Rotavirus is the leading cause of severe diarrhea in infants and young children worldwide. Two oral rotavirus vaccines, Rotarix and RotaTeq, were licensed in the 2000s and introduced in national immunization programs. Rotarix is a live-attenuated monovalent G1P[8] human strain, while RotaTeq is a pentavalent human-bovine reassortant vaccine. Both vaccines have shown high efficacy rates against severe rotavirus gastroenteritis in clinical trials. Efforts are ongoing to develop more affordable rotavirus vaccines, such as the Indian vaccine Rotavac, which is currently in phase III trials.

1. Rotavirus Vaccine
Presented By:
Manali Baghel
Ph.D. Ist Sem
College of Biotechnology
DUVASU

2. INTRODUCTION
 A rotavirus vaccine protects children from
rotaviruses, which are the leading cause of severe
diarrhea among infants and young children.
 More than 600,000 young children die and
approximately 2.4 million hospitalize annually from
rotavirus disease.
 There are five main strains that cause more than 90
percent of human rotavirus infections.
 Because of the tremendous global burden of
rotavirus, WHO has prioritized vaccine development
and introduction to control this disease.

3. History
 Efforts to develop a rotavirus vaccine began in 1980s.
 In 1998, a rotavirus vaccine was licensed and
introduced as a live attenuated rhesus rotavirus
vaccine (RotaShield) in the US market.
 Unfortunately it was withdrawn from the market in
1999 after reports of increased risk of intussusception
among vaccinated infants.
 In 2006, two new oral rotavirus vaccines were
licensed and introduced in the USA following large-
scale safety and efficacy studies in Europe and North
and Latin America and later in Asia.

4. Discovery of Rotavirus
 Human rotavirus was first isolated by Ruth Bishop in
1973 from epithelial cells of the small intestine of
children with diarrhea.
 Abundant viral particles were identified in the
epithelial cells lining the upper villous surface.
 The virus was identified as being reovirus-
like/orbivirus-like, with a close resemblance to
viruses already implicated as cause of diarrhea in
neonatal mice and in calves.
 The virus could readily be identified by electron-
microscopy of negatively stained fecal extracts as 70-
nm particles

5.  The wheellike structure seen by electron-microscopy
eventually led to agreement to accept the name
Rotavirus (rota = Latin for wheel).
 The rotaviruses comprise the genus Rotavirus within
the family Reoviridae.
 The clock of rotavirus research in India goes back as
early as 1977 when a group of scientists from
Christian Medical College Hospital, Vellore
discovered rotavirus from the electron microscopy of
the stools from children below 2 years of age
suffering from acute diarrhea.
 Rotaviruses have now been shown to be a cause of
diarrhea in the young of many mammalian and avian
species.

6. Rotavirus: Virology
!
Rotavirus has an 11-
segmented double-stranded
RNA genome that is
surrounded by three protein
shells: a core,an inner capsid,
and outer capsid.
The RNA gene segments
encodes for six structural
viral proteins (VP1–VP4,
VP6, VP7) and six non-
structural proteins (NSP1–
NSP6).
Schematic representation of a
rotavirus virion.

7.  Based on the two structural proteins, VP7 and VP4,
forming the outer shell, rotavirus strains are
characterized:
• VP7 neutralizing antigens is termed G-type (since
VP7 is a glycoprotein or G protein).
• VP4 neutralizing antigens is termed P-type (since
VP4 is a protease sensitive protein or P Protein).
 So far, 23 G-types and 32 P-types of rotavirus have
been reported.
 Based on G and P type, a particular strain is known
by describing its G and P types together, e.g. G1P2A,
meaning this rotavirus strain belongs to G-type 1, P-
serotype 2A.

8. Rotavirus Infection
 Rotavirus is very contagious, it spreads when infants
or young children come into contact with an infected
person’s body fluids or feces, or items that have come
in contact with the feces of an infected person.
 Most cases of rotavirus occur in children ages 3
months to 35 months old.
 The primary mode of transmission of rotavirus is the
passage of the virus in stool to the mouth of another
child, known as a fecaloral route of transmission.
 The virus can live for hours on hands and even longer
on hard surfaces.

9. Symptoms of Rotavirus Infection
o Frequent vomiting
o Abdominal pain
o Lethargy (child won’t focus on you, is less responsive to touch
or words)
o Less frequent urination
o No tears when crying
o Dry, cool skin
o Fever
o Frequent, watery diarrhea (often foulsmelling, green or brown)
o Dry or sticky mouth
o Extreme thirst

10. Rotavirus Vaccine
 A realistic goal for a rotavirus vaccine is to duplicate
the degree of protection against disease that follows
natural infection.
 Introduction of rotavirus vaccines in national vaccine
policy along with other childhood vaccines may result
in significant reduction in mortality in children in
poor socioeconomic countries.
 Four major structural and nonstructural proteins are
of interest in vaccine development: VP6, NSP4, VP7,
and VP4.
 The current and previous candidate rotavirus vaccines
can be categorized in two groups on the basis of their
development:

11. Vaccine Strategies
Attenuation of rotaviruses for use as oral vaccines may be
achieved in several ways-
 First Generation Vaccines (Jennerian Approach):
These early rotavirus vaccines were single-animal strains that
were naturally attenuated in that they did not cause clinical
disease in humans but conferred protection against subsequent
infection with human rotavirus strains.
 Second Generation Vaccines (Modified Jennerian Approach) :
I. Animal-human reassortant: these reassortants contain an
animal strain which incorporate additional genes from
human strains by capitalizing on the viruses’ ability to
reassort in vitro.
II. Human attenuated strains: these are vaccines developed
through attenuation of human rotavirus strains.

