendix). During the entire study
period, 83 deaths occurred among infants in the pooled
vaccine group (2.5%; 95% CI, 2.0 to 3.1) and 43 deaths
occurred among those in the placebo group (2.6%; 95%
CI, 1.9 to 3.5). A single case of intussusception occurred 11
weeks after the third dose of rotavirus vaccine in a 6-month-
old child who was assigned to the three-dose vaccine group.
The child underwent bowel resection and recovered fully.
Three adverse events were judged by the investigators to
be related to vaccination — two cases of sepsis and one of
otitis media.
Immunogenicity
At 1 month after the last dose of vaccine was administered,
the seroconversion rates for antirotavirus IgA in South
Africa were 57.1% (95% CI, 44.7 to 68.9) in the two-dose
group and 66.7% (95% CI, 54.0 to 77.8) in the three-dose
group. The seroconversion rates in Malawi were 47.2% (95%
CI, 30.4 to 64.5) in the two-dose group and 57.1% (95% CI,
42.2 to 71.2) in the three-dose group. In the placebo group,
the seropositivity rates for antirotavirus IgA at 1 month after
the last dose were 16.7% (95% CI, 14.2 to 19.5) in South
Africa and 40.4% (95% CI, 34.9 to 46.1) in Malawi.
Discussion
This study shows that a live, oral rotavirus vaccine
signicantly reduces the episodes of severe rotavirus
gastroenteritis in African children during the rst year of life.
The attack rate for severe rotavirus gastroenteritis was higher
in these populations than has been reported in other studies
Effect of Human Rotavirus Vaccine on Severe Diarrhea in African Infants
n engl j med 362;4 nejm.org january 28, 2010
293
Effic acy
Severe gastroenteritis caused by circulating rota-
virus was detected in 70 of 1443 infants in the
placebo group (4.9%) as compared with 56 of
2974 infants in the pooled vaccine group (1.9%),
resulting in a vaccine efficacy against the primary
outcome of severe rotavirus gastroenteritis of
61.2% (95% confidence interval [CI], 44.0 to 73.2;
P<0.001) (
Table 1
). Vaccinat ion with t he rot avirus
vaccine prevented 5.0 episodes of severe rotavirus
gastroenteritis per 100 infant-years (
Table 2
). The
vaccine showed efficacy against severe rotavirus
gastroenteritis both in infants who received two
doses of vaccine (58.7% efficacy; 95% CI, 35.7 to
74.0) and in those who received t hree doses (63.7%
efficacy; 95% CI, 42.4 to 77.8). In South Africa,
the efficacy of the vaccine was 76.9% (95% CI,
56.0 to 88.4), and in Malawi the vaccine efficacy
was 49.4% (95% CI, 19.2 to 68.3); 4.2 and 6.7 epi-
sodes of severe rotavirus gastroenteritis per 100
i n f a nt-ye a r s were pre vent e d by vacc i n at io n i n Sout h
Africa and Malawi, respectively (
Tables 1 and 2
).
The efficacy of the rotavirus vaccine against ro-
tavirus gastroenteritis of any severity is presented
in
Table 2
in the Supplementary Appendix.
