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Indian Pediatr 2016;53: S65-S69 |
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Introduction of
Inactivated Poliovirus Vaccine in National Immunization Program
and Polio Endgame Strategy
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Vipin M Vashishtha, Jaydeep Choudhary, Sangeeta Yadav, Jeeson C Unni,
Pramod Jog, Sachidanand S Kamath, Anupam Sachdeva, Sanjay Srirampur,
Baldev Prajapati and Bakul J Parekh, for Indian Academy of Pediatrics
(IAP) Advisory Committee on Vaccines and Immunization Practices (ACVIP)
From the Indian Academy of Pediatrics (IAP) Advisory
Committee on Vaccines and Immunization Practices (ACVIP),
Mumbai, India.
Correspondence to: Dr Vipin M Vashishtha, Convener,
IAP-ACVIP.
Email: [email protected]
Received: April 12, 2016;
Initial review: April 21, 2016;
Accepted: April 23, 2016.
Published online: April 23, 2016. PII:
S097475591600001
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The World Health Organization declared India – among other 10 countries
in South East Region – as ‘polio-free’ in 2014. Since then, the
Government of India (GoI) has scaled up its initiatives against polio
endgame which targets virus eradication and sequential withdrawal of
type 2 virus from oral polio vaccine (OPV). However, prior to choosing
the switch from trivalent OPV (t-OPV) to bivalent OPV (b-OPV), it was
suggested to include inactivated poliovirus vaccine (IPV) in the
national immunization schedule to protect vaccine naïve population
against type 2 poliovirus. The GoI declared introduction of single dose
of intramuscular IPV at 14 weeks since October 2015. In addition,
anticipating the scarcity of IPV at present in India, GoI also
recommended two intradermal doses of IPV in few states since April 2016.
This review discusses the programmatic implications of these strategies
along with recommendations by the Advisory Committee on Vaccines and
Immunization Practices of Indian Academy of Pediatrics (IAP-ACVIP) on
polio endgame strategy.
Keywords: Eradication, Global polio eradication
initiative, oral poliovirus vaccine, Poliomyelitis, Prevention.
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In January 2013, the Global Polio Eradication
Initiative (GPEI) launched the Polio Eradication and Endgame Strategic
Plan 2013-2018, which was developed with an approach to tackle both wild
and vaccine virus eradication in parallel rather than sequential manner
[1]. In the November 2013 meeting, the Strategic Advisory Group of
Experts (SAGE) on immunization recommended a global, coordinated
withdrawal of the type 2 component of trivalent oral polio vaccine (tOPV)
from immunization programmes by April 2016. For countries which use only
tOPV in their routine infant immunization programmes, this will require
switching from tOPV to bOPV (containing only types 1 and 3) for that
purpose [2]. Prior to this switch, SAGE recommends that all countries
introduce at least one dose of inactivated poliovirus vaccine (IPV) into
their infant immunization schedules as a risk mitigation measure by
providing immunity in case a type 2 poliovirus re-emerges or is
reintroduced [2]. Initially, the plan stresses the need to introduce IPV
at least 6 months in advance to the proposed switch date in order to
provide adequate time to enhance population immunity against type 2 [1].
SAGE recommends that one dose of IPV should be administered at or after
14 weeks of age through routine immunization (RI), in addition to the
3-4 doses of OPV. The group also offers flexibility to countries to
consider alternative schedules (e.g. earlier IPV administration)
based on local conditions; for example, documented risk of
vaccine-associated paralytic poliomyelitis (VAPP) prior to 4 months of
age [2].
Three main risks are identified following type 2
poliovirus removal. These include immediate time-limited risk of
circulating vaccine-derived poliovirus type 2 (cVDPV2) emergence;
medium- and long-term risks of type 2 poliovirus re-introduction from a
vaccine manufacturing site, research facility, diagnostic laboratory or
a bioterrorism event; and spread of virus from rare immune-deficient
individuals who are chronically infected with OPV2 [3]. All these risks
have the potential to cause substantial polio outbreaks or even
re-establishment of polio virus transmission in polio-free regions.
