Live Attenuated Human Rotavirus Vaccine, Rotarix™: David I. Bernstein, MD, MA
Live Attenuated Human Rotavirus Vaccine, Rotarix™: David I. Bernstein, MD, MA
Live Attenuated Human Rotavirus Vaccine, Rotarix™: David I. Bernstein, MD, MA
Rotavirus infections are the leading cause of severe gastroenteritis in young children
worldwide. Recently two new rotavirus vaccines have entered the world market. This review
provides a summary of the rationale, development, and evaluation of one of these vaccines,
Rotarix*. Rotarix* is a live oral rotavirus vaccine developed from a single protective human
strain following multiple passages in tissue culture to attenuate the strain. The vaccine is
administered as two oral doses at approximately 2 and 4 months of age. Large safety and
efficacy trials have shown the vaccine is safe, not associated with intussusception, and
effective against the most common circulating human serotypes. Efficacy against severe
rotavirus gastroenteritis and hospitalization have ranged from 85 to 100 percent.
Semin Pediatr Infect Dis 17:188-194 © 2006 Elsevier Inc. All rights reserved.
188 1045-1870/06/$-see front matter © 2006 Elsevier Inc. All rights reserved.
doi:10.1053/j.spid.2006.08.006
Live attenuated human rotavirus vaccine, Rotarix™ 189
Figure 1 Rotavirus structure illustrating 11 genome segments and the proteins they encode on the left. Schematic
diagram of structure in the middle and computer-generated image on the right.
fected child, designated 89-12, was selected and serially pas- Dose 1
saged 26 times in primary African Green Monkey kidney cells 100
(AGMK), then seven times in a serially passaged AGMK cell 90 RIX4414
line.57 To determine whether the passages in cell culture had 80 Placebo
70
attenuated the virus, researchers conducted studies in adults
60
followed by studies in children with previous rotavirus infec-
50
%
tions.57 After these trials provided evidence of attenuation 40
based on a lack of signs or symptoms of rotavirus disease, the 30
10
small number of infants and dose-ranging studies were com-
0
pleted, the evaluation proceeded to a multicenter efficacy Fever ( 38°C) Diarrhea Vomiting Irritability Loss of
Appetite
trial.
In the initial randomized placebo-controlled, double-blind Dose 2
%
cific antibody responses developed in 94.4 percent of vaccine 40
20
obtained on day 7 after immunization. In the first year after
10
vaccination was given, vaccine efficacy was 89 percent against
0
any rotavirus disease, the highest reported for any multicenter Fever ( 38°C) Diarrhea Vomiting Irritability Loss of appetite
Table 1 Efficacy of RotarixTM Against Rotavirus Gastroenteritis importance, efficacy against hospitalization because of gastroen-
in Latin America and Finland teritis of any cause was 75 percent.
Rotarix™ Placebo In conclusion, efficacy of this vaccine is excellent against se-
(n ⴝ 9009) (n ⴝ 8858) Efficacy vere rotavirus disease regardless of the serotype, although effi-
Severe disease 12 77 85
cacy is reduced against strains that do not share either the VP7 or
Hospitalization 9 59 85 VP4 proteins. Efficacy is somewhat increased in the most devel-
Vesikari scale >11 11 71 85 oped countries compared with lesser developed countries, as
Vesikari scale >19 0 16 100 evidenced by comparison of the efficacy in the large trial in Latin
G1 P[8] 3 36 92 America with the one in Europe. Thus, comparison of efficacy in
G3, G4 or G9 and 4 31 87 Europe with any previous vaccine trial shows that Rotarix™
P[8] meets or exceeds previous rates of protection.