The distribution of rotavirus G and P types
Table 1. Efficacy of Rotavirus Vaccine with Respect to the Development of Severe Rotavirus Gastroenteritis and Hospitalization for Rotavirus
Gastroenteritis.*
Variable Infants with at Least One Event Vaccine Efficacy P Value†
Rotavirus Vaccine Placebo
no./total no. % (95% CI) no./total no. % (95% CI) % (95% CI)
Severe rotavirus gastroenteritis
Overall
Pooled 56/2974 1.9 (1.4–2.4) 70/1443 4.9 (3.8–6.1) 61.2 (44.0–73.2) <0.001
Two-dose 30/1496 2.0 (1.4–2.9) — — 58.7 (35.7–74.0) <0.001
Three-dose 26/1478 1.8 (1.2–2.6) — — 63.7 (42.4–77.8) <0.001
Malawi
Pooled 41/1030 4.0 (2.9–5.4) 38/483 7.9 (5.6–10.6) 49.4 (19.2–68.3) 0.003
Two-dose 21/525 4.0 (2.5–6.0) — — 49.2 (11.1–71.7) 0.01
Three-dose 20/505 4.0 (2.4–6.1) — — 49.7 (11.3–72.2) 0.01
South Africa
Pooled 15/1944 0.8 (0.4–1.3) 32/960 3.3 (2.3–4.7) 76.9 (56.0–88.4) <0.001
Two-dose 9/971 0.9 (0.4–1.8) — — 72.2 (40.4–88.3) <0.001
Three-dose 6/973 0.6 (0.2–1.3) — — 81.5 (55.1–93.7) <0.001
Rotavirus-type–specific severe rota -
virus gastroenteritis‡
Overall
G1 strain 17/2974 0.6 (0.3–0.9) 23/1443 1.6 (1.0–2.4) 64.1 (29.9–82.0) 0.002
Non-G1 strain 39/2974 1.3 (0.9–1.8) 47/1443 3.3 (2.4–4.3) 59.7 (37.1–74.4) <0.001
Malawi
G1 strain 6/1030 0.6 (0.2–1.3) 5/483 1.0 (0.3–2.4) 43.7 (<0–85.7) 0.34
Non-G1 strain 35/1030 3.4 (2.4–4.7) 33/483 6.8 (4.7–9.5) 50.3 (17.4–70.0) 0.005
South Africa
G1 strain 11/1944 0.6 (0.3–1.0) 18/960 1.9 (1.1–2.9) 69.8 (32.5–87.1) 0.002
Non-G1 strain 4/1944 0.2 (0.1–0.5) 14/960 1.5 (0.8–2.4) 85.9 (55.1–96.6) <0.001
Hospitalization for rotavirus
gastroenteritis‡
14/2974 0.5 (0.3–0.8) 16/1443 1.1 (0.6–1.8) 57.5 (7.2–80.8) 0.02
* A total of 4417 infants were included in the efficacy analysis — 2974 in the pooled vaccine group and 1443 in the placebo group.
† P values were calculated with the use of a two-sided Fisher’s exact test. P values of less than 0.05 were considered to indicate a statistically
significant difference.
‡ Data in the rotavirus vaccine group are for the pooled vaccine cohort.
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Malawi Medical Journal 28 (3): September 2016
College of Medicine Silver Jubilee Special Issue
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Effect of human rotavirus vaccine on severe diarrhea in African infants 112
of rotavirus vaccines.
4,5
Because of this high incidence of
severe disease, a vaccine efcacy of 61.2% resulted in a
substantial vaccine-attributable reduction in severe rotavirus
gastroenteritis (reduction of 5.0 cases per 100 infant-years).
In addition, the rotavirus vaccine was associated with a
reduction in all-cause severe gastroenteritis of 30.2%.
This reduction in the incidence of the disease occurred in
a trial that was designed to simulate real-world conditions
of use; thus, the rotavirus vaccine is expected to deliver a
considerable public health benet when it is introduced into
similar settings.
The overall efcacy of the rotavirus vaccine in preventing
episodes of severe rotavirus gastroenteritis (61.2%) was
lower than that observed in European studies and Latin
American studies (96.4% and 84.8%, respectively), which
included some low- to middle-income countries.
4-6,15
This
nding is consistent with ndings from other studies of
live oral vaccines, such as the oral poliovirus vaccine,
16
the cholera vaccine,
17
oral typhoid vaccines,
18
and earlier
rotavirus vaccines,
19
none of which were as immunogenic
or effective in populations in developing countries as they
were in populations in industrialized countries. Several
mechanisms have been proposed to explain why live oral
rotavirus vaccines may not be as efcacious in populations
of infants from low-income countries.
20
Possible reasons
include host characteristics, such as poor nutritional status
and enteric coinfections; levels of antirotavirus antibodies
in breast milk; and interference by maternal antibody or by
coadministration of the oral poliovirus vaccine, which may
reduce rotavirus antibody levels.
21,22
The potential role of
these and other factors will be important to elucidate, in
order to further improve the performance of these vaccines
in populations where they are most needed.
