This document provides an overview of poliovirus, the immune response to poliovirus infection, and polio vaccines. It discusses the basic virology of poliovirus including its structure, genome, replication cycle, and pathogenesis. Regarding immunity, it describes the innate and adaptive immune response to poliovirus including the roles of dendritic cells, B cells, T cells, antibodies, and interferons. It also discusses immune evasion mechanisms employed by the virus. Finally, it summarizes the two main polio vaccines - the live oral polio vaccine and inactivated polio vaccine - and compares their mechanisms of action and immune responses elicited. It notes some challenges with the oral vaccine including the potential for vaccine-

1. POLIOVIRUS - IMMUNE
RESPONSE AND VACCINES
Moreno-Amador K., Vitus E., Sánchez-Martínez A.
Course: IMI
November 27th, 2020

2. To understand the immune response to
poliovirus infection
To learn key differences between IPV and OPV
To inform about the actual challenges in polio
vaccines
Learning objectives

3. Index
• Basic aspects of Poliovirus
A. Virion and genome, tropism and replication
B. Dissemination and pathogenesis
C. Epidemiology
• Immune response to Poliovirus
A. Innate and adaptive response (cellular and humoral)
B. Response in mucosa
C. Evasion mechanisms
• Vaccines
A. OPV and IPV
B. VDPV
C. nOPV2

4. Introduction
• Poliovirus or poliomyelitis (from the Greek words for grey and marrow = spinal cord, and –it
is = inflammation.
• Polio mainly affects children under 5 years of age.
• 1 in 200 infections leads to irreversible paralysis. Among those paralysed, 5% to 10% die
when their breathing muscles become immobilized.
• In the mid-20th century, inactivated vaccines and live attenuated vaccines has proved very
effective in preventing polio.

5. Basic aspects of
Poliovirus

6. Poliovirus
Characteristics
• Icosahedral capsid
• Diameter:30nm
• Genome: ssRNA+
• Lenght:7-8kb
• Causal agent of
paralytic poliomyelitis
Group: Group IV
Order: Picornavirales
Family: Picornaviridae
Genus: Enterovirus
Species: Enterovirus C
Subtype: Poliovirus
Poliovirus Types
Classification
5´Noncoding Region
• Internal Ribosome
Entry Site (IRES)
• Binding side
Capsid proteins Nonstructural Proteins
• Protein processing
• Host shutoff
• RNA repllication
3´Noncoding Region
Binding site for
replicase complex
Acheson, 2007.
WPV1
WPV2
WPV3

7. Viral replication • Viral Cycle
Acheson, 2007; Sutter et al., 2018
• Receptor interaction
• Poliovirus Viral Receptor CD155
VPg
VP1 N-termini
VP4
Capsid
CD155
VP1 N-termini
VP4

8. Virus dissemination
Primary sites of
multiplication in
the mucosa
Virus sheding
Replication in
motor neurones
Subside due
to INF α/β, Ab
Blondel et al., 2005; Sutter et al.,2018

9. In the CNS, the main target is the motor neuron
Virus effect on the CNS
Hypothesis on PV dissemination to the CNS
Blondel et al.,2005; Ohka et al.,2012
v
a) By infected monocytes
b) Though the endotelial
cells in the BBB
c) Via axonal transfer from
peripheral motor neurons
into the spinal cord
v
a
b
c

10. Pathogenesis
• The majority of exposed patients (around 95%)
are asymptomatic.
• Initial symptoms are fever, fatigue, headache,
vomiting, stiffness of the neck and pain in the
limbs.
• Self-limiting episodes of gastroenteritis,
respiratory tract infection, and influenza-like
illness can occur.
PV result in poliomyelitis in only 1%–2% of cases
Spinal poliomyelitis
Most common
Bulbar poliomyelitis
(2%)
Bulbospinal
poliomyelitis
(around 19%)
Mehndiratta et al., 2014

11. Epidemiology
Current situation
99%
Reduction
Sutter et al.,2018; WHO, 2020
Polio cases by world region
Polio eradication by country
Vaccination efficacy though time

