Bovine Rotavirus Pentavalent Vaccine Development in India

Vaccine 32S (2014) A124–A128

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Vaccine

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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 a

t i c l e i n f o b s t r a c t

Article history: 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

Keywords: collaboration with the National Institute of Allergy and Infectious Diseases (NIAID), USA. The vaccine

Bovine rotavirus pentavalent rotavirus

underwent animal toxicity studies and Phase I and II studies in adults, toddlers and infants. It has been

vaccine (BRV-PV)

found safe and immunogenic and will undergo a large Phase III study to assess efﬁcacy against severe

Serum Institute of India Ltd.

rotavirus gastroenteritis.

Development

Clinical trials

(http://creativecommons.org/licenses/by-nc-nd/3.0/).

1. Introduction must be supported by an adequate supply of high-quality WHO-

prequaliﬁed vaccines by manufacturers in developing countries

Black et al. estimated annual global mortality in 2008 due to without relying on multi-national corporations.

diarrheal diseases in children 0–5 years of age was around 1.5 The epidemiology of rotavirus is a complex, dynamic phe-

million, based on single-cause disease models and analysis of nomenon. Globally, ﬁve genotypes (G1–G4, and G9) account for 88%

vital registration data, about 500,000 of which were attributed to of all strains [7]. Researchers have extensively studied the molec-

rotavirus infection. The world’s poorest countries of Asia and sub- ular epidemiology of rotaviruses in India [8]. The most common

Saharan Africa bear the maximum burden of these deaths [1]. Based G (VP7) serotypes found were G1 and G2, however, studies have

on a systematic review and meta-analysis of studies which assessed observed a high prevalence of G9 strains of up to 15% in various

rotavirus diarrhea, Tate et al. calculated 453,000 global deaths in Indian cities. In a recent study conducted by SII in collaboration

2008 (95% CI 420,000–494,000) in children younger than ﬁve years; with the National Institute of Cholera and Enteric Diseases (NICED)

22% of them (98,621 deaths) in India alone [2]. It is also estimated in a rural area of West Bengal, India, G9 P[4] (27%), G1 [P8] (18%)

that rotavirus causes 457,000–884,000 hospitalizations and over and G2 P[4] (14%) were the predominant genotypes in the study

two million outpatient visits every year in India [3]. population [9].

Although rotavirus vaccines are commercially available, they are Rotavirus candidate vaccine development has followed two

unaffordable in developing countries. Notwithstanding the recent views regarding the importance of serotype-speciﬁc protection.

recommendation by the World Health Organization (WHO) for the Many candidates are based on the theory that protection is not

inclusion of rotavirus vaccination in the national immunization solely dependent on neutralizing antibody. These candidates con-

schedules of all countries, the vaccine’s supply continues to be an tain single rotavirus strains and include the Rotarix vaccine. On

issue for the countries with greatest need [4]. The need is urgent the other hand, several candidate vaccines are based on the con-

because children in low-income countries are infected earlier in life cept that neutralizing antibody is the primary determinant of

and with limited access to health care, their illness is likely to be protection. These candidates, including RotaTeq, are composed

severe, even leading to death [5]. of multiple rotavirus strains representative of the major human

Widespread use of rotavirus vaccines is estimated to be able to rotavirus serotypes [10]. The SIIL candidate vaccine belongs to the

avert 2.4 million deaths by 2025, with annual reductions of up to latter group and includes ﬁve most prevalent serotypes [7].

225,000 child deaths [6]. However, realizing the vaccine’s potential

1.1. Bovine reassortant vaccines

∗ The most extensively evaluated approach for live attenu-

Corresponding author at: Serum Institute of India Ltd., 212/2 Hadapsar, Pune,

ated oral vaccines is based on the “Jennerian” concept, involving

India. Tel.: +91 20 26602384; fax: +91 20 26993945.