The efcacy of the rotavirus vaccine in Malawian infants
in this study was lower than that in their South African
counterparts (49.4% vs. 76.9%). In addition to potential
The
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n engl j med 362;4 nejm.org january 28, 2010
294
differed between South Africa and Malawi (
Fig. 1
in the Supplementary Appendix). The G1P[8] strain
was detected in 57.0% of the episodes among
recipients of the placebo in South Africa and in
12.9% of the episodes among recipients of the
placebo in Malawi. The type-specific efficacy
against severe rotavirus gastroenteritis and the
difference in incidence rates between the vaccine
groups and the placebo group are shown in
Ta-
ble 1 and Table 2
, respectively.
The incidence rate of severe gastroenteritis
from any cause was 8.6% in the pooled vaccine
group as compared with 12.3% in the placebo
group, corresponding to a reduction in the rate
with vaccination of 30.2% (95% CI, 15.0 to 42.6;
P<0.001) (
Table 3
). The reductions in all-cause
severe gastroenteritis were statistically signifi-
cant in both countries. The efficacy of the vac-
cine in the total vaccinated cohort was similar to
that in the per-protocol efficacy cohort (
Tables
3 to 6
in the Supplementary Appendix).
Safety
At least one serious adverse event occurred dur-
ing the study period in 319 of the 3298 infants in
the pooled vaccine group (9.7%; 95% CI, 8.7 to
10.7) and in 189 of the 1641 infants in the pla-
cebo group (11.5%; 95% CI, 10.0 to 13.2) (Table
7 in the Supplementary Appendix). During the
entire study period, 83 deaths occurred among
infants in the pooled vaccine group (2.5%; 95%
CI, 2.0 to 3.1) and 43 deaths occurred among
those in the placebo group (2.6%; 95% CI, 1.9 to
3.5). A single case of intussusception occurred 11
weeks after the third dose of rotavirus vaccine in
a 6-month-old child who was assigned to the
three-dose vaccine group. The child underwent
bowel resection and recovered fully. Three adverse
Table 2. Risk of Severe Rotavirus Gastroenteritis in the Pooled Vaccine Group and the Placebo Group, According to
Dose, Country, and Rotavirus Strain.*
Cohort Rotavirus Vaccine Placebo
Difference in Rate
(95% CI)†
No. in
Cohort
Episodes/
100 Infants/Yr
(95% CI)
No. in
Cohort
Episodes/
100 Infants/Yr
(95% CI)
Severe rotavirus gastroenteritis
Pooled 2974 3.0 (2.3–3.9) 1443 8.0 (6.3–10.1) 5.0 (3.1–7.2)
Two-dose 1496 3.2 (2.2–4.6) — — 4.8 (2.6–7.1)
Three-dose 1478 2.8 (1.9–4.1) — — 5.2 (3.0–7.5)
Country‡
Malawi 1030 6.5 (4.8–8.8) 483 13.1 (9.6–18.0) 6.7 (2.4–11.9)
South Africa 1944 1.2 (0.7–2.0) 960 5.4 (3.8–7.7) 4.2 (2.4–6.5)
Rotavirus type‡
Total cohort 2974 1443
G1 strain 0.9 (0.6–1.5) 2.6 (1.7–3.9) 1.7 (0.6–3.0)
Non-G1 strain 2.1 (1.5–2.9) 5.3 (4.0–7.1) 3.2 (1.7–5.1)
Malawi 1030 483
G1 strain 0.9 (0.4–2.1) 1.7 (0.7–4.0) 0.7 (<0–3.1)
Non-G1 strain 5.5 (4.0–7.7) 11.3 (8.1–16.0) 5.8 (1.9–10.7)
South Africa 1944 960
G1 strain 0.9 (0.5–1.6) 3.0 (1.9–4.8) 2.1 (0.8–3.9)
Non-G1 strain 0.3 (0.1–0.9) 2.4 (1.4–4.0) 2.0 (0.9–3.7)
* The analyses are based on the efficacy cohort, which comprised 4417 infants — 2974 in the pooled vaccine group and
1443 in the placebo group.
† The difference in rate is calculated as the episodes per 100 infants per year in the placebo group minus the episodes
per 100 infants per year in the rotavirus vaccine group.
‡ Data in the rotavirus vaccine group are for the pooled vaccine cohort.
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Effect of Human Rotavirus Vaccine on Severe Diarrhea in African Infants
n engl j med 362;4 nejm.org january 28, 2010
295
events were judged by the investigators to be re-
lated to vaccination — two cases of sepsis and
one of otitis media.
