HUMAN VACCINES & IMMUNOTHERAPEUTICS

2017, VOL. 13, NO. 9, 2032–2037

https://doi.org/10.1080/21645515.2017.1318236

RESEARCH PAPER

Safety and immunogenicity of Bio PoxTM , a live varicella vaccine (Oka strain) in Indian
children: A comparative multicentric, randomized phase II/III clinical trial
Anand Prakash Dubeya, Mohammad Moonis Akbar Faridib, Monjori Mitrac, Iqbal Rajinder Kaurd, Aashima Dabasa,
Jaydeep Choudhuryc, Mallar Mukherjeec, and Devendra Mishraa
a
Department of Pediatrics, Maulana Azad Medical College, New Delhi, India; bUniversity College of Medical Sciences, Delhi, India; cInstitute of Child
Health, Kolkata, India; dDepartment of Microbiology University College of Medical Sciences, Delhi, India

ABSTRACT ARTICLE HISTORY

Varicella or chickenpox is a highly contagious disease with a high secondary attack rate. Almost 30% of Received 4 January 2017
Indian adolescents lack protective antibodies against varicella, emphasizing the need of routine varicella Revised 30 March 2017
immunization. The Oka VZV is a well-established, safe and efficacious vaccine strain that is highly Accepted 7 April 2017
immunogenic and produces lifelong protective immunity. The present multicentric, open label, KEYWORDS
randomized, controlled Phase II/III study, compared the Bio PoxTM (indigenous investigational vaccine) chickenpox; Glycoprotein
with a licensed vaccine, VarivaxTM [a], for its safety and immunogenicity profile in 252 healthy subjects in Enzyme Linked Immunoassay
the age group of 1–12 y (cohort I: 6–12 years, II:1–6 years) in 3 tertiary medical institutions. Antibodies (Gp ELISA); immunogenicity;
were measured by VZV Glycoprotein Enzyme Linked Immunoassay (IgG ELISA) kit. Seroconversion seroconversion; safety;
percentage in children having pre-vaccination anti VZV IgG titer <10 mIU/mL (< 5 gp ELISA units/mL) Varicella
were 80% for Bio PoxTM and 77% for VarivaxTM (p D 0.692). The seroconversion rate in the group receiving
Bio PoxTM was non-inferior to the group that received VarivaxTM . There were mild local reactions for both
the vaccines; none of the patient had fever or required hospitalization or medication. The Bio PoxTM was
found to be safe and immunogenic in children against VZV infection.

Introduction
Varicella, commonly known as chickenpox, is a highly conta-
gious, acute and common disease of childhood that is prevalent
globally.1-3 Varicella is usually a self-limiting disease that affects
healthy individuals who are younger than 15 y of age.4 The dis-
ease spreads by airborne route and carries high morbidity and
mortality in infants and in individuals with impaired immu-
nity. The disease is associated with direct medical costs and
indirect costs due to work absenteeism, which result in a sub-
stantial economic burden on the community.5 A high suscepti-
bility to varicella infection has been reported across tropical
countries unlike temperate countries. The seroprevalence of
varicella antibodies among Indian children was reported as
29% in the age group of 1–5 years, 51.1% in 5–10 y and 71.7%
in 11–15 years.6
The Oka strain of VZV was developed by Takahashi et al.,
from vesicular fluid of a child patient by passaging in human
lung cells and guinea pig fibroblast cells and finally in WI-38
human diploid cells. After licensure in the USA in 1995, Advi-
sory Committee on Immunization Practice (ACIP), American
Academy of Paediatrics, recommended universal use of
varicella vaccination. The incidence of varicella and related
hospitalizations were reduced by approximately 90% in USA
after introduction of the vaccine.7,8 This decline in varicella
incidence was seen not only in the vaccinated children but also
in unvaccinated population, suggestive of herd effect. Similar
effect of varicella vaccine has been noticed in Australia, Canada
and European countries.9-11 At present, the vaccine is not
included in the National Immunization schedule of India.
The vaccine based on Oka strain manufactured by Biken,
Merck and GSK has been widely used globally and found to
possess similar safety and immunogenicity.12 A live attenu-
ated varicella vaccine VarivaxTM (manufactured by Chang-
chun Keygen Biological Products Ltd., China), is already
licensed and marketed in India. However, in the absence of
an indigenous varicella vaccine, this was the only available
substitute which faced occasional shortage for clinical use.
Bio-Med (P) Ltd developed the technology of manufacturing
varicella vaccine from Oka strain in India using MRC-5
human diploid cell culture with proprietary name Bio
PoxTM . The production and development of this vaccine in
India shall result in wider availability, better compliance
and lowering of cost. The present study was conducted to
evaluate and compare the immunogenicity profile of Bio
PoxTM (investigational vaccine) with the licensed vaccine
(VarivaxTM ) in the study population by estimating the per-
centage seroconversion in the recipients measured as anti-
VZV titres with the help of VZV glycoprotein IgG ELISA

