Rotavirus Vaccine

Presented By:

Manali Baghel

Ph.D. Ist Sem

College of Biotechnology

DUVASU

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.

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Unfortunately it was withdrawn from the market in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.

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

The wheellike structure seen by electron-microscopyeventually led to agreement to accept the nameRotavirus (rota = Latin for wheel).

The rotaviruses comprise the genus Rotavirus withinthe family Reoviridae.

The clock of rotavirus research in India goes back asearly as 1977 when a group of scientists fromChristian Medical College Hospital, Vellorediscovered rotavirus from the electron microscopy ofthe stools from children below 2 years of agesuffering from acute diarrhea.

Rotaviruses have now been shown to be a cause ofdiarrhea in the young of many mammalian and avianspecies.

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.

Based on the two structural proteins, VP7 and VP4,forming the outer shell, rotavirus strains arecharacterized:

• VP7 neutralizing antigens is termed G-type (sinceVP7 is a glycoprotein or G protein).

• VP4 neutralizing antigens is termed P-type (sinceVP4 is a protease sensitive protein or P Protein).

So far, 23 G-types and 32 P-types of rotavirus havebeen reported.

Based on G and P type, a particular strain is knownby describing its G and P types together, e.g. G1P2A,meaning this rotavirus strain belongs to G-type 1, P-serotype 2A.

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.

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

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:

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.

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

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

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

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)

Human-Bovine Rotavirus

Reassortant Vaccine (RotaTeq)

Current human-animal reassortant rotaviruses for useas vaccines include either human VP7 or VP4 genes.

RotaTeq vaccine is manufactured by Merck and waslicensed 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 proteinfrom the human rotavirus parent strain and theattachment protein (P7) from bovine rotavirus parentstrain WC3.

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.

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.

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.

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.

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).

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.

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.

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.