Vaccine 32S (2014) A124A128

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

Bovine rotavirus pentavalent vaccine development in India

Jagdish K. Zade, Prasad S. Kulkarni , Sajjad A. Desai, Rajendra N. Sabale, Sameer P. Naik,
Rajeev M. Dhere
Serum Institute of India Ltd., Pune, India

a r t i c l e

i n f o

Article history:
Keywords:
Bovine rotavirus pentavalent rotavirus
vaccine (BRV-PV)
Serum Institute of India Ltd.
Development
Clinical trials

a b s t r a c t
A bovine rotavirus pentavalent vaccine (BRV-PV) containing rotavirus human-bovine (UK) reassortant
strains of serotype G1, G2, G3, G4 and G9 has been developed by the Serum Institute of India Ltd, in
collaboration with the National Institute of Allergy and Infectious Diseases (NIAID), USA. The vaccine
underwent animal toxicity studies and Phase I and II studies in adults, toddlers and infants. It has been
found safe and immunogenic and will undergo a large Phase III study to assess efcacy against severe
rotavirus gastroenteritis.
2014 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/3.0/).

1. Introduction
Black et al. estimated annual global mortality in 2008 due to
diarrheal diseases in children 05 years of age was around 1.5
million, based on single-cause disease models and analysis of
vital registration data, about 500,000 of which were attributed to
rotavirus infection. The worlds poorest countries of Asia and subSaharan Africa bear the maximum burden of these deaths [1]. Based
on a systematic review and meta-analysis of studies which assessed
rotavirus diarrhea, Tate et al. calculated 453,000 global deaths in
2008 (95% CI 420,000494,000) in children younger than ve years;
22% of them (98,621 deaths) in India alone [2]. It is also estimated
that rotavirus causes 457,000884,000 hospitalizations and over
two million outpatient visits every year in India [3].
Although rotavirus vaccines are commercially available, they are
unaffordable in developing countries. Notwithstanding the recent
recommendation by the World Health Organization (WHO) for the
inclusion of rotavirus vaccination in the national immunization
schedules of all countries, the vaccines supply continues to be an
issue for the countries with greatest need [4]. The need is urgent
because children in low-income countries are infected earlier in life
and with limited access to health care, their illness is likely to be
severe, even leading to death [5].
Widespread use of rotavirus vaccines is estimated to be able to
avert 2.4 million deaths by 2025, with annual reductions of up to
225,000 child deaths [6]. However, realizing the vaccines potential

must be supported by an adequate supply of high-quality WHOprequalied vaccines by manufacturers in developing countries
without relying on multi-national corporations.
The epidemiology of rotavirus is a complex, dynamic phenomenon. Globally, ve genotypes (G1G4, and G9) account for 88%
of all strains [7]. Researchers have extensively studied the molecular epidemiology of rotaviruses in India [8]. The most common
G (VP7) serotypes found were G1 and G2, however, studies have
observed a high prevalence of G9 strains of up to 15% in various
Indian cities. In a recent study conducted by SII in collaboration
with the National Institute of Cholera and Enteric Diseases (NICED)
in a rural area of West Bengal, India, G9 P[4] (27%), G1 [P8] (18%)
and G2 P[4] (14%) were the predominant genotypes in the study
population [9].
Rotavirus candidate vaccine development has followed two
views regarding the importance of serotype-specic protection.
Many candidates are based on the theory that protection is not
solely dependent on neutralizing antibody. These candidates contain single rotavirus strains and include the Rotarix vaccine. On
the other hand, several candidate vaccines are based on the concept that neutralizing antibody is the primary determinant of
protection. These candidates, including RotaTeq, are composed
of multiple rotavirus strains representative of the major human
rotavirus serotypes [10]. The SIIL candidate vaccine belongs to the
latter group and includes ve most prevalent serotypes [7].

1.1. Bovine reassortant vaccines

Corresponding author at: Serum Institute of India Ltd., 212/2 Hadapsar, Pune,
India. Tel.: +91 20 26602384; fax: +91 20 26993945.
E-mail address: drpsk@seruminstitute.com (P.S. Kulkarni).