CONTACT Mohammad Moonis Akbar Faridi mmafaridi@yahoo.co.in, drmmafaridi@gmail.com MD, DCH, MNAMS, FIAP, FNNF, Director Professor and Head,
University College of Medical Sciences, E-9 GTB Hospital Campus, Delhi-110095, India.
[a]
Please note that this article refers to the product named VARIVAX as manufactured by Changchun Keygen Biological Products Ltd., China and marketed in India by VHB
Life Sciences Limited, Mumbai, and not the product VARIVAXÒ owned by Merck Sharp & Dohme Corp., Rahway, New Jersey, USA. Merck Sharp & Dohme Corp. have
asked us to make clear that the product manufactured by Changchun Keygen Biological Products Ltd. is unrelated to and is not sponsored, endorsed or otherwise
authorised by Merck Sharp & Dohme Corp.
© 2017 Taylor & Francis
 HUMAN VACCINES & IMMUNOTHERAPEUTICS 2033

Figure 1. Flow of the study and subject disposition.

Kit. The secondary objective was to compare safety and tol-
erability of the 2 vaccines by monitoring the side effects up
to 42 § 7 d of the vaccination.
Results
A total number of 252 subjects were included in the study; 84
subjects at each study center who were randomized to receive
investigational vaccine or licensed vaccine (Fig. 1) Equal number
of children were recruited in cohort I (> 6–12 years) and cohort
II (1–6 years) at each center. There was a drop-out rate of 5.9%
(15/252). The weight and gender of the ‘vaccinees’ were compara-
ble in all the groups and cohorts. The mean age of the vaccinees
was also comparable between investigational vaccine and licensed
vaccine (cohort I-8.35 § 1.54yr, 8.39 § 1.66yr; cohort II- 3.40 §
1.40yr, 3.26 § 1.43yr), p>0.05 respectively. At the end of the
study, total post immunization blood samples were obtained in
116 (92.06%) and 121 (96.03%) children from cohort I and
cohort II, respectively, at all the 3 study centers.
Evaluation of immunogenicity
In cohort I, out of 116 paired serum samples, 114 samples were
analyzed as 2 serum samples were haemolysed. The pre-
immune anti-VZV titres were <10 mIU/mL in 47.36% (n D
54/114) and 79.33% (n D 96/121) children in cohort I and
cohort II, respectively, indicating their susceptibility to varicella.
The seroconversion rates were similar for both vaccines in
cohort II (Bio PoxTM : 82%, VarivaxTM : 83%) and cohort I
(Bio PoxTM : 77%, VarivaxTM : 68%) as shown in Table 1, and
the difference was not significant (p>0.05). The seroconversion
rate in the group receiving Bio PoxTM was non-inferior to the
group that received VarivaxTM . In both the study arms, there
was a significant increase (p<0.001) in the pre immune anti
varicella titres from <10mIU/mL to 20.1 mIU/mL (IQR 13.9–
26.0) and 21.1mIU/mL (IQR 10–35.9) after immunization with
Bio PoxTM and VarivaxTM respectivelyin the children of 2 age
cohorts.
The increase in the post-immune median values was similar
between both vaccine arms in both cohorts; cohort I (p D
0.713), and cohort II (p D 0.360) and combined cohort I and II
(p D 0.275). Therefore, the immunogenicity of Bio PoxTM and
VarivaxTM was comparable (Table 1).
Evaluation of safety
Of the 252 subjects recruited, 237 completed the full study pro-
tocol for safety. Fifteen subjects did not come for evaluation on
day 42 § 7 post vaccination. The observations are summarized
in Table 2. The reactions were categorized by adverse reaction
scale on 3 different safety levels in both the groups, self-
reported by the vaccines (Table 2). Skin reactions (papules/
vesicles) at >5 d post vaccination was noted in one subject vac-
cinated with VarivaxTM . Papules or vesicles were systemic and

