Global polio eradication efforts continue to
achieve results. Of the three types, wild poliovirus type 2 (WPV2) was
eradicated in 1999 and certified in 2012 by the Global Commission for
the Certification of the Eradication of Poliomyelitis [1]. No wild
poliovirus type 3 (WPV3) has been detected anywhere in the world for
over three years, since November 2012 [2]. So, it is likely that WPV3
has also been eradicated; however, the Certification Commission will
have to scrutinize all information before making a final declaration.
India interrupted all WPV transmission in 2011 after which the South
East Asia Region was certified as having eliminated WPV in 2014, a major
milestone in the eradication trajectory [3]. In 2015, wild poliovirus
type 1 (WPV1) continued to circulate only in Pakistan and Afghanistan,
but with only 74 polio cases, the lowest in history [2]. Both countries
are inching towards interrupting WPV1 transmission.
These successes were achieved using oral poliovirus
vaccine (OPV) containing live attenuated polioviruses – trivalent (tOPV
with types 1, 2 and 3), monovalent (mOPV with type 1 or 3) and bivalent
(bOPV with types 1 and 3). However, the vaccine (Sabin) genotypes of
polioviruses can regain neurovirulence and very rarely cause
vaccine-associated paralytic polio (VAPP) either in the vaccinated child
or in a close contact [4]. Where OPV coverage is sub-optimal, Sabin
genotypes can spread among non-immune children, leading to rare lineages
of vaccine-derived polioviruses (VDPVs) that have regained both the
neurovirulence and transmissibility characteristics of WPV. Circulating
VDPVs (cVDPVs) can cause polio outbreaks [4]. Since 2000, more than 600
persons have been paralyzed in outbreaks caused by type 2 cVDPVs [5].
For a polio-free world, not only WPVs but also VAPP
and cVDPVs must be stopped from occurring. Discontinuing OPV inoculation
will prevent VAPP, but the resultant immunity gap in the community will
constitute a risk for the emergence of cVDPVs and polio outbreaks, a
setback we cannot accept [6]. The major reason cVDPVs can be generated
after OPV is stopped is if some places have stocks of OPV and continue
to use the vaccine. These areas can serve as reservoirs to infect
completely unvaccinated populations which will foster vaccine virus
transmission and regaining of the wild virus phenotype causing
outbreaks. This can happen if OPV is the only vaccine to be used to
prevent polio. But as noted below, there is another tool to prevent
polio, the inactivated polio vaccine (IPV).
In 2013, the World Health Organization (WHO) unveiled
the ‘Polio Eradication and Endgame Strategic Plan 2013-2018’, in which
the term ‘eradication’ addresses WPVs and ‘endgame’ addresses VAPP and
VDPVs [7]. The tool for mitigation of risks related to withdrawing OPV
is IPV, consisting of killed polioviruses. India pioneered advocacy for
IPV to complete and conclude eradication [8,9]. The endgame is a new
strategy for completion of polio eradication – rid the world of polio
due either to WPV or vaccine viruses. According to the strategic plan,
global endgame interventions and WPV eradication interventions in
Pakistan and Afghanistan will run concurrently [7].
In recent years, countries using OPV had an estimated
300-500 cases of VAPP annually with 26-31% of all VAPP cases caused by
Sabin type 2 virus [10]. The majority of VAPP in contacts of vaccinated
children is due to Sabin type 2 [11]. Of all cases of polio due to
cVDPVs, nearly 90 percent were due to Sabin 2 serotype [5]. Therefore,
the global need to stop all Sabin 2 related polio, VAPP and cVDPVs, is
extremely urgent. The beginning of the endgame will have two components
– introduction of IPV universally in all countries currently using OPV
exclusively, and globally synchronized withdrawal of Sabin type 2 from
all OPV [7]. The latter was achieved through a switch from tOPV to bOPV
which took place in April 2016. Eventually, after eradication of WPVs 1
and 3, bOPV will be discontinued and all countries will use IPV
exclusively, until further decisions are made. Polio eradication saves
money through productivity increases of individuals saved from paralytic
polio [12].
Role of IPV in the Endgame
The introduction of IPV in OPV-using countries
started in 2015 in a staggered manner and will continue in 2016 and
beyond until every country has IPV in their national immunization
program. IPV is highly efficacious and very safe – no serious adverse
events have been attributed to IPV [13,14]. Two or three doses, given at
appropriate age intervals, are sufficient for ~100% antibody response to
the three types of polioviruses, with quite high titers [15-17]. Higher
titers and seroconversion rates are obtained when IPV is given after
maternal antibody wanes and with intervals of over 8 weeks [15-17]. One
dose induces seroconversion in 19-41% for type 1; 32-63% for type 2; and
28-54% for type 3 [18]. The remaining children are immunologically
primed so that a second dose results in a rapid anamnestic response in
<7 days [19].