Government of India Initiatives
Following SAGE recommendations and GPEI directives,
the Government of India (GoI) has taken following decisions regarding
polio immunization during implementation of endgame strategies in India:
• Introduction of at least single dose of
intramuscular IPV (IM-IPV) administration at 14 weeks or first
contact afterwards in the RI along with 3rd dose of DTP in 6 states
viz Bihar, Uttar Pradesh, Madhya Pradesh, Gujarat, Punjab and
Assam [4];
• Nationally coordinated switch from tOPV to bOPV
all over the country on 25th April 2016 associated with cessation of
use, withdrawal, destruction and validation of all available tOPV
stocks from all over the country [5].
• Introduction of fractional dose (0.1 mL)
intradermal IPV (ID-fIPV) at 6 and 14 weeks in Orissa, Andhra
Pradesh, Telangana, Tamil Nadu, Kerala, Karnataka, Maharashtra and
Puducherry from April, 2016 [6]. This change in approach from
single-dose intramuscular IPV to fractional-dose intradermal IPV is
mainly due to scarcity of IPV.
Perspectives of Advisory Committee of Vaccines and Immunization
Practices (ACVIP) of Indian Academy of Paediatrics (IAP)
Role of IPV in raising population immunity against
type 2 poliovirus before the ‘switch’
The GPEI has recommended introduction of IPV in RI
well-before (i.e. six months prior) to the proposed ‘switch’ in
order to raise population immunity against type 2 [1]. The committee has
reviewed the practical aspects of this decision and concludes that the
impact of IPV would not be significant in raising population immunity
against type 2 virus before the ‘switch’. There are many states that
have not yet introduced IPV in their immunization schedules. On the
other hand, there is no data regarding the coverage of single dose of
IPV from the Indian states that have already introduced the vaccine. The
‘population immunity’ is a product of IPV immunogenicity and coverage.
Hence, the immunity provided by tOPV, through RI and supplementary
immunization activities (SIAs) would ultimately determine the population
immunity against type 2 poliovirus prior to proposed global switch to
bOPV from tOPV. The committee believes that a high performance round
with tOPV would have benefitted more than IPV introduction to raise
population immunity against type 2 before the switch. In recent trials,
tOPV is found to be more immunogenic than IPV against type 2 poliovirus
[7].
Single dose of intramuscular IPV at 14 weeks: Will it
be effective?
The ACVIP has also reviewed the decision to
administer a single dose of IM-IPV at 14 weeks. It believes that the
combined schedule of bOPV and IPV shall provide adequate protection
against type 1 and 3 polioviruses; however, it is the protection against
type 2 polioviruses, especially for the children born post-switch that
should be the major concern. A single dose of IPV at 14 weeks may not
provide adequate seroconversion, especially against type 2 in the
vaccinees. The committee reiterates its earlier recommendation that at
least two doses of IPV – given at or after 8 weeks of age with 8 week
interval – are mandatory to provide adequate seroprotection to all the
three serotypes of poliovirus [8]. A recent systematic review conducted
on immunogenicity and effectiveness of 1 or 2 doses of IPV vaccine has
also reaffirmed ACVIP’s above recommendations. The review concludes that
routine immunization with two full or fractional doses of IPV given
after 10 weeks of age is likely to protect >80% of recipients against
all types of polioviruses [9]. According to this review, one and two
full doses of intramuscular IPV seroconverted 41% and 80% subjects,
respectively, against serotype 2 [9]. The GPEI’s decision of introducing
a single dose of IPV is based on a Cuban study [10] in which 63% of
subjects seroconverted to a single dose when given at 4 months of age
and among those who did not seroconvert (37%), 98% had a priming
response to a subsequent dose of IPV [10]. However, there are certain
issues that deserve attention. First, there is no incontrovertible proof
of reasonably good seroconversion of single dose of IPV at 14 weeks. In
the Cuban trial, the first dose of IPV was given at 4 months, not at 14
weeks. It is not yet clear whether immunological priming after a single
dose of IPV is protective against paralytic disease. Another risk would
be leaving children ‘unprotected’ against type 2 for first 3-4 months of
life. Further, the coverage attained with 14-week IPV dose would be
considerably less than at 6 weeks, considering the current ‘drop-out’
rates of DTP 3. A recent study from Bangladesh [7] revealed promising
degree of priming with an early (6 week) dose of IPV. The cumulative
effect of one dose given at 6 weeks (seroconversion and priming) was
seen in 90.2% of subjects [7]. The committee opines that decisions
having far reaching impact on global health should have broader evidence
base; solely relying on few studies may prove perilous.