Immunogenicity
At 1 month after the last dose of vaccine was
administered, the seroconversion rates for anti-
rotavirus IgA in South Africa were 57.1% (95%
CI, 44.7 t o 68.9) in t he t wo-dose group and 66.7%
(95% CI, 54.0 to 77.8) in the three-dose group.
The seroconversion rates in Malawi were 47.2%
(95% CI, 30.4 to 64.5) in the two-dose group and
57.1% (95% CI, 42.2 to 71.2) in the three-dose
group. In the placebo group, the seropositivity
rates for antirotavirus IgA at 1 month after the
last dose were 16.7% (95% CI, 14.2 to 19.5) in
South Africa and 40.4% (95% CI, 34.9 to 46.1) in
Malawi.
DISCUSSION
This study shows that a live, oral rotavirus vac-
cine significantly reduces the episodes of severe
rotavirus gastroenteritis in African children dur-
ing the f irst year of life. The attack rate for severe
rot avir us gast roenterit is was higher in these pop-
ulations than has been reported in other studies
of rot avirus vaccines.
4,5
Because of t his high inci-
dence of se vere disease, a vaccine ef f icacy of 61.2%
resulted in a substantial vaccine-attributable re-
duction in severe rot avirus gast roenteritis (reduc-
tion of 5.0 cases per 100 infant-years). In addition,
the rotavirus vaccine was associated with a reduc-
tion in all-cause severe gastroenteritis of 30.2%.
This reduction in the incidence of the disease oc-
curred in a trial that was designed to simulate
real-world conditions of use; thus, the rotavirus
vaccine is expected to deliver a considerable pub-
lic health benefit when it is introduced into sim-
ilar settings.
The overall eff icacy of the rotavirus vaccine in
preventing episodes of severe rotavirus gastroen-
teritis (61.2%) was lower than that observed in
European studies and Latin American studies
(96.4% and 84.8%, respectively), which included
some low- to middle-income countries.
4-6,15
This
finding is consistent with findings from other
studies of live oral vaccines, such as the oral
poliovirus vaccine,
16
the cholera vaccine,
17
oral ty-
phoid vaccines,
18
and earlier rotavirus vaccines,
19
none of which were as immunogenic or effective
in populations in developing countries as they
were in populations in industrialized countries.
Several mechanisms have been proposed to ex-
plain why live oral rotavirus vaccines may not be
as efficacious in populations of infants from low-
income countries.
20
Possible reasons include host
characteristics, such as poor nutritional status
and enteric coinfections; levels of antirotavirus
antibodies in breast milk; and interference by
maternal antibody or by coadministration of the
oral poliovirus vaccine, which may reduce rota-
virus antibody levels.
21,22
The potential role of
these and other factors will be important to elu-
cidate, in order to further improve the perfor-
mance of these vaccines in populations where
they are most needed.
The efficacy of the rotavirus vaccine in Mala-
wian infants in this study was lower than that in
their South African counterparts (49.4% vs.
76.9%). In addition to potential differences men-
tioned above, rotavirus circulation differs in the
two countries (a winter–spring peak in South
Africa
8,9
as compared with year-round circulation
in Malawi
10
), and that difference was reflected in
the study enrollment strategies (preceding the
Table 3. Efficacy of Rotavirus Vaccine against All-Cause Severe Gastroenteritis.*
Cohort Infants with at Least One Event of All-Cause Severe Gastroenteritis Vaccine Efficacy P Value†
Rotavirus Vaccine Placebo
no./total no. % (95% CI) no./total no. % (95% CI) % (95% CI)
Overall 256/2974 8.6 (7.6–9.7) 178/1443 12.3 (10.7–14.1) 30.2 (15.0–42.6) <0.001
Malawi 187/1030 18.2 (15.8–20.6) 117/483 24.2 (20.5–28.3) 25.1 (4.7–40.8) 0.007
South Africa 69/1944 3.5 (2.8–4.5) 61/960 6.4 (4.9–8.1) 44.1 (19.8–61.0) <0.001
* The analyses are based on the efficacy cohort, which comprised 4417 infants — 2974 in the pooled vaccine group and
1443 in the placebo group.
† P values were calculated with the use of a two-sided Fisher’s exact test. P values of less than 0.05 were considered to
indicate a statistically significant difference.
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