Effective mucosal immunity to protect against WPV
infection may be needed at the pharyngeal and intestinal levels. IPV
induces pharyngeal immunity similar to that of OPV, but much less
intestinal immunity [15,20]. On the other hand, in OPV-immunized
children, a dose of IPV boosts both humoral and intestinal immunity
several-fold higher than a dose of OPV [15,20]. This is the basis for
the endgame recommendation to give one dose of IPV at the time of the
third dose of OPV, at age 14 weeks or more. There is no restriction
intended as one dose only, as the document calls for ‘at least one
dose’.
Thus, IPV will mitigate the risk of cVDPV2 emergence
after the tOPV-bOPV switch and will also enhance immunity against types
1 and 3 that should protect Indian children in case of virus
re-introduction from any source – importation or laboratory breach. In
case of an outbreak of cVDPV2, a dose of IPV will rapidly boost immunity
in primed children. Furthermore, IPV-primed children will mount quicker
and higher humoral antibody response to a dose of mOPV2 than in
exclusively OPV-inoculated children [21]. These are the advantages of
introducing IPV, even if the coverage may not be as high as desired.
For an outbreak response by way of ‘mop-up’
vaccination, OPV has been the vaccine of choice for ease of inoculation,
but IPV used in campaign mode in the future will offer additional
benefits. The greatest risk of re-introduction of live vaccine virus
type 2 or cVDPV type 2 will be within one or two years after the switch
[22]. IPV avoids the risk of re-seeding vaccine virus type 2 that will
be inherent in mOPV2 given in campaigns. The age cohorts already given
OPV doses will be rapidly boosted with both humoral and intestinal
immunity, helping in interruption of transmission. Children born after
the switch would either have received IPV or had not received it due to
incomplete coverage – both groups will benefit from a dose of IPV as
described above.
India has begun giving IPV in some States in November
2015 and will continue until the entire country is covered. One dose of
IPV is given intramuscularly in the right thigh (for easy recall by
mothers), while pentavalent vaccine is given on the left thigh, in the
same sitting. When India rolls out pneumococcal conjugate vaccine (PCV),
expected in the near future, IPV will be given in the right and
pentavalent and PCV in the left thigh with >2.5 cm gap. The safety and
effectiveness of giving two, three or four injected vaccines in one
clinic visit is supported by good evidence [23-25].
The introduction of IPV in all OPV using countries
has resulted in demand greater than supply; this is hopefully a very
short term problem. Such shortage has resulted in two reactions – one,
some countries have chosen to delay introduction or stagger in-country
coverage expansion and second, countries are considering giving
fractional doses of IPV intradermally (ID). The excellent immunogenicity
of ID fractional (one-fifth) dose of IPV was documented in pioneering
research in India, confirmed by many recent studies [19,26,27]. A single
ID fractional dose at age 14 weeks may not induce as good an immune
response as one full intramuscular dose. However, two ID fractional
doses given at 6 and 14 weeks induce comparable seroconversion to one
intramuscular full dose at 14 weeks; surprisingly, the antibody titers
after two doses were much higher than one full dose [28]. Recently, the
Government of India has decided to use available IPV in this ID
fractional two-dose schedule in selected States – even though such use
is at present off-label (Haldar P, personal communication) [29]. This
policy was decided upon as an interim measure to tide over the shortage
of supply and the 2 ID fractional IPV doses will be given in lieu of one
full intramuscular dose.
Short-Medium and Long-term IPV Use
Endgame activities are expected to take place until
2018 and beyond. During this period all OPV using countries will give
bOPV according to the usual schedule under the Expanded Program on
Immunization (EPI) and at least one dose of IPV to all children. Several
countries have decided to offer more than one full intramuscular dose;
India has not considered this option as yet. All children who reach 14
weeks of age after the tOPV-bOPV switch will not receive any Sabin type
2 vaccine virus at all. The question if they should get more than one
dose of IPV also has not been considered in India. Following the switch,
we anticipate a few instances of VDPV2 emergence arising out of chains
of transmission that may begin by vaccine virus transmission from those
who got Sabin 2 vaccine virus, to those who did not get it. The
probability, frequency and time sequence of such cVDPV2 emergences are
unknown since the world has not had any experience with this unique
situation.
Mathematical modeling using best assumptions predict
the highest risk of cVDPV2 emergence to exist during the 6-12 months
post-switch [22]. Others, notably one of us (TJJ), suspect that the
probability of detection of cVDPV2 may be higher during the 12 to 24
month-period 6 months after the switch. This risk may likely end about
three years after the last large scale inoculation of Sabin 2 vaccine
virus. If containment of all laboratory-held viruses is not perfect,
release from a laboratory could constitute a possible risk. Once such a
situation occurred in India, during 2002-2003, when circulation of a
WPV2 strain with genetic sequences not seen in humans for a long time
was identified [29]. IPV will serve as an ‘insurance policy’ against
such contingencies.