Intradermal fractional doses of IPV at 6 and 14
weeks: IAP ACVIP’s viewpoint
The ACVIP has not yet approved the use of intradermal
fractional-dose IPV (ID-fIPV) for office-practice. However, in wake of
recent developments, the committee has reviewed all the available recent
studies on immunogenicity and priming of ID-fIPV [7,10-14] (Table
I). Most of these studies have reported lower immunogenicity of
a one-fifth (i.e. 0.1 mL) ID-fIPV dose compared with full dose (i.e.
0.5 mL) IM-IPV. Also, the geometric mean titers (GMTs) of
poliovirus-specific serum neutralizing antibodies were found
significantly lower than full dose IM-IPV [7,10-14]. Seroconversion
appears to be dependent on the age at administration of the first dose
and the interval between the doses. However, despite limited
seroconversion with first dose, a considerable priming responses were
observed even after one dose of ID-fIPV given at different ages [7,10].
In all of these studies, barring one [11], different types of
needle-free devices (jet injectors or micro-needle based devices) were
utilized to deliver ID dose of IPV. In the Indian study conducted in
Vellore [11], needle and syringes were used to deliver ID-fIPV. In this
study, the seroconversion against type 2 poliovirus after 4 weeks of 2nd
dose at 14 weeks was 70% [11].
TABLE I Seroconversion After Two Intradermal Fractional (1/5th) Dose of Inactivated Poliovirus Vaccine (ID-fIPV)
Reference |
Place |
Schedule |
Age at which |
Mode of delivery |
Number of |
SC by serotype*(%) |
SC by serotype* (%) |
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|
(age at doses) |
SC measured |
(of ID-fIPV) |
participants |
(After 1st dose) |
(After 2nd dose) |
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|
|
|
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|
P1 |
P2 |
P3 |
P1 |
P2 |
P3 |
Nirmal, et al. 1998 [11] |
India |
6, 14 wks |
18 wk |
Needle & syringe |
30 |
- |
- |
- |
90 |
70 |
97 |
Resik, et al. 2010 [12] Cuba |
6, 10 wks |
10 and 14 wk |
Biojector 2000 |
187 |
5 |
19 |
7 |
27 |
55 |
43 |
|
Mohammed, et al. 2010 [13] |
Oman |
2 mo, 4 mo |
4 and 6 mo |
Biojector 2000 |
186 |
10 |
17 |
|
|
|
|
|
9 |
70 |
72 |
72 |
|
|
|
|
|
|
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Estívariz, et al.2012 [14]** |
India |
6-9 mo |
4 wks later |
PharmaJet |
Variable# |
100# |
59 |
36 |
- |
- |
- |
Resik, et al. 2013 [10] |
Cuba |
4 mo, 8 mo |
8 and 9 mo |
Biojector 2000 |
157 |
17 |
47 |
15 |
94 |
98 |
93 |
Anand, et al. 2015 [7] |
Bangladesh |
6, 14 wks |
14 and 18 wk |
MicronJet 600 |
155 |
13 |
19 |
14 |
88 |
81 |
89 |
SC: Seroconversion; ID-fIPV: Intradermal
fractional dose IPV; *Definition of seroconversion: 4-fold
increase in serum neutralising antibodies over expected titre
based on 28-30 day half-life of maternal antibodies, or a change
from undetectable to detectable antibodies; **In this study
conducted in Moradabad, India, the enrolled subjects had already
received multiple doses of OPV; #A single dose of fIPV was given
to 6-9 mo old children. The above figure shows seroconversion of
seronegative children. In type 1 group, only 1 child was
seronegative; in type 2 and type 3 groups, 41 and 78 children
were seronegative, respectively. In children who were type-1
seropositive, an increase of more than four times in antibody
titre was detected 56% (9/16) subjects 28 days after they were
given intradermal IPV.