Table 1. Seroconversion: Comparative analysis and non inferiority analysis for subjects with pre-immune titer <10 mIU/mL cohort I and II receiving Bio PoxTM and
VarivaxTM at all study centers.
P value (between the groups for P value (between the groups for
Group Seroconversion N (%) Post-immune Median (IQR) seroconversion) post-immune titres)

Cohort I
Bio PoxTM (n D 26) 20 (77) 15.7 (10–20.7) 0.528 0.713
VarivaxTM (n D 28) 19 (68) 19 (5–37.7)
Cohort II
Bio PoxTM (n D 49) 40 (82) 21.6 (17.7–26.1) 0.897 0.360
VarivaxTM (n D 47) 39 (83) 21.9 (18.5–33.0)
Combined
Bio PoxTM (n D 75) 60 (80) 20.1 (13.9–26.0) 0.692 0.275
VarivaxTM (n D 75) 58 (77) 21.1 (10–35.9)

IQR: Inter quartile range, p value for cohort I and cohort II (within the groups, pre-immune median and post-immune median): <0.001; p value (between the groups):

represents number of children having pre-immune anti VZV IgG titers< 10mIU/ml
2034 A. P. DUBEY ET AL.

Table 2. Adverse events (local, systemic and skin reactions) and post-immunization safety profile recorded for combined cohort I (> 6 to 12 years) and cohort II (1 to
6 years) at different time intervals of post vaccination for Bio PoxTM and VarivaxTM at all study centers.
Adverse Events Bio PoxTM , N VarivaxTM , N Status Bio PoxTM, N/% VarivaxTM, N/%

30 min
Pain 40 33 Excellent 99/(78.6) 105/(83.3)
Erythema 6 8 Good 24/(19.0) 21/(16.7)
Inflammation /induration (swelling) 15 14 Fair/ Bad 3/(2.4) 0
60 min
Pain 19 7 Excellent 110/(87.3) 117/(92.9)
Erythema 3 4 Good 16/(12.7) 9/(7.1)
Inflammation /induration (swelling) 16 10 Fair/ Bad 0 0
90 min
Pain 4 1 Excellent 120/(95.2) 123/(97.6)
Erythema 2 1 Good 6/(4.8) 3/(2.4)
Inflammation /induration (swelling) 14 6 Fair/ Bad 0 0
120 min
Pain 0 0 Excellent 124/(98.4) 126/(100)
Erythema 0 1 Good 2/(1.6) 0
Inflammation /induration (swelling) 11 5 Fair/ Bad 0 0
>5–42 days
Papules (systemic) 0 1 Excellent 126/(100) 125/(99.2)
Good 0 0
Fair/ Bad 0 0