E-mail address: [email protected] (P.S. Kulkarni). immunization with animal rotaviruses considered to be naturally

http://dx.doi.org/10.1016/j.vaccine.2014.03.003

J.K. Zade et al. / Vaccine 32S (2014) A124–A128 A125

attenuated for humans [11]. In view of the inconsistency of pro- formulated using 9.6 g/l of citric acid and 25.6 g/l of sodium bicar-

tection from animal rotavirus-based vaccines, efforts began to bonate together with water for injection.

develop reassortant rotavirus strains that contained some genes The viruses are grown in Vero cells which are kidney epithelial

from the animal rotavirus parent and some genes from the human cells of African green monkey (Cercopithecus aethiops) and were

rotavirus parent, termed the “modiﬁed Jennerian” approach [12]. procured from American Type Culture Collection (ATCC), USA. The

VP7 was thought to be important for protection; therefore, human- Vero cell bank was prepared at SIIL and characterized to qualify

animal reassortant rotaviruses for use as vaccines included human for the vaccine production. Cell growth kinetics and virus growth

VP7 genes to provide protective immune responses. A pentava- kinetics were studied and the formulation with the lyophilization

lent human-bovine (WC3) reassortant live-attenuated, oral vaccine cycle was developed at SIIL. The pre-clinical toxicity and clinical lots

(RotaTeq) developed by Merck Research Co. is currently licensed were manufactured in a dedicated facility at SIIL in compliance with

[13]. current good manufacturing practices (cGMP). These lots showed

Another multivalent bovine-human reassortant vaccine was excellent lot-to-lot consistency and stability. The vaccine is stable

◦ ◦ ◦

independently developed by the National Institute of Allergy and for three years at 2–8 C, and 25 C, for two years at 37 C and for

◦

Infectious Diseases (NIAID). This bovine rotavirus tetravalent (BRV- six months at 40 C.

TV) vaccine incorporates four reassortant viruses with a VP7 gene The SII BRV-PV was initially formulated as a combination of the

of either a G1, G2, G3, or G4 human serotype and 10 genes from the six reassortants at equivalent titers. These reassortants represent

bovine rotavirus UK strain. NIAID conducted phase1 studies of the the most common G serotypes. The G9 component is of particular

individual vaccine components, as well as phase 1 and 2 studies interest to India as it has circulated in Indian infants for over two

of a quadrivalent version of the vaccine in the US and in Finland decades.

[14–16]. The live attenuated vaccine has a three dose regimen since it is

The initial studies in adults, children and infants with this known that, natural rotavirus infection confers protection against

tetravalent G1–G4 BRV formulation (BRV-TV) in the US, demon- subsequent infection and that this protection increases with each

strated that each of the components was able to infect the new infection and reduces the severity of the diarrhea [18]. Rotateq,

volunteers as determined by vaccine shedding in the stools and the another bovine reassortant vaccine is already licensed for a three

induction of immune responses [14]. The vaccine was safe; and had dose schedule.

no impact on the immune responses of routine childhood immu-

nizations. Vesikari et al. in Finland compared the same tetravalent

vaccine to the rhesus tetravalent vaccine (RRV-TV, later licensed 1.3. Preclinical toxicology studies

as RotaShield) [15]. Both vaccines were equally efﬁcacious, how-

ever, the BRV-TV was less reactogenic than the RRV-TV, which was SII conducted single- and repeated-dose toxicity studies of

associated with febrile reactions and diminished appetite. In the rotavirus vaccine in rodents (Wistar rats) and non-rodents (New

study, the vaccine induced immune responses in 97% of the infants Zealand white rabbits) by oral gavage administrations in an accred-

tested and showed 90% efﬁcacy against severe rotavirus gastroen- ited laboratory in India under strict good laboratory practices (GLP).

teritis (SRVGE) during two rotavirus seasons (CI: 35–99%), though These studies were conducted with a hexavalent vaccine which

the size of this study was limited. These ﬁndings clearly support included G1, G2, G3, G4, G8 and G9 reassortants. Single dose stud-

the immunogenicity, safety and potential for efﬁcacy of BRV-PV. ies included 60 rats and 18 rabbits in three groups while repeated

dose studies included 70 rats in four groups and 18 rabbits in three

1.2. Vaccine development at Serum Institute of India Ltd. groups. The vaccine formulation had virus titers in the range of

6.62 7.79

10 FFU to 10 FFU.

With the emergence of the G9 and G8 serotypes, the NIAID A dose of 2.5 ml of reconstituted vaccine, placebo or normal

added human-bovine (UK) reassortants with G8 and G9 speciﬁcities saline were administered on day one to animal groups. In repeated

to the tetravalent vaccine, thereby formulating a hexavalent vac- dose studies, additional doses were administered on day 15, 29

cine for use in developing countries [17]. The UK bovine rotavirus and 43. All the animals were observed for mortality, clinical signs,