12. Past and Current Rotavirus Vaccines
First Generation (animal Backbone):
Acronym
(trade
name)
Backbone Valency Antigens Status
RI T 4237 Bovine single-
strain
G6, P6 Discontinued
RRV -
MMU
Rhesus single-
strain
G3,P3 Discontinued
WC3 (non-
reassortant)
Bovine Single-
strain
G6, P5 Discontinued
LLR Lamb Single-
strain
G10P Licensed

13.  Second Generation (animal-human reassortants):
Acronym
(trade name)
Backbone Valency Antigens Status
Wa X UK Bovine-
Human
single-
strain
G6P Active Phase I
RRV –TV
(Rotashield)
Rhesus Four-
strain
G1P, G2,
G3, G4
Withdrown
Reassortant
WC3 (Rotataq)
Bovine Five-
strain
G1, G2,
G3, G4,
P
Licensed

14.  Second Generation (Human attenuated strains) :
Acronym
(trade name)
Backbone Valency Antigens Status
M37 Human single-strain G1P Doscontinued
Rotarix Human single-strain G1P Licensed
116E Human single- strain G9P Active Phase I

15. Currently Licensed Vaccine In Use
 Two safe and effective vaccines are now licensed in
100 countries but used in 17 countries.
 In April 2009, WHO provided a recommendation for
global introduction of these vaccines in national
immunization programs of developing countries
worldwide.
o Rotarix (RV1;GlaxoSmithKline)
o RotaTeq (RV5;Merck)

16. Human-Bovine Rotavirus
Reassortant Vaccine (RotaTeq)
 Current human-animal reassortant rotaviruses for use
as vaccines include either human VP7 or VP4 genes.
 RotaTeq vaccine is manufactured by Merck and was
licensed by the FDA in 2006.
 It is a pentavalent human-bovine reassortant live-
attenuated, oral vaccine.
 This vaccine contains five live reassortant rotaviruses.
 Four reassortant rotaviruses express the VP7 protein
from the human rotavirus parent strain and the
attachment protein (P7) from bovine rotavirus parent
strain WC3.

17.  The fifth reassortant virus expresses the attachment
protein (P1A) from the human rotavirus parent strain
and the outer capsid protein G6 from the bovine
rotavirus parent strain.
 Other ingredients include sucrose, sodium citrate,
sodium phosphate monobasic monohydrate, sodium
hydroxide, polysorbate 80, cell culture media, and
trace amounts of fetal bovine serum.
 Schedule: RotaTeq is administered in three oral doses
at 1- to 2-month intervals beginning at 6 to 12 weeks
of age.

18. Safety, Immunogenicity and Efficacy
 In a large clinical trial conducted primarily in the US
and Finland, RotaTeq showed an efficacy of 98%
against severe rotavirus gastroenteritis.
 Protection was good against all G1-4 and G9
serotypes (range 88–100%)
 A substantial reduction (59%) in admissions from all-
cause gastroenteritis was also noted in the trial.
 In the US, field effectiveness of the vaccine (88%–
100%) was similar to that observed in the clinical
trial.

19. Human Rotavirus Vaccine (Rotarix)
 Rotarix vaccine is manufactured by GlaxoSmithKline
and was licensed by the FDA in 2008.
 A live-attenuated human rotavirus vaccine (strain 89-
12) was originally developed in Cincinnati, OH, by
tissue culture passage of a wild-type human rotavirus
isolate.
 This vaccine is a P1A[8]G1 strain and thus represents
the most common of the human rotavirus VP7 and
VP4 antigens.
 The vaccine was further developed by Avant
Immunotherapeutics.

20.  It was licensed to GlaxoSmithKline Biologicals
who further modified the vaccine by cloning and
tissue culture passaging of the parent 89-12
vaccine strain.
 It is a monovalent vaccine.
 Schedule: Rotarix is administered at 2 and 4
months of age.

21. Safety, Immunogenicity and Efficacy
 A large-scale trial of more than 63,000 infants
enrolled in 11 Latin American countries and Finland
was done to confirm that the vaccine did not cause
intussusception.
 A subset of 20,000 infants in this large trial was
monitored for efficacy (73). The results demonstrated
a protection rate of 85% against severe rotaviral
gastroenteritis and 100% protection against the most
severe dehydrating rotaviral gastroenteritis episodes.
 It also proved to be strongly efficacious in preventing
rotavirus gastroenteritis of any severity caused by the
predominant G1 serotype (92% efficacy) and
serotypes G3, G4, or G9 (88% efficacy).

22. Issues with RotaTeq & Rotarix
Rotarix and RotaTeq vaccine were recently
found to be contaminated with porcine
circovirus viral DNA and were temporarily
suspended by US FDA in March 2010.
However it was proven that porcine circovirus
did not impose any threat to human and thus
both vaccines have been declared safe for use.

23. Vaccines In Development
 An Indianmade rotavirus vaccine, Rotavac, is in
development, in phase III trials.
 If approved by the Drugs Controller General of India,
it would be available at Rs. 54 per dose, more
affordable than the two vaccines now available
costing more than Rs. 1,000 per dose.
 Other vaccines are undergoing clinical trials, these
include- A human neonatal P[6]G3 strain, RV3,
developed by Ruth Bishop and colleagues in
Australia, a neonatal strain vaccine (G9P11) being
developed by Bharat Biotech in India.

24.  Other approaches to the development of rotavirus
vaccines are also being pursued like-
 Rotavirus antigens for parenteral delivery have
received some attention as viruslike particles
prepared in baculovirus, expressed antigens, DNA
vaccines, and killed virus.
 These novel approaches are being pursued using
animal models.