The most extensively evaluated approach for live attenuated oral vaccines is based on the Jennerian concept, involving
immunization with animal rotaviruses considered to be naturally

http://dx.doi.org/10.1016/j.vaccine.2014.03.003
0264-410X/ 2014 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

J.K. Zade et al. / Vaccine 32S (2014) A124A128

attenuated for humans [11]. In view of the inconsistency of protection from animal rotavirus-based vaccines, efforts began to
develop reassortant rotavirus strains that contained some genes
from the animal rotavirus parent and some genes from the human
rotavirus parent, termed the modied Jennerian approach [12].
VP7 was thought to be important for protection; therefore, humananimal reassortant rotaviruses for use as vaccines included human
VP7 genes to provide protective immune responses. A pentavalent human-bovine (WC3) reassortant live-attenuated, oral vaccine
(RotaTeq) developed by Merck Research Co. is currently licensed
[13].
Another multivalent bovine-human reassortant vaccine was
independently developed by the National Institute of Allergy and
Infectious Diseases (NIAID). This bovine rotavirus tetravalent (BRVTV) vaccine incorporates four reassortant viruses with a VP7 gene
of either a G1, G2, G3, or G4 human serotype and 10 genes from the
bovine rotavirus UK strain. NIAID conducted phase1 studies of the
individual vaccine components, as well as phase 1 and 2 studies
of a quadrivalent version of the vaccine in the US and in Finland
[1416].
The initial studies in adults, children and infants with this
tetravalent G1G4 BRV formulation (BRV-TV) in the US, demonstrated that each of the components was able to infect the
volunteers as determined by vaccine shedding in the stools and the
induction of immune responses [14]. The vaccine was safe; and had
no impact on the immune responses of routine childhood immunizations. Vesikari et al. in Finland compared the same tetravalent
vaccine to the rhesus tetravalent vaccine (RRV-TV, later licensed
as RotaShield) [15]. Both vaccines were equally efcacious, however, the BRV-TV was less reactogenic than the RRV-TV, which was
associated with febrile reactions and diminished appetite. In the
study, the vaccine induced immune responses in 97% of the infants
tested and showed 90% efcacy against severe rotavirus gastroenteritis (SRVGE) during two rotavirus seasons (CI: 3599%), though
the size of this study was limited. These ndings clearly support
the immunogenicity, safety and potential for efcacy of BRV-PV.
1.2. Vaccine development at Serum Institute of India Ltd.
With the emergence of the G9 and G8 serotypes, the NIAID
added human-bovine (UK) reassortants with G8 and G9 specicities
to the tetravalent vaccine, thereby formulating a hexavalent vaccine for use in developing countries [17]. The UK bovine rotavirus
G6[P5] strain was used to construct single gene substitution
reassortants in which the G gene derives from human rotavirus
serotypes G1, G2, G3, G4, G8 and G9, and all the other genes derived
from the UK bovine strain.
Non-exclusive licenses for the production of the human-bovine
(UK) vaccine were granted to the Chengdu Institute of Biological Products (CDIBP) (China), Instituto Butantan (Brazil), Shantha
Biotech (India) and Serum Institute of India Ltd. (SIIL) (India). SIIL
signed the agreement with NIAID in 2005.
SIIL is one of the largest vaccine manufacturers in the world.
Headquartered at Pune, India, it has been manufacturing vaccines since 1971. Since 1992, SIIL has supplied vaccines to UNICEF
and Pan-American Health Organization (PAHO) after receiving the
mandatory WHO prequalication for the quality of its vaccines.
Currently, 19 of its vaccines are WHO prequalied and supplied
to immunization programs of many developing countries. It is estimated that SIIL is the largest supplier of DTwP-HB-Hib vaccine and
measles vaccine in the world.
After transfer of these reassortants from NIAID, SIIL started
working on them in 2007. The vaccine was formulated as a
lyophilized product which was resuspended in antacid buffer
just before use to address the issue of potential inactivation
of rotaviruses in the stomach. The antacid buffer diluent was

A125

formulated using 9.6 g/l of citric acid and 25.6 g/l of sodium bicarbonate together with water for injection.
The viruses are grown in Vero cells which are kidney epithelial
cells of African green monkey (Cercopithecus aethiops) and were
procured from American Type Culture Collection (ATCC), USA. The
Vero cell bank was prepared at SIIL and characterized to qualify
for the vaccine production. Cell growth kinetics and virus growth
kinetics were studied and the formulation with the lyophilization
cycle was developed at SIIL. The pre-clinical toxicity and clinical lots
were manufactured in a dedicated facility at SIIL in compliance with
current good manufacturing practices (cGMP). These lots showed
excellent lot-to-lot consistency and stability. The vaccine is stable
for three years at 28 C, and 25 C, for two years at 37 C and for
six months at 40 C.
The SII BRV-PV was initially formulated as a combination of the
six reassortants at equivalent titers. These reassortants represent
the most common G serotypes. The G9 component is of particular
interest to India as it has circulated in Indian infants for over two
decades.
The live attenuated vaccine has a three dose regimen since it is
known that, natural rotavirus infection confers protection against
subsequent infection and that this protection increases with each
new infection and reduces the severity of the diarrhea [18]. Rotateq,
another bovine reassortant vaccine is already licensed for a three
dose schedule.