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The recent recommendation of GPEI/GoI to use
fractional dose IPV by ID route is based on the trial done in Bangladesh
[7]. In this study, ID-fIPV failed the non-inferiority test (i.e.
with a non-inferiority margin of 10% in seroconversion) when compared
with full dose IM-IPV for all serotypes for seroconversion and priming
observed with 1 or 2 doses. The seroconversion at 18 weeks following two
doses of fIPV at 6 and 14 weeks was 80.9% whereas the corresponding rate
for IM-IPV was 91% [7]. Further, the GoI intends to use standard BCG
needle and syringe for intradermal administration of ID-fIPV whereas in
the Bangladesh study, a microneedle based device (MicronJet 600) was
used [7]. It would have been more appropriate to consider Vellore study
[11] while recommending two-dose ID-fIPV schedule for eight states as in
this study, needle and syringes instead of needle-free devices were used
as GoI is now planning to utilize in field.
The Current Scenario and the New Objectives of
IAP-ACVIP Recommendations
With the introduction of single dose of intramuscular
IPV in RI of six Indian states from November 2015, and GoI’s proposed
introduction of two doses of ID-fIPV in rest of the country from April
2016, there is a lot of confusion amongst pediatricians/IAP members
regarding the exact IPV schedule for primary immunization. The scarcity
of IPV, particularly in private market, has further aggravated the
confusion. The IAP-ACVIP is recommending three doses of IPV, given
intramuscularly at 6, 10, and 14 weeks or two doses at 8 and 16 weeks of
age for primary immunization in its schedule [8].
The main objective of GoI’s initiatives (described
above) is to enhance population immunity against type 2 poliovirus just
prior to proposed switch from t-OPV to b-OPV in April 2016 so that the
risks associated with the complete removal of type 2 vaccine virus can
be mitigated. The decision to employ only a single dose of IPV and two
doses of intradermal IPV is only an interim arrangement owing mainly to
the limited supply and availability of IPV. On the other hand, the main
aim of existing IAP-ACVIP guidelines on polio immunization [8] is to
provide almost 100% protection against VAPP along with the best possible
humoral and mucosal protection against polioviruses to an individual
child in office practice setting. Considering the recent initiatives
taken by the GoI as described above, the ACVIP will have to add another
objective, i.e. to provide protection against type 2 poliovirus
to naive children born post-switch. IPV would be the only source of
providing immunity against type 2 poliovirus to children after April
2016. Therefore, the focus would be protection against VAPP along with
provision of protection against type 2 poliovirus by maximizing type 2
population immunity. Since the threat of cVDPV type 2 emergence would be
greatest, at least for one year following tOPV to bOPV switch, the
latter objective would need to override the former for the time being.
Recommendations
In context to the GoI’s initiatives regarding polio
endgame strategy and the anticipated situation of shortage of
IPV, there is an urgent need of providing immunity against type 2
poliovirus. It is thus imperative to provisionally follow the suggested
schedule of two ID-fIPV doses given at 6 and 14 weeks of age against
type 2 poliovirus. However, review of literature shows that intradermal
mode of administration of IPV results in significantly lower
seroconversion, priming and GMTs against all types of poliovirus than
the full dose intramuscular IPV. There is a felt need to undertake more
studies particularly with ID-fIPV for evaluating seroprotection,
schedule and delivery through conventional BCG needles and syringes.
Therefore, full dose of IM-IPV needs to be offered to children at least
after 8 weeks interval of the second dose of ID-fIPVdose for enhanced
and improved seroconversion/seroprotection. Similarly, for the
recipients of single dose of IM-IPV at 14 weeks, another dose of IM-IPV
should be offered at least 8 weeks after the first dose.
Funding: None; Competing interests:
None stated.
ANNEXURE
IAP Advisory Committee on Vaccines & Immunization
Practices, 2016-17: Office-bearers: Pramod Jog (Chairperson),
Sachidanand S. Kamath (Chairperson), Anupam Sachdeva (Chairperson),
Vipin M Vashishtha (Convener), Jaydeep Choudhary (Convener), Bakul J
Parekh (lAP Coordinator); Members: Jeeson C Unni, Sangeeta Yadav,
Sanjay Srirampur, Baldev Prajapati
Indian Academy of Pediatrics: Pramod Jog
(President), Sachidanand S Kamath (Immediate Past-President), Anupam
Sachdeva (President-Elect), VP Goswami, (Vice-President), Bakul J Parekh
(Secretary General), Sandeep B Kadam (Treasurer), Dheeraj Shah
(Editor-in-Chief Indian Pediatrics), P Ramachandran (Editor-in-Chief,
Indian Journal of Practical Pediatrics), Ajay Gambhir (Joint Secretary).
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