G6[P5] strain was used to construct single gene substitution weight changes and food intake. We collected stool samples 72 h

reassortants in which the G gene derives from human rotavirus after each administration. Necropsy was carried out on day 8 and 57

serotypes G1, G2, G3, G4, G8 and G9, and all the other genes derived during the single dose and repeat dose toxicity studies, respectively.

from the UK bovine strain. The vaccine in single- and repeated-dose toxicity studies in

Non-exclusive licenses for the production of the human-bovine Wistar rats had no effects on their general health. There were no

(UK) vaccine were granted to the Chengdu Institute of Biologi- changes in body temperature, cumulative net body weight gains

cal Products (CDIBP) (China), Instituto Butantan (Brazil), Shantha and hematological, clinical chemistry and urinalysis parameters in

Biotech (India) and Serum Institute of India Ltd. (SIIL) (India). SIIL animals of either sex. Fecal samples were negative for the pres-

signed the agreement with NIAID in 2005. ence of rotavirus antigen in all the animals. No gross or microscopic

SIIL is one of the largest vaccine manufacturers in the world. histopathological changes were detected.

Headquartered at Pune, India, it has been manufacturing vac- The vaccine administered as single and repeated dose by the oral

cines since 1971. Since 1992, SIIL has supplied vaccines to UNICEF route in New Zealand white rabbits also showed no effects on gen-

and Pan-American Health Organization (PAHO) after receiving the eral health. There were no toxic signs and mortality; no effects on

mandatory WHO prequaliﬁcation for the quality of its vaccines. body temperature, body weight, cumulative net body weight gains

Currently, 19 of its vaccines are WHO prequaliﬁed and supplied and food intake. There were no changes on the hematological, clin-

to immunization programs of many developing countries. It is esti- ical chemistry and urinalysis parameters tested in animals of either

mated that SIIL is the largest supplier of DTwP-HB-Hib vaccine and sex. Fecal samples were negative for the presence of rotavirus anti-

measles vaccine in the world. gen in all the animals. No gross or microscopic histopathological

After transfer of these reassortants from NIAID, SIIL started changes were detected in either sex.

working on them in 2007. The vaccine was formulated as a All the animals were positive for rotavirus antibodies before

lyophilized product which was resuspended in antacid buffer administration of the vaccine and remained positive 43 days after

just before use to address the issue of potential inactivation vaccination. The IgA was determined by using enzyme-linked

of rotaviruses in the stomach. The antacid buffer diluent was immunosorbent assay (ELISA) as described previously [19].

A126 J.K. Zade et al. / Vaccine 32S (2014) A124–A128

Table 1 Table 2

5.2 5.6

Reactogenicity of 10 FFU/serotype BRV-PV vaccine in infants. Reactogenicity of 10 FFU/serotype BRV-PV vaccine in infants.

Solicited symptom BRV-PV Placebo Solicited symptom BRV-PV Placebo

Participants assessed 27 30 Participants assessed 30 30

At least one solicited symptom, n (%) 14 (51.85%) 21 (70.00%) At least one solicited symptoms, n (%) 18 (60.00%) 20 (66.67%)

Diarrhea, n (%) 1 (3.70%) 2 (6.67%) Diarrhea, n (%) 3 (10.00%) 2 (6.67%)

Vomiting, n (%) 11 (40.74%) 13 (43.33%) Vomiting, n (%) 8 (26.67%) 7 (23.33%)

Fever, n (%) 3 (11.11%) 8 (26.67%) Fever, n (%) 3 (10.00%) 5 (16.67%)

Decreased appetite, n (%) 5 (18.52%) 5 (16.67%) Decreased appetite, n (%) 6 (20.00%) 4 (13.33%)

Decreased activity, n (%) 4 (14.81%) 1 (3.33%) Decreased activity, n (%) 3 (10.00%) 2 (6.67%)

Irritability, n (%) 9 (33.33%) 12 (40.00%) Irritability, n (%) 9 (30.00%) 6 (20.00%)

Respiratory symptoms, n (%) 5 (18.52%) 9 (30.00%) Respiratory symptoms 11 (36.67%) 9 (30.00%)

Antipyretic use, n (%) 4 (14.81%) 7 (23.33%) Antipyretic use, n (%) 9 (30.00%) 5 (16.67%)