1.3. Preclinical toxicology studies

SII conducted single- and repeated-dose toxicity studies of
rotavirus vaccine in rodents (Wistar rats) and non-rodents (New
Zealand white rabbits) by oral gavage administrations in an accredited laboratory in India under strict good laboratory practices (GLP).
These studies were conducted with a hexavalent vaccine which
included G1, G2, G3, G4, G8 and G9 reassortants. Single dose studies included 60 rats and 18 rabbits in three groups while repeated
dose studies included 70 rats in four groups and 18 rabbits in three
groups. The vaccine formulation had virus titers in the range of
106.62 FFU to 107.79 FFU.
A dose of 2.5 ml of reconstituted vaccine, placebo or normal
saline were administered on day one to animal groups. In repeated
dose studies, additional doses were administered on day 15, 29
and 43. All the animals were observed for mortality, clinical signs,
weight changes and food intake. We collected stool samples 72 h
after each administration. Necropsy was carried out on day 8 and 57
during the single dose and repeat dose toxicity studies, respectively.
The vaccine in single- and repeated-dose toxicity studies in
Wistar rats had no effects on their general health. There were no
changes in body temperature, cumulative net body weight gains
and hematological, clinical chemistry and urinalysis parameters in
animals of either sex. Fecal samples were negative for the presence of rotavirus antigen in all the animals. No gross or microscopic
histopathological changes were detected.
The vaccine administered as single and repeated dose by the oral
route in New Zealand white rabbits also showed no effects on general health. There were no toxic signs and mortality; no effects on
body temperature, body weight, cumulative net body weight gains
and food intake. There were no changes on the hematological, clinical chemistry and urinalysis parameters tested in animals of either
sex. Fecal samples were negative for the presence of rotavirus antigen in all the animals. No gross or microscopic histopathological
changes were detected in either sex.
All the animals were positive for rotavirus antibodies before
administration of the vaccine and remained positive 43 days after
vaccination. The IgA was determined by using enzyme-linked
immunosorbent assay (ELISA) as described previously [19].

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Table 1
Reactogenicity of 105.2 FFU/serotype BRV-PV vaccine in infants.

Table 2
Reactogenicity of 105.6 FFU/serotype BRV-PV vaccine in infants.

Solicited symptom

BRV-PV

Placebo

Solicited symptom

BRV-PV

Placebo

Participants assessed
At least one solicited symptom, n (%)
Diarrhea, n (%)
Vomiting, n (%)
Fever, n (%)
Decreased appetite, n (%)
Decreased activity, n (%)
Irritability, n (%)
Respiratory symptoms, n (%)
Antipyretic use, n (%)

27
14 (51.85%)
1 (3.70%)
11 (40.74%)
3 (11.11%)
5 (18.52%)
4 (14.81%)
9 (33.33%)
5 (18.52%)
4 (14.81%)

30
21 (70.00%)
2 (6.67%)
13 (43.33%)
8 (26.67%)
5 (16.67%)
1 (3.33%)
12 (40.00%)
9 (30.00%)
7 (23.33%)

Participants assessed
At least one solicited symptoms, n (%)
Diarrhea, n (%)
Vomiting, n (%)
Fever, n (%)
Decreased appetite, n (%)
Decreased activity, n (%)
Irritability, n (%)
Respiratory symptoms
Antipyretic use, n (%)

30
18 (60.00%)
3 (10.00%)
8 (26.67%)
3 (10.00%)
6 (20.00%)
3 (10.00%)
9 (30.00%)
11 (36.67%)
9 (30.00%)

30
20 (66.67%)
2 (6.67%)
7 (23.33%)
5 (16.67%)
4 (13.33%)
2 (6.67%)
6 (20.00%)
9 (30.00%)
5 (16.67%)

Thus, SII hexavalent BRV vaccine did not cause any toxicity when
administered as single and repeated dose by the oral route in Wistar rats and New Zealand white rabbits. The studies also proved that
along with the antigens, the formulation which contains stabilizers and antacid is safe. These results opened prospects for human
clinical studies on the vaccine.