12. Immune response to
Poliovirus: Innate and
adaptative

13. • “Despite a great deal of prior research, the early
pathogenic events in natural oral poliovirus infection
remain poorly defined”. (Shen, et al., 2017)
• Dendritic Cells and Macrophages are
productively infected by poliovirus (Wahid, et al.,
2004).
• B cells can be permissive to PV infection (express
CD155); however these cells are not susceptible
to PV infection (Wahid, et al., 2004).
• Pharyngeal-intestinal mucosa support viral
replication and infection after oral exposure in
macaques (Shen, et al., 2017).
Shen, et al., (2017). Journal of virology
Initial targets and dissemination

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Mucosal immune response
w

15. • Profile typical of Th1 cells (Mahon, et al.,1995)
• Both CD4+ and CD8+ T cells secrete IFNg in
response to PV antigens and are cytotoxic via the
perforin/granzyme (Wahid, et al., 2005)
• The epitopes on VP4 were conserved between serotypes, and
this may account for the predominantly cross-reactive poliovirus-
specific T-cell response (Mahon, et al., 1992)
T, B and NK cells

16. T, B and NK cells
• Spontaneous clearance of iVDPV infection in CID
could be partly attributed to the innate immune
cellsincreased number of NK cells (Mohanty, et
al., 2019, Shaghaghi, et al., 2018)
• Poliovirus-specific blood ASCs, and especially α4β7+
ASC--> biomarkers of mucosal immunity (Dey, et al.,
2016)

17. • Neutralizing Abs coincided
temporally with resolution of
viremia and virus shedding in
oropharynges and stool.
Shen, et al., (2017). Journal of virology
• Neutralizing antisera produced in humans
and animals are type-specific (Baj, et al.,
2015). But 90% of NAb are target VP1
(Cruz-Perez, et., 2013)
• IgM and IgG antibodies appear 3–4 days
after infection. Secretory IgA becomes
detectable 1 week post-exposure (Shen, et
al., 2017)
Nathason, 2008, Advances in virus research.
Antibodies

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• Type I IFNs are determinant for
the differential susceptibility of
tissues to poliovirus (Ohka et al.,
2007; Ida-Hosonuma et al.,
2005)
• Different sites inside the RIG-
I/MDA-5 pathway are attacked
by PV (Doutzauer and Kremer,
et al., 2012)
• Rare variants are found in host
genes involved in interferon
signaling, viral replication,
apoptosis, and autophagy in
severe cases (Andersen, et al.,
2019)
Immune Evasion

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• Both 2A and 3C mediate
apoptosis causing
mitochondrial damage,
release of cytochrome c, and
activation of the caspases 3
and 9 (Belov, et al., 2003)
Immune Evasion
• eIF4G (necessary for cap-
dependent initiation of cellular
protein translation), and PABP
are cleavaged (Kräusslich, et
al., 1987; Kuyumcu-Martinez, et
al., 2004 )

20. Influence of Microbiota
A. Virus incubated with LPS or PG was more
efficient at binding permissive cells than
virus alone (Kuss, et al., 2011)
B. Bacterial polysaccharides promote
poliovirus attachment to PVR (Robinson,
et al., 2014) Garg and Karst, 2016, Viral Gastroenteritis.
Adaptative immune antagonism
• MHC-I -dependent antigen presentation is inhibited by poliovirus protein 3A
(Deitz, et al., 2001)
• Poliovirus 3A Protein limits IL-6, IL-8, and IFN-beta secretion during viral
Infection (Dodd, et al., 2000)

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3D
CD155
Shen, et al., (2017). Journal of virology
Infection of the CNS requires or is
at least supported by viral
spread through blood, and
therefore significantly depends on
the velocity and strength of the
antibody response.