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

and well tolerated. A summary of the solicited vaccine reactogenic-

Thus, SII hexavalent BRV vaccine did not cause any toxicity when

ity is summarized in Table 2. Almost all the events were mild

administered as single and repeated dose by the oral route in Wis-

and transient. Two SAEs (urinary tract infections and septicemia)

tar rats and New Zealand white rabbits. The studies also proved that

unrelated to study vaccines were reported and both recovered

along with the antigens, the formulation which contains stabiliz-

uneventfully. We saw no effect on laboratory parameters.

ers and antacid is safe. These results opened prospects for human

Three doses of the vaccine were found immunogenic. The sero-

clinical studies on the vaccine.

conversion post dose 2 was 36% and 7.14%, in vaccine and placebo

arms respectively (p = 0.0160). The corresponding post dose 3 sero-

1.4. Clinical studies conversion 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

Considering rotavirus serotype distribution in India, a pen- 7.31 U/ml.

tavalent formulation which comprised of G1, G2, G3, G4 and G9 Following these satisfactory results, a randomized, double-

serotypes was used for clinical development (Fig. 1). Three clinical blind, placebo controlled Phase IIb study was conducted which

5.6

studies (Phase I, Phase IIa and Phase IIb) have been conducted on SII assessed the formulation of 10 FFU/serotype in 60 healthy

BRV-PV in India (Registration numbers CTRI/2009/091/000821 and infants. SII BRV-PV/placebo was administered in 1:1 ratio as three

CTRI/2010/091/003064). The study populations included adults, doses with at least four weeks interval.

toddlers and infants. This formulation of the vaccine was also found safe and well

All studies were approved by the Drug Controller General of tolerated. A summary of the solicited vaccine reactogenicity is

India (DCGI) and institutional ethics committees. They complied summarized in Table 2. Almost all the events were mild and tran-

with all the national regulatory and ethical standards as well as sient. No SAE was reported and there was no effect on laboratory

the ICH good clinical practices (GCP). An independent Data Safety parameters.

5.6

Monitoring Board (DSMB) monitored the safety and rights of the Three doses of the 10 FFU/serotype formulation induced a sig-

study subjects. The sera samples for rotavirus speciﬁc IgA antibod- niﬁcant immune response (Table 3). The seroconversion post dose

ies were tested using IgA ELISA at the Christian Medical College, 2 was 56.67% and 11.54%, in vaccine and placebo arms respectively

Vellore (India) [19] and stool samples for shedding were tested (p value <0.05). The corresponding post dose 3 ﬁgures were 60%

using rotavirus antigen detection kit (Generic Assays, Germany) and 7.69% (p < 0.05).

5.6

at Metropolis Laboratory, Pune. Seroconversion was deﬁned as a The seroconversion rates indicated that the 10 FFU/serotype

≥ ≥

change in IgA concentration from <20 U/ml to 20 U/ml, or 3 fold formulation is immunogenic in infants. These results are similar

≥

rise in IgA titers in case of baseline titers 20 U/ml. to those reported for the Rotarix (GSK) in an Indian study where

The Phase I study was a randomized, double-blind, placebo con- the seroconversion rates were 58.3% [95% CI: 48.7; 67.4] in the

trolled study to assess the safety of a single oral dose of SII BRV-PV Rotarix group and 6.3%; [95% CI: 2.5; 12.5] in the placebo group

sequentially in healthy adults, toddlers and infants. The study also [20]. Another Indian study on the 116E vaccine showed 89.7% sero-

assessed the immunogenicity and shedding of the vaccine. A single conversion in the vaccine arm and 28.1% in the placebo arm [21].

oral dose of the vaccine containing 10 FFU/serotype was investi- Another Indian study on Rotateq showed 83% 3-fold rise (serocon-

gated in 54 subjects (18 adults, 18 toddlers and 18 infants) who version) in serum IgA antibodies; however the study had no placebo

received vaccine or placebo in 2:1 ratio. arm [22].