Unfortunately, we do not have data on the durability
of immunity induced by a single dose of IPV. All high income countries
use IPV but they are liberal with doses, many giving 4-7 doses [30]. In
low income countries, the recommendation regarding the number of doses
is likely to change and evolve, particularly if we discover: (1) waning
antibody over time; (2) priming alone is not protective; or (3) a higher
proportion of seroconversion than provided by a single dose is
necessary. Theoretically, two doses given at an interval of 4-6 months,
with the first dose given after maternal antibody has waned, ought to
provide long term immunity. This is based on the knowledge that
long-lived memory and antibody-secreting plasma cells are elicited if
the booster is delayed by 4-6 months [15]. Another inactivated
picornavirus vaccine (hepavirus in hepatitis A vaccine), given as two
doses 6 months apart, induces immunity that is anticipated to last
life-long [31].
The endgame plan envisages the eradication of WPV1
shortly; thereafter the opportunity to discontinue even bOPV will
present in the near future – expected in 2018-2020. The current global
recommendation is to continue IPV for a period of at least 5 more years,
after which decisions on continuation/discontinuation may be allowed for
individual countries [7].
Operational Challenges to IPV Introduction in India
Globally, the rapid introduction of a vaccine
covering more than 100 nations is an unprecedented exercise and poses
many challenges. Since 2013, over 90 countries have introduced IPV in
their EPI schedule [32]. A dose of IPV is 5-fold or more expensive than
a dose of OPV [33]. Thus, introduction of IPV can lead to financial
stress for both individual countries and the Global Polio Eradication
Initiative (GPEI). The Vaccine Alliance (GAVI) is assisting financially
some 73 countries, including India [34,35].
IPV manufacturers also have been facing problems of
rapid up-scaling of production [36]. The necessary quantities of IPV for
all countries are not available; therefore, GPEI has classified
countries on a scale of risk of cVDPV emergence and/or spread and
proposed a schema for late introductions [6]. India is considered a high
priority country, considering the population size, conditions of
sanitation and hygiene, <90 per cent coverage of EPI vaccines and
recurrent emergences of cVDPV in the recent past. At the same time,
India is a potential large scale supplier of IPV, but production delays
have affected the supply prospects. Under these circumstances, India
will use an antigen-sparing approach in selected states, by way of two
ID fractional doses (each 1/5 of a full dose), as stated earlier.
Future Prospects Regarding Polio Immunization
The world is sailing in unchartered waters of global
polio eradication and the endgame, but we do expect complete success in
a few years. Obviously all countries will continue to use IPV for a
number of years. Currently almost all IPV is made from laboratory
maintained fully virulent WPVs, which demands an exceptionally secure
environment for fear of accidental release. Much research had been done
on making IPV using Sabin attenuated vaccine strains, with far less
serious consequences in case of any accidental release. Recently, Japan
licensed such indigenously made Sabin IPV and currently it is the
vaccine used in the national immunization program [37]. China has
successfully manufactured and tested Sabin IPV [38]. Other manufacturers
are actively exploring the shift from WPVs to vaccine viruses as vaccine
raw material.
We referred to hepatitis A vaccine, which is
adjuvanted with aluminium salt. The potential of antigen-sparing with
use of adjuvant in IPV is being actively explored in several places
[39]. Devices for needle-free inoculation of IPV intradermally, both
injection devices and micro-needle patch are currently under rigorous
testing; they will be very helpful for IPV given in campaign mode
especially in outbreak response [39]. Recently, a monovalent IPV with
type 2 antigen has been tested successfully; it will offer another
intervention tool against any future outbreak of cVDPV 2 [39]. Combining
IPV with other childhood injected vaccines is a method currently used in
most high income countries. The usual preservative thimerosal cannot be
used as it damages the immunogenic epitopes in IPV [40]. Therefore
combinations should be preservative free or compatible with the
alcoholic (phenoxy ethanol) preservative that is safe for IPV. These
conditions are satisfactory when the pertussis component is acellular,
but not killed whole cell pertussis vaccines. India and many low and
middle income countries use thimerosal-containing pentavalent vaccine;
hence we cannot expect a hexavalent vaccine with IPV any time soon.
However one Indian manufacturer is in advanced stage of clinical trials
with such a combination vaccine.
As with the effort to eliminate WPVs, navigating the
endgame and securing total eradication of all polio is a test of
political will, strategy adaptation, and cooperation across several
fronts and agencies, including in public and private sectors. The
pediatric professionals and the Indian Academy of Pediatrics will, we
hope, continue to lead in this Himalayan task.
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