22. There is no specific treatment for poliomyelitis.
Treatment
Pharmacological interventions Non pharmacological interventions
• Amantadine, bromocriptine
and modafinil
• Insulin-like growth factor
(IGF-I) and human growth
hormone
• Coenzyme Q10 and
selegiline
• Rehabilitation
Neutralizing monoclonal
antibodies specific to
each PV serotype

23. There is no cure for polio
¡BUT¡
It CAN be PREVENTED
Polio vaccine, given multiple times, can protect a child for life
Vaccines

24. Vaccines
POLIO VACCINE
SALK (1954)
- IPV
- Humoral Immunity
- Comparatively expensive
SABIN (1961)
- OPV
- Humoral, Cellular and Mucosal
Immunity
- Provides herd immunity
- Cheaper and easy to administer
- Vaccine-Associated Paralytic
Poliomyelitis

25. VACCINE SCHELDULES IN DIFFERENT COUNTRIES
India:
Mostly OPV.
First dose at birth, three more doses at an interval of 4 weeks each. Booster dose
between 16-24 month.
(https://www.apolloclinic.com/)
THE USA:
Only IPV since 2002.
One dose at each of the following ages : 2 months, 4 months, 6 through 18 months,
and 4 through 6 years. ( www.cdc.gov)
Spain:
Only IPV since 2010.
One dose at the following ages: 2 months, 4 months, 11 months, 6 years,
(https://www.analesdepediatria.org/)

26. Oral Polio Vaccine (OPV)
• The oral polio vaccine is made using the attenuated
form of 3 strains of Poliovirus. Now bivalent OPV is
used ( type 1 and 3).
• This vaccine has the ability to mimic the effect of wild
type polio infections and induces mucosal immunity
by replication in gut epithelium.
• The virus sheds like in wild type infections and
therefore has the potential to extend protection to
unvaccinated individuals.
• Easy to administer.
• However, it can induce VDPM in rare cases.
O'Grady M, Bruner PJ. Polio Vaccine. [Updated 2020 Aug 11]

27. • Inactivated antigens are used to induce immune
response. The vaccine is administered intramuscularly.
• Since it is in the inactivated form, the replicative
ability is affected which influences the elicited
immune response.
• Excellent method of preventing paralytic
poliomyelitis in the vaccinated individual but is not
effective to curb spread of the virus in communities.
• Series of doses required. Used as a trivalent vaccine.
• Safe to administer to immunocompromised
individuals.
Inactivated Polio Vaccine (IPV)

28. • OPV induces both humoral and mucosal
immunity.
• Initial predominance of IgM. IgG – prolonged
protection.
• The humoral response is not completly
serotype specific.
• Significance of cell-mediated immunity is not
fully known (Sutter, et al., 2018, Poliovirus
vaccine –Live)
Immune response in OPV
Weekly excretion rates of
homotypic virus by index children
after administration of monovalent
poliovaccines.
Weekly excretion rates of homotypic
virus following administration of type 2
monovalent vaccine for index children,
their siblings younger than 5 years of
age, and extrafamilial contacts

29. • IPV protection against paralysis
is conferred by preventing
viremia not by preventing
infection.
• Since both vaccines induce similar
levels of circulating antibodies,
this indicates that mucosal
immunity plays an important role
in preventing spread of
polioviruses in the community.
Immune response in IPV
Henry JL, et al., (1966). Journal of Hygiene.

30. • Cause Vaccine Derived Paralytic Polio
(VDPP)
• Mutations due to continuous replication of
virus results in reversion to virulent strain
or recombination with other enteroviruses
can also occur
• High susceptibility seen in B cell deficient
individuals and in communities with low
vaccine coverage
• The current response strategy to cVDPV2
outbreaks is to vaccinate with monovalent
OPV type 2 vaccine (mOPV2).
Vaccine Derived Polio Viruses (VDPV)
• This approach, however, can itself generate
new cVDPV2 strains, as recently observed
in parts of Africa.
O'Grady M, Bruner PJ. Polio Vaccine. [Updated 2020 Aug 11]

31. • Engineered Sabin vaccine to
prevent regaining of
neurovirulence by the
attenuated virus.
• The modifications make the
virus less likely to revert to
gain neurovirulance while
preserving its