ndia used multiple innovative strategies and
interventions to overcome technical and operational barriers during its
journey towards polio eradication. Research played a pivotal role in
identifying and overcoming many challenges by guiding programmatic
actions and fine-tuning strategies. Analytical research studies and
clinical trials led to a better understanding of the risk factors for
poliovirus transmission and immunogenicity of available polio vaccines.
Independent program evaluations through periodic seroprevalence surveys
contributed to optimization of the use of different polio vaccines.
Vaccine trials and epidemiological analysis have guided the development
of polio endgame strategy [1].
India led many research studies to fill information
gaps at various stages of the Global Polio Eradication Initiative
(GPEI). Globally, a lot of efforts was undertaken in recent years to
address the information/understanding gap which might impede the
progress towards global eradication. However, many potential gaps still
persist in the understanding of polio vaccination and immunity. As the
polio program enters an uncertain phase of endgame strategy, it is
extremely important to identify and address these gaps in information;
for a predictable and risk-free progress towards a lasting world free of
wild and vaccine polioviruses. A few issues pertaining to the switch
from trivalent to bivalent oral polio vaccine (tOPV-bOPV), the
introduction of inactivated polio vaccine (IPV) in routine immunization
schedule, and the best response options against potential circulating
vaccine-derived poliovirus (cVDPV) outbreaks need immediate attention.
Lack of comprehensive understanding of mucosal immunity in populations
may affect mitigating the risks of poliovirus importations and emergence
of cVDPVs in polio free countries. Further clarity is needed on some
operational issues and vaccine interference due to co-administration of
polio and other EPI vaccines. Lack of clarity on mechanisms to identify
and manage long-term poliovirus excretors will be important for the
polio program even after global eradication of poliovirus.
Information Gaps
tOPV-bOPV Switch and Sequential Sabinvirus Withdrawal
Continued use of tOPV, despite global eradication of
type-2 poliovirus in 1999 is responsible for >95% of all cVDPV cases and
approximately 30% of vaccine-associated paralytic poliomyelitis (VAPP)
cases in the last few years [2]. Switching to bOPV from tOPV, besides
eliminating the risk of type-2 VDPV and VAPP, will also provide an
additional push to eradicate wild poliovirus (WPV) types 1 and 3 by
virtue of superiority of bOPV over tOPV [3]. The 65th World Health
Assembly endorsed the global switch from tOPV to bOPV in all OPV-using
countries and the Strategic Group of Experts (SAGE) on immunization
reaffirmed that the switch should be undertaken in April 2016. It has
also been recommended that all OPV using countries should introduce at
least one dose of IPV in their program as a part of this switch process
[4,5]. Many research studies have guided the OPV switch plan [6,7]. Yet,
many questions relevant to the use of bOPV in combination with IPV at
DPT3 in the routine immunization (RI) schedule still remain unanswered.
(i) Just a couple of months prior to the
switch, >200 million doses of tOPV would have been given to children
in India immunized as a part of the National Immunization Days
(NIDs). These vaccine strains (Sabin poliovirus) may continue to
circulate in communities if immunity levels against type-2
poliovirus are low. Post tOPV-bOPV switch, an OPV2-naive birth
cohort would develop and accumulate with time. This cohort would be
deprived of mucosal immunity against type-2 poliovirus [6].This will
pose the risk of emergence of cVDPV2 post tOPV-bOPV switch from any
circulating OPV2 strains from the pre-switch tOPV administered. The
risk will be highest during the immediate post-switch period.
Similar risk situations will be encountered for cVDPV1 and cVDPV3
when bOPV is finally removed from the program. Though no effective
tool seems to be available presently against this extremely
important risk associated with tOPV-bOPV switch, there are some
efforts to develop combined IPV formulations with added mucosal
adjuvant; the double mutant of a bacterial heat-labile toxin (dmLT).
Though animal data suggest that vaccination with dmlT-IPV
combination results in specific induction of mucosal immunity,
further human trials are needed for development of these vaccines
[8-10].
(ii) Post tOPV-bOPV switch, type-2
OPV-naive birth-cohort will result in accumulating gap in mucosal
immunity in the community. Simultaneously, type-2 OPV virus
circulating in this cohort from the previous tOPV immunization may
be emerging as VDPVs. A mathematical modelling is needed to estimate
the ‘breakeven’ duration, after tOPV-bOPV switch, when the
incremental gap in mucosal immunity in this birth cohort could lead
to an outbreak of cVDPVs in the community. This understanding is
extremely important to pre-empt all potential cVDPV2 outbreaks in
future.