the number was about 40–50. The local and systemic side
effects of both the varicella vaccines were mild and self-limiting
without any sequel. None of the subjects had any systemic reac-
tion such as fever and febrile reactions or required
hospitalization.
Evaluating the lot to lot consistency of Bio PoxTM
There was no statistically significant difference (p>0.05) in the
levels of the post immune anti varicella titres between the par-
ticipating centers, in which 3 different batch of BioPoxTM was
used. This finding was indicative of the lot to lot consistency of
BioPoxTM .
Discussion
Seroconversion in tropical countries is reported at a later age
than in temperate countries. As a consequence, the younger age
group (12 months to 12 years) is more susceptible to infection
which is associated with high morbidity and mortality.13 Immu-
nization during this period of life provides maximum protection
against VZV.14 In view of this information, study subjects were
enrolled between 12 months to 12 y to compare the safety and
immunogenicity between an indigenous investigational vaccine
Bio PoxTM and VarivaxTM (licensed vaccine). Bio PoxTM was
found non-inferior to VarivaxTM in the present trial.
A large number of clinical trials globally have proved good
immunogenicity, safety and tolerability of Oka strain varicella
vaccines in susceptible children (including immune compro-
mised) and adults.15,16 Studies conducted in the United States
using VarivaxTM (Merck), reported seroconversion rate up to
96% among children from 12 months to 17 y of age with resid-
ual seroprotection in 99% subjects at end of first year.17 The
vaccine efficacy with single dose has been reported between
70–81% for all forms of varicella and 98–100% against severe
varicella.18,19 However, despite a reasonable protection against
varicella with a single dose, 2 doses of varicella vaccine are
recommended to interrupt transmission, prevent outbreaks in
settings with high contact rates and prevent disease in the
adults.20
Overall, vaccines using Oka strain have been found to be
extremely safe in children and adults.2 In the present study, a
low percentage of unsolicited AEs were observed during 6 weeks
of post vaccination period. The incidence of AEs within 2 hours
of administration of either vaccine was low, of very mild nature
and was comparable between 2 study arms. Varicella like rashes
were observed in one child vaccinated with VarivaxTM , similar
to earlier reports in the literature.2
The method of determination of specific immune response
to varicella vaccine is important. In the present study serologi-
cal estimation was performed using a highly reliable gp ELISA-
kit VaccZymeTM .21,22 A 6 week postimmunization antibody
titer of at least 5 gp ELISA units/mL has been proposed as a
reasonable correlate of sero-protection.23,24 The proportion of
children who achieved postimmunization titres of  5 gp
ELISA units after single dose of varicella has been reported to
vary from 76–90%.17,21 Li et al. have reported the efficacy of a
single dose varicella vaccine at 6 weeks postimmunization as
95.5% among children with an antibody titres of  5 gp ELISA
unit/mL, compared to 83.5% among children with an antibody
titres of < 5 gp ELISA units/mL.23 In the present study the
investigational vaccine achieved seroconversion rate of 77%
and 82% in the cohort I and cohort II, respectively, similar to
comparator vaccine. In a recent study from India, Mitra et al.
reported seroconversion in 85% children aged 12 months to
12 years, 6 weeks after administering varicella (Oka-RIT strain)
vaccine. The incidence and severity of AEs were also similar to
our observations.21
In our study, a small proportion of younger children (20.7%,
n D 25/121) were found to have pre immune gp ELISA titres of
 10 mIU/mL as compared with older children (52.6%, n D
60/114). Lokeshwar et al. reported varicella sero-positivity rate
of > 70% [95% CI; 50.9–91.3] between the ages of 11–15 years
in the Indian children, which increased to nearly 90% (95% CI:
71.1–88.7) at the age of 30 years.6 Bartoloni et al. reported sero-