G2 P[4] 6 10 41*
*In a large meta-analysis, efficacy was 67%. Intussusception and Rotarix™
Because of the association of the previously licensed
Rotashield™ vaccine with intussusception, large safety trials
months of age. Infants received routine immunizations accord- have been conducted with both Rotateq™ and Rotarix™. As
ing to local regulations, but oral polio was provided at least 2 stated previously, Rotarix™ was evaluated in a randomized
weeks before or after administration of the vaccine. In the safety placebo controlled trial of more than 63,000 infants in Latin
cohort, significantly fewer serious adverse events and hospital- America.64 In that trial, 31,373 infants ages 6 to 17 weeks
izations were reported in the vaccine group than in the placebo were randomized to receive two doses of vaccine and 31,552
group. to receive placebo. The mean age at the administration of the
first dose was 8.2 weeks and at the second dose was 15.8
weeks of age. The primary endpoint of the study was the
Efficacy occurrence of intussusception as defined by the Brighton
collaboration group within 30 days of receiving either dose of
The first efficacy study with RIX4414 was conducted in Fin-
vaccine. A secondary evaluation involved cases occurring
land during two rotavirus epidemic seasons, 2001 to 2002,
during the duration of the study. Cases were captured by
with a relatively low, suboptimal, dose of vaccine virus (104.7
active hospital surveillance and scheduled for visits after each
ffu). In this randomized, double-blind, placebo-controlled
dose. An independent surveillance system also was in place
trial of 405 infants, the vaccine was well tolerated and immu-
to ensure that all cases were identified. Cases were reviewed
nogenic.65 In this trial, efficacy against any episode of rotavi-
by a blinded expert and monitored by an independent data
rus gastroenteritis was 73 percent, whereas efficacy against
monitoring board. Seven cases, two after the first dose was
any severe episode of rotavirus gastroenteritis was 90 percent administered, were identified in the placebo group compared
in the first season and 72 or 85 percent, respectively, over the with six, one following the first dose administered, in the
entire follow-up period. Thus, no decrease in efficacy was vaccine group. No clustering in the initial 1 to 2 weeks was
seen in the second year compared with the first. Thirty-five of identified after the receipt of either dose (Fig. 3). During the
the 38 cases of rotavirus gastroenteritis were caused by virus duration of the study, 16 cases occurred in the placebo group
of the same G1 serotype as the vaccine. compared with nine in the vaccine group. Thus, no evidence
In the large study conducted in Latin America and Finland, was found that Rotarix™ was associated with intussusception.
efficacy was 85 percent against severe rotavirus diarrhea and
hospitalizations.64 Of note, efficacy was high (more than
86%) against severe rotavirus diarrhea caused not only by Current Status
G1P[8] strains but also by the VP4-related G3[8], G4[P8], Rotarix™ currently is available in the European Union, 15
and G9[P8] strains (Table 1). Efficacy against the few G2P[4] Latin American countries, and 29 other countries, including
strains was less, 41.0 percent. However, in several meta-
analysis studies, the efficacy was 67 to 71 percent, with 95
percent CIs of 15 to 87 percent, indicating that the vaccine Table 2 Efficacy of RotarixTM Against Rotavirus Gastroenteritis
will be efficacious against strains that do share VP4 or VP7 in Europe
proteins (personal communications, GSK).66 Efficacy (95% CI)
In the most recent trial conducted in six European countries, Any disease 87% (80-92%)
4274 infants were randomized in a 2:1 ratio to receive Rotarix™ Severe disease 96% (90-99%)
or placebo concomitantly with routine vaccinations.66 Protec- Hospitalization 100% (82-100%)
tion was 87 percent against any rotavirus gastroenteritis, 96 Severe disease
percent against severe disease, and 100 percent against hospi- G1 96 (86-100%)
talization attributable to rotavirus (Table 2). Furthermore, in G3 100% (45-100%)
agreement with the study discussed previously, efficacy against G4 100% (65-100%)
G3, G4, and G9 was similar to that against G1 and exceeded 95 G9 95% (78-99%)
G2 P[4] 75% (ⴚ386 to 89%)
percent, whereas efficacy against G2 strains was 75 percent. Of
Live attenuated human rotavirus vaccine, Rotarix™ 193
Vaccine
First Dose Placebo
Infants with Intussusception
5 10 15 20 25 30 35 40
Second Dose
5 10 15 20 25 30 35 40
Figure 3 Number of cases of intussusception after the administration of Rotarix™ or placebo.
several in Asia. Ongoing discussions with the Food and Drug 7. Bernstein DI, Ward RL: Rotaviruses, in Feigin RD, Cherry JD (eds):
Administration will determine when approval is sought in Textbook of Pediatric Infectious Diseases (ed 5). W.B. Philadelphia, PA,
Saunders, 2004, pp 2110-2133
the United States.
8. Ball JM, Tian P, Zeng CQ, et al: Age-dependent diarrhea induced by a
rotaviral nonstructural glycoprotein. Science 272:101-104, 1996
Summary 9. Gorziglia M, Larralde G, Kapakian AZ, et al: Antigenic relationships
among human rotaviruses as determined by outer capsid protein VP4.
The evidence to date indicates that two oral doses of Rotarix™ is Proc Natl Acad Sci USA 87:7155-7159, 1990
safe and immunization is not associated with either fever or 10. Staat MA, Azimi PH, Berke T, et al: Clinical presentations of rotavirus
infection among hospitalized children. Pediatr Infect Dis J 21:221-227,
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2002
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been no impact on the immunogenicity of concurrently admin- viraemia: a common event? Lancet 362:1445-1449, 2003
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ies also will be seen in the least developed nations of the world, 15. Bernstein DI, Sander DS, Smith VE, et al: Protection from rotavirus rein-
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