(iii) Similar concern, as above, is
applicable to mucosal immunity profile against type-1 and 3
polioviruses, of a similar cohort during bOPV withdrawal currently
schedule for 2019-20. It is also worthwhile knowing the both humoral
and mucosal immunogenicity against type-1 poliovirus when mOPV1 is
given in EPI schedule to support the program to understand the risk
associated with a switch from bOPV to mOPV1 before withdrawal of all
OPVs.
Introduction of IPV in Routine Immunization
In response to the World Health Assembly (WHA)
declaration in 2012, the Polio Eradication and Endgame Strategic Plan
2013-2018 was developed [11]. WHO now recommends at least one dose of
IPV into RI as a strategy to mitigate the potential risk of re-emergence
of type-2 polio following the withdrawal of Sabin type-2 strains from
live OPV [12]. IPV could also be put to use in future polio outbreaks
[13]. India has already introduced a single dose of IPV at DPT3 contact
in RI schedule. Recent research studies have provided useful information
on potential routes (full/fractional), doses, schedule, immunogenicity,
priming effect and mucosal response associated with IPV introduction in
RI [6,7,14,15]. Many gaps; however, still persist in the understanding
related to IPV use:
(i) IPV given to OPV-primed individuals is
known to boost mucosal immunity [6,7]. However, not much is known on
the duration of mucosal response induced by a dose of IPV in these
individuals; an important fact needed to predict population mucosal
immunity and the nature of response, should an outbreak occur during
the polio endgame.
(ii) Depending upon the global
epidemiology of polio in the future, the program may either switch
to mOPV1 (plus IPV at DPT3) from bOPV (plus IPV at DPT3) or opt for
an all IPV in the RI schedule. As these are definitive futuristic
vaccine options, it is important to understand the immunogenicity of
IPV against poliovirus types 2 and 3 when administered with mOPV1 at
DPT3 contact in RI schedule.
(iii) The polio program needs to
understand better the number of doses, schedule and immunogenicity
of an IPV-only schedule in RI, after the final cessation of all live
OPV.
(iv) In the concluding phase of global
polio eradication, bio-security and containment concerns would
require that wild poliovirus is not used by manufacturers to produce
IPV. Sabin-IPV or possibly a virus-free polio vaccine may be
considered. Additional data on immunogenicity and safety of
Sabin-IPV formulation will be required before its potential use in
India.
Mucosal Immunity/Response
Data from several sources suggest a strong likelihood
of older individuals participating in international spread of
polioviruses [16]. Indian infants have high levels of humoral immunity
with seroprevalence rates >90% for all poliovirus types [17]. Humoral
protection alone; however, cannot guarantee the interruption of
poliovirus transmission in a community. A good intestinal mucosal
immunity prevents infection of gut with poliovirus and subsequent
multiplication, excretion and spread among communities. Research studies
indicate that the intestinal mucosal immunity wanes significantly after
vaccination with OPV [7,18]. Outbreaks of polio may continue to occur if
intestinal mucosal immunity is not sustained at high levels until global
polio eradication is achieved [16,19]. Given the importance of mucosal
immunity in the final push towards eradication of poliovirus, many
studies have addressed issues related to mucosal immunity [6,7,18].
Nonetheless, further studies are required to address the remaining gaps
pertaining to the polio endgame strategy:
(i) Due to a waning of the mucosal
immunity, older age groups may participate in the transmission of
poliovirus. In the eventuality of a wild poliovirus (WPV)
importation in a polio-free country or the circulation of Sabin
virus in the community, the older age group may facilitate the
spread of WPV or the emergence of cVDPV, especially after tOPV-bOPV
switch. The potential role of older age groups in future
transmission of poliovirus requires a better understanding by
assessing the mucosal immunity profile of young and elderly
population.
(ii) It will be very helpful to be aware
of the precise number of polio campaigns required and the
‘lead-time’ needed for effective development of mucosal immunity in
the community to interrupt transmission during an outbreak of polio
in future.
(iii) To keep the populations continually
‘sanitized’ against WPV and VDPVs, after an outbreak, it is
important to keep the mucosal immunity to such levels that WPV
importations or emerging VDPVs do not re-establish transmission.
This needs a precise knowledge of duration of mucosal protection
after the last dose of OPV or IPV in immunized populations. This
information will help to precisely plan the intervals between
OPV/IPV campaigns against any future outbreaks.