positivity rate of 21.2% in 1–4 year, 56.9% in 5–9 years and
83.7% in 10–14 years old children.25 Similar observation has
been made by other authors.26,27
The trial had certain limitations like (a) statistical analysis of
postimmune titres were not performed in those children who
were seropositive at the time of enrolment (b) side effects were
recorded based on patient self reporting after first day and (c)
the sample size based on the anticipated seroconversion rate
seemed insufficient. However, minimum loss of vaccinees to
follow up, and estimation of anti VZV antibodies by standard
ELISA kit calibrated against international standard for Varicella
Zoster immunoglobulin (1987) code W1044, are the strengths
of the study.
Conclusion
Bio PoxTM , a live attenuated Oka strain varicella vaccine, is
safe, immunogenic and is well tolerated by children aged
1–12years.
Materials and methods
This was an open label, controlled and randomized trial
(phase II/III) conducted at 3 centers across India (Maulana
Azad Medical College and Lok Nayak Hospital, New Delhi
(MAMC), University College of Medical Sciences and Guru
Teg Bahadur Hospital, Delhi (UCMS) and Institute of Child
Health, Kolkata (ICH)). The subjects were enrolled from
March to June 2015 at all 3 centers. The study was per-
formed after approval from the Drug Controller General of
India (DCGI) (CT-01/2014 dated 21/02/2014) and registra-
tion with the Clinical Trial Registry, India (CTRI/2014/03/
004445 dated 05/03/2014). The ethical committee permis-
sion was obtained at all the study centers.
Inclusion/exclusion criteria
Healthy Indian children between the ages of 1–12 years who
were siblings of subjects attending out-patient department were
screened. They were enrolled after parent(s)/guardian(s) con-
sented to give written and audio-visual informed consent and
would comply with all the study related procedures. Subjects
with a previous history of chicken pox disease or varicella
immunization, history of adverse or allergic reactions during
previous vaccinations, history of immunodeficiency or any
auto-immune disease, history of intake of steroids, antimicro-
bials or immunosuppressive drugs and those having any signs
of acute infection were excluded. Subjects participating in any
other study at present or during past 3 months were also not
included in the study.
Vaccine
Bio PoxTM , varicella live vaccine, is a lyophilized preparation of
attenuated ‘Oka’ strain of VZV. The vaccine contains  2000
PFU of attenuated ‘Oka’ strain varicella virus propagated in
MRC-5 human diploid cells. Bio PoxTM was found to be safe in
Phase I, open, unicentric clinical trial (CTRI/2012/11/003156
HUMAN VACCINES & IMMUNOTHERAPEUTICS 2035
dated 29/11/2012) in adult subjects.28 Three consecutive
batches of Bio PoxTM were used in the clinical trial. Each center
was randomly assigned one batch of Bio PoxTM . These batches
were found to be of standard quality at Central Drugs Labora-
tory, Kasauli, Himachal Pradesh, India.
Vaccination and patient safety
Randomization of the subjects into 2 groups was done by com-
puter generated random numbers. Allocation concealment was
performed by a secret code number to the subject given by a
third person who was not associated with the study. The
appearance of the investigational and comparator vaccines
were different, double blinding was not feasible. However, labo-
ratory personnel who measured the VZV antibodies in the
serum samples were double blinded.
Physical examination and medical history was recorded for
every subject in the case report forms (CRFs) at enrolment.
Pre-immunization blood sample was collected on day ‘0’ and
the child was immunized with the reconstituted vaccine using a
dose of 0.5 mL subcutaneously in the left upper arm. Post-
immunization blood sample was collected on day 42 § 7. The
recruitment and vaccination of the children was done in a
sequential manner; first in cohort I (age >6 to 12 years) fol-
lowed by cohort II (age 1 to 6 years). The younger group
(cohort II) was recruited after the older group (cohort I) had
completed the study and safety audit was reviewed before the
vaccine was administered to cohort II.
The subjects were observed for the development of any local
or systemic adverse events (AEs; pain, erythema, inflamma-
tion/induration (swelling), fever, febrile reactions, papules) and
skin vesicles. The observations were noted for 30, 60, 90 and
120 minutes after vaccination. Subject diaries were maintained
to record any adverse event following immunization (AEFI)
and any treatment if taken. Papules and vesicular eruptions on
the skin were monitored from 5th till 14 days post vaccination.
Telephonic calls were made to all participants after 2 weeks of
immunization for active surveillance of any side effects. The PI
and team scrutinized the subject diaries after completion of