1.4. Clinical studies

Considering rotavirus serotype distribution in India, a pentavalent formulation which comprised of G1, G2, G3, G4 and G9
serotypes was used for clinical development (Fig. 1). Three clinical
studies (Phase I, Phase IIa and Phase IIb) have been conducted on SII
BRV-PV in India (Registration numbers CTRI/2009/091/000821 and
CTRI/2010/091/003064). The study populations included adults,
toddlers and infants.
All studies were approved by the Drug Controller General of
India (DCGI) and institutional ethics committees. They complied
with all the national regulatory and ethical standards as well as
the ICH good clinical practices (GCP). An independent Data Safety
Monitoring Board (DSMB) monitored the safety and rights of the
study subjects. The sera samples for rotavirus specic IgA antibodies were tested using IgA ELISA at the Christian Medical College,
Vellore (India) [19] and stool samples for shedding were tested
using rotavirus antigen detection kit (Generic Assays, Germany)
at Metropolis Laboratory, Pune. Seroconversion was dened as a
change in IgA concentration from <20 U/ml to 20 U/ml, or 3 fold
rise in IgA titers in case of baseline titers 20 U/ml.
The Phase I study was a randomized, double-blind, placebo controlled study to assess the safety of a single oral dose of SII BRV-PV
sequentially in healthy adults, toddlers and infants. The study also
assessed the immunogenicity and shedding of the vaccine. A single
oral dose of the vaccine containing 106 FFU/serotype was investigated in 54 subjects (18 adults, 18 toddlers and 18 infants) who
received vaccine or placebo in 2:1 ratio.
BRV-PV was found safe and well tolerated in all three age groups.
There was no serious adverse event (SAE). The few adverse events
reported were mild and transient. Vaccine related events included
nausea, loss of appetite, diarrhea and vomiting (Table 1). Except
for a few minor changes, the hematology, biochemistry and urine
analysis results remained normal in all the groups.
No shedding was seen in stool samples. As expected, the single
dose of the vaccine did not show immune response in adults and
toddlers. However, infants showed a small immune response (28%)
which was encouraging.
This was followed by a randomized, double-blind, placebo controlled Phase IIa study which assessed the formulation of 105.2
FFU/serotype in 60 healthy infants. SII BRV-PV/placebo was administered in 1:1 ratio as three doses with at least four weeks interval
between doses. The study assessed the safety, immunogenicity and
shedding of the vaccine.

Close post-vaccination follow-up showed the vaccine to be safe

and well tolerated. A summary of the solicited vaccine reactogenicity is summarized in Table 2. Almost all the events were mild
and transient. Two SAEs (urinary tract infections and septicemia)
unrelated to study vaccines were reported and both recovered
uneventfully. We saw no effect on laboratory parameters.
Three doses of the vaccine were found immunogenic. The seroconversion post dose 2 was 36% and 7.14%, in vaccine and placebo
arms respectively (p = 0.0160). The corresponding post dose 3 seroconversion were 48% and 21.43% (p = 0.0492) (Table 3). The post
dose 3 GMTs in vaccine and placebo arms were 18.55 U/ml; and
7.31 U/ml.
Following these satisfactory results, a randomized, doubleblind, placebo controlled Phase IIb study was conducted which
assessed the formulation of 105.6 FFU/serotype in 60 healthy
infants. SII BRV-PV/placebo was administered in 1:1 ratio as three
doses with at least four weeks interval.
This formulation of the vaccine was also found safe and well
tolerated. A summary of the solicited vaccine reactogenicity is
summarized in Table 2. Almost all the events were mild and transient. No SAE was reported and there was no effect on laboratory
parameters.
Three doses of the 105.6 FFU/serotype formulation induced a signicant immune response (Table 3). The seroconversion post dose
2 was 56.67% and 11.54%, in vaccine and placebo arms respectively
(p value <0.05). The corresponding post dose 3 gures were 60%
and 7.69% (p < 0.05).
The seroconversion rates indicated that the 105.6 FFU/serotype
formulation is immunogenic in infants. These results are similar
to those reported for the Rotarix (GSK) in an Indian study where
the seroconversion rates were 58.3% [95% CI: 48.7; 67.4] in the
Rotarix group and 6.3%; [95% CI: 2.5; 12.5] in the placebo group
[20]. Another Indian study on the 116E vaccine showed 89.7% seroconversion in the vaccine arm and 28.1% in the placebo arm [21].
Another Indian study on Rotateq showed 83% 3-fold rise (seroconversion) in serum IgA antibodies; however the study had no placebo
arm [22].
In developed countries, the seroresponses to rotavirus vaccines
are high. The examples include a Korean study on Rotarix (88.1%)
[23], a Korean study on Rotateq (94.7%) [24], a Japanese study on
Rotarix (85.3%) [25], an European study on Rotarix (85.589.2%)
[26], and a Finnish study on Rotarix (83.790.5%) [27].
However, for reasons not completely understood, the seroresponses are lower in developing countries. The examples include
an African study on Rotateq (73.882.5%) [28], a Brazil study on
Rotarix (54.774.4%) [29] and a Latin American study on Rotarix
(6165%) [30]. Our results on the 105.6 FFU/serotype formulations
are in line with these studies.
2. Planned Phase III studies
A large Phase III clinical trial on the 105.6 FFU/serotype formulation is now planned to achieve licensure in India as well as