(iv) As mucosal immunity takes center
stage towards the final push for eradication, an easy and rapid
correlate (surrogate marker) of mucosal immunity will be very
valuable (such as serum IgA and secretory IgA levels, gingival fluid
IgA and ELISPOT test). A consensus on this matter is needed through
further research and analysis.
The salient findings of few important studies on
mucosal immunity on polio are detailed in Table I.
Table I Salient Findings of Important Studies on Polio Mucosal Immunity
| 1. bOPV given
in routine schedule with IPV at week 14 provides the best
mucosal response against poliovirus types 1 & 3 but poor mucosal
response against type 2 [6]. |
| 2. IPV
in OPV primed individuals boosts intestinal mucosal immunity
[7]. |
| 3. Intestinal
mucosal immunity after infection with OPV appears to wane
significantly within a year of vaccination [18]. |
| 4. IPV alone
does not induce sufficient intestinal mucosal immunity [20]. |
| 5. The
mucosal response correlated with seropositivity for neutralising
antibody against poliovirus [21]. |
| 6.
Supplementary dose of IPV given to OPV primed children
substantially boosts intestinal immunity [22]. |
Outbreak Responses to cVDPV2 post OPV Switch
One of the greatest risks to polio program in the
immediate future is the outbreak of cVDPV2 post bOPV-tOPV switch.
Research and global consensus is needed on VDPV detection, mitigation
strategy and best response to an outbreak. Few urgent questions are as
follows:
(i) What are the best vaccine options to
respond against a cVDPV2 outbreak (mOPV2 vs IPV vs
combined or sequential response)?
(ii) What is the immunogenicity and safety
profile of m-IPV2 (increased type-2 antigen content monovalent IPV)
in children and adults?
(iii) Is there a need to redefine the
VDPVs to a lesser number of nucleotide changes on VP1 segment of the
poliovirus genome (presently 6 nucleotide changes for VDPV2 and 10
for VDPV 1 and 3) for early detection and pro-active response?
Immunodeficient Long-term Poliovirus Excretors
A small number of immunodeficient individuals may
exhibit prolonged excretion of VDPV (iVDPVs) following infection with
oral poliovirus vaccines. These individuals pose the risk of
reintroduction of live poliovirus even after global wild poliovirus
eradication has been achieved [23].
(i) Intensified efforts are needed to
develop mechanisms to identify individuals whom are long-term
poliovirus excretors in the communities and develop anti polio viral
drugs to clear iVDPV infections in these patients.
(ii) Research studies are needed to be
undertaken to better understand the genomic dynamics and
characterization of Sabinvirus in the emergence of VDPVs, especially
in immunodeficient long-term poliovirus excretors. Could a genomic
profile be standardized to indicate the progression in a person
towards long-term excretor status and ‘catch them early on’?
Interference Between Polio Vaccines and Other EPI
Vaccines
Interference by other vaccines co-administered with
OPV/IPV is known to occur [24]. It is known that IPV diminishes antibody
response to the pertussis vaccine [25]. Somewhat lower responses against
poliovirus type 2 were observed after co-administration of both PHiD-CV
and 7vCRM vaccine [26]. As programs introduce range of newer vaccines,
interference between polio and other RI vaccines may have an unexpected
interference. (e.g. rotavirus, pentavalent, Yellow fever, PCV,
measles etc.). Studies are needed to better understand any such
interference.
Efforts to Address Information Gaps
As the world gets closer to global polio eradication,
research studies to fill major information gaps will have to continue,
for a confident, scientifically sound and effective traction of the
polio endgame. Many international agencies including the WHO, UNICEF,
US-CDC, BMGF, PATH, national governments, academic institutions and
other organizations are already working to address many of the concerns
listed in this article; many in coordination with the global Polio
Research Committee (PRC) at WHO headquarter. The India Expert Advisory
Group (IEAG) on polio eradication and the Immunization Technical
Advisory Group (ITAG) and Advisory Committee on Health Research (ACHR)
of the South East Asia Region of WHO have endorsed many studies to fill
gaps relevant for the planning and implementation of the polio end game
strategy. India has lined up many collaborative research projects on
vaccine trials, mucosal immunity and seroprevalence studies addressing
the gaps pertaining to the implementation of polio endgame. These
studies are proposed to be done in partnership with the WHO, the
Government of India, Indian Council of Medical Research (ICMR), and
medical institutes and other stakeholders across India.
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