observation period of 42 § 7 days post vaccination. The safety
levels were assessed as excellent [local reaction (redness, indu-
ration)  5 mm in diameter and axillary temperature  38.0 C
lasting less than 72 hrs], good (local reaction of > 5–20 mm in
diameter and axillary temperature of 38.1–39 C lasting 
4 days), fair (local reaction >20 mm in diameter and axillary
temperature >38.1–39 C for >5 days) and bad (local reaction
>20 mm in diameter and axillary temperature >39 C for
>5 days, papule formation  5 numbers, vesicle formation  5
numbers in >5 days post vaccination.
Evaluation of immunogenicity
Blood samples were drawn at each center, serum was separated,
coded, transported and stored at ¡20 C or below in the
Department of Microbiology, U.C.M.S. and G.T.B. Hospital,
Delhi. Pre immune and post immune sera were tested for anti-
VZV antibody titres. IgG antibodies against VZV in coded
serum samples were quantified using VZV glycoprotein IgG
2036 A. P. DUBEY ET AL.
low level enzyme immunoassay kit (VaccZymeTM ).22,29,30 This
kit has been used previously for vaccine immunogenicity and
safety in clinical trial CTRI/2014/08/004858. The assay was per-
formed by the standard procedure of enzyme immunoassay (as
detailed by the manufacturer of ELISA kit; The Binding Site
Group Birmingham, UK). It was calibrated against the first
international standard for Varicella Zoster immunoglobulin
(1987) code W1044, with a stated target value of 50 mIU/mL,
supplied by the National Institute for Biological Standards and
Control (NIBSC: www.nibsc.ac.uk).
The ELISA kit was having a measuring range of 10 mIU/
mL to 810 mIU/mL. For the purpose of statistical analysis,
immune titres <10 mIU/mL were considered as 5 mIU/mL
and values >810 mIU/mL were taken as 810 mIU/mL.
Since subjects with  10 mIU/mL titres were considered as
already immune due to natural exposure, the data of sub-
jects with pre immune titer <10 mIU/mL were statistically
analyzed. A titer of 5 gp ELISA units/mL (equivalent
to10 mIU/mL, by the International reference standard) at
6 weeks after immunization is associated with a high degree
of protection against breakthrough infection during 7 years
of follow up.23 Hence 10 mIU/mL anti-VZV IgG titer was
taken as positive seroconversion in this study. The vaccine
codes were decoded and matched against the coded serum
samples only after the results of the antibody titres were
communicated to all 3 clinical centers.
Statistical analysis
As per the “Drug & Cosmetics Rules, 1945” for a drug which is
already marketed in other countries, the minimum number of
subjects for Phase III clinical trial should be atleast100 distrib-
uted over 3–4 centers primarily to confirm the efficacy and
safety of the drug. Considering the same, 252 subjects were
enrolled. Anticipated seroconversion rate in the candidate vac-
cine was taken as 90% or more, the number of subjects per
group required to detect a change in seroconversion rates of at
least 9%, with an alfa-error 5% and 80% power, was 121.
Therefore, based on non-inferiority testing, 84 subjects (42
subjects for Bio PoxTM vaccine and 42 subjects for VarivaxTM
vaccine; 21 subjects each in cohort I and cohort II) were
recruited at each of the 3 study centers.
Age and weight of the subjects were summarized as
mean § SD. Student’s t-test was used to compare age and
weight distribution of subjects between 2 arms of the study.
For immunogenicity profile, pre and post immune antibody
titer values for each of the 2 study arms were summarized
as median and inter quartile range (IQR). Comparison of
immune titres between 2 study arms was done using Wil-
coxon rank sum test. Categorical variable was summarized
by frequency (%) and Chi-square test/Fisher’s exact test was
used. Positive seroconversion for non-inferiority of Bio
PoxTM as compared with VarivaxTM was done by comput-
ing effect size (test group minus reference group) and its
95% confidence interval (CI). To evaluate consistency of
Bio PoxTM between the 3 centers, Kruskal Wallis test was
used to compare the post immune titres. Stata 10.0 statisti-
cal software was used for statistical analysis. A p value
<0.05 was considered as statistically significant.
Clinical trials registry
CTRI/2014/03/004445 dated 05/03/2014
Disclosure of potential conflicts of interest
The authors report no conflict of interest.
Acknowledgment
The authors acknowledge Knowledge Isotopes Pvt. Ltd. (www.knowledgei
sotopes.com) for their medical writing support.
Funding
The work was supported by Bio-Med (P) Ltd, India under grant number
BM/CT/VAR/2014.
Authorship
APD, MMAF, MM (Mitra) and IRK conceptualized the study. APD,
MMAF, MM (Mitra), IRK, AD, JC, MM and DM contributed in designing
the study, acquisition and analysis of data. All authors participated in
drafting the article and approved the final submission.
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