J.K. Zade et al. / Vaccine 32S (2014) A124A128

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Fig. 1. Human and bovine reassortant pentavalent vaccine with VP7 serotype G1, G2, G3, G4 and G9 specicity.
Modied from Ref. [14].

Table 3
Seroconversion with 105.2 FFU/serotype formulation (Phase IIa) and 105.6 FFU/serotype formulation (Phase IIb) of SII BRV-PV.
Study arm

SII BRV-PV
Placebo
p-Valuea
a

Phase IIa

Phase IIb

Post dose 2

Post dose 3

Post dose 2

Post dose 3

9/25 (36.00%)
2/28 (7.14%)
0.0160

12/25 (48.00%)
6/28 (21.43%)
0.0492

17/30 (56.67%)
3/26 (11.54%)
0.0006

18/30 (60.00%)
2/26 (7.69%)
0.0001

Fishers exact test.

prequalication by WHO for global application. Given the limited

knowledge on correlates of protection for rotavirus vaccine, this
phase III clinical trial is designed to demonstrate that the vaccine
is efcacious against rotavirus gastroenteritis. In addition, through
close surveillance, the trial will greatly expand the safety database
available for the product.
This double blind randomized placebo controlled study will be
conducted in around 7500 infants at multiple sites in India. BRV-PV
or placebo will be administered in 1:1 ratio at 6, 10 and 14 weeks
of age along with Universal Immunization program (UIP) vaccines.
A close follow up will be maintained for rotavirus gastroenteritis
cases as well as safety issues till two years of age. Immunogenicity
of the vaccine will be assessed in a subset along with polio type 1,
2 and 3 antibodies.
Since UIP vaccines will be given concurrently with the three
doses of BRV-PV, a separate Phase III study will formally assess
the potential interference of the vaccine with routine UIP immunizations. In that study, the immunogenicity of three consecutively
manufactured lots will also be assessed to establish manufacturing
lot-to-lot consistency.
3. Future plans
Apart from the lyophilized presentation, SIIL is also working on
a fully liquid formulation; ready-to-use vaccine which contains the
reassortants of the same serotypes. Animal toxicity studies of this
formulation are anticipated to start in 2014.

4. Conclusions
After technology transfer from NIAID, SIIL successfully continued the further development of the BRV-PV. The results of the
pre-clinical and clinical studies of the formulation developed at SIIL
have shown that it is safe and immunogenic. The vaccine is now
poised to enter the pivotal study for licensure. Eventual commercial availability of the vaccine will be important for public health
programs in the developing world.
Funding
The pre-clinical and clinical studies were funded by Serum Institute of India Ltd., Pune.
Acknowledgements
We gratefully acknowledge the contribution of late Dr. A.Z.
Kapikian; The National Institute of Allergy and Infectious Diseases
(NIAID); USA, Dr. Carl Kirkwood of Murdoch Childrens Research
Institute, Australia; Dr. Gagandeep Kang and Dr. Sudhir Babji
of Christian Medical College, Vellore, Dr. Ashish Bavdekar; KEM
Hospital Research Centre, Pune, and Dr. Sanjay Lalwani; Bharati
Veedyapeeth Medical College, Pune.
Conict of interest: All study authors are employed by Serum
Institute of India Ltd., Pune.

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