BRV-PV was found safe and well tolerated in all three age groups. In developed countries, the seroresponses to rotavirus vaccines

There was no serious adverse event (SAE). The few adverse events are high. The examples include a Korean study on Rotarix (88.1%)

reported were mild and transient. Vaccine related events included [23], a Korean study on Rotateq (94.7%) [24], a Japanese study on

nausea, loss of appetite, diarrhea and vomiting (Table 1). Except Rotarix (85.3%) [25], an European study on Rotarix (85.5–89.2%)

for a few minor changes, the hematology, biochemistry and urine [26], and a Finnish study on Rotarix (83.7–90.5%) [27].

analysis results remained normal in all the groups. However, for reasons not completely understood, the serore-

No shedding was seen in stool samples. As expected, the single sponses are lower in developing countries. The examples include

dose of the vaccine did not show immune response in adults and an African study on Rotateq (73.8–82.5%) [28], a Brazil study on

toddlers. However, infants showed a small immune response (28%) Rotarix (54.7–74.4%) [29] and a Latin American study on Rotarix

5.6

which was encouraging. (61–65%) [30]. Our results on the 10 FFU/serotype formulations

This was followed by a randomized, double-blind, placebo con- are in line with these studies.

5.2

trolled Phase IIa study which assessed the formulation of 10

FFU/serotype in 60 healthy infants. SII BRV-PV/placebo was admin- 2. Planned Phase III studies

istered in 1:1 ratio as three doses with at least four weeks interval

5.6

between doses. The study assessed the safety, immunogenicity and A large Phase III clinical trial on the 10 FFU/serotype for-

shedding of the vaccine. mulation is now planned to achieve licensure in India as well as

J.K. Zade et al. / Vaccine 32S (2014) A124–A128 A127

Fig. 1. Human and bovine reassortant pentavalent vaccine with VP7 serotype G1, G2, G3, G4 and G9 speciﬁcity.

Modiﬁed from Ref. [14].

Table 3

5.2 5.6

Seroconversion with 10 FFU/serotype formulation (Phase IIa) and 10 FFU/serotype formulation (Phase IIb) of SII BRV-PV.

Study arm Phase IIa Phase IIb

Post dose 2 Post dose 3 Post dose 2 Post dose 3

SII BRV-PV 9/25 (36.00%) 12/25 (48.00%) 17/30 (56.67%) 18/30 (60.00%)

Placebo 2/28 (7.14%) 6/28 (21.43%) 3/26 (11.54%) 2/26 (7.69%)

p-Value 0.0160 0.0492 0.0006 0.0001

Fisher’s exact test.

prequaliﬁcation by WHO for global application. Given the limited 4. Conclusions

knowledge on correlates of protection for rotavirus vaccine, this

phase III clinical trial is designed to demonstrate that the vaccine After technology transfer from NIAID, SIIL successfully contin-

is efﬁcacious against rotavirus gastroenteritis. In addition, through ued the further development of the BRV-PV. The results of the

close surveillance, the trial will greatly expand the safety database pre-clinical and clinical studies of the formulation developed at SIIL

available for the product. have shown that it is safe and immunogenic. The vaccine is now

This double blind randomized placebo controlled study will be poised to enter the pivotal study for licensure. Eventual commer-

conducted in around 7500 infants at multiple sites in India. BRV-PV cial availability of the vaccine will be important for public health

or placebo will be administered in 1:1 ratio at 6, 10 and 14 weeks programs in the developing world.

of age along with Universal Immunization program (UIP) vaccines.

A close follow up will be maintained for rotavirus gastroenteritis

Funding

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,

The pre-clinical and clinical studies were funded by Serum Insti-

2 and 3 antibodies.

tute of India Ltd., Pune.

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 immu- Acknowledgements

nizations. In that study, the immunogenicity of three consecutively

manufactured lots will also be assessed to establish manufacturing We gratefully acknowledge the contribution of late Dr. A.Z.

lot-to-lot consistency. Kapikian; The National Institute of Allergy and Infectious Diseases

(NIAID); USA, Dr. Carl Kirkwood of Murdoch Children’s Research

3. Future plans Institute, Australia; Dr. Gagandeep Kang and Dr. Sudhir Babji

of Christian Medical College, Vellore, Dr. Ashish Bavdekar; KEM

Apart from the lyophilized presentation, SIIL is also working on Hospital Research Centre, Pune, and Dr. Sanjay Lalwani; Bharati

a fully liquid formulation; ready-to-use vaccine which contains the Veedyapeeth Medical College, Pune.

reassortants of the same serotypes. Animal toxicity studies of this Conﬂict of interest: All study authors are employed by Serum

formulation are anticipated to start in 2014. Institute of India Ltd., Pune.

A128 J.K. Zade et al. / Vaccine 32S (2014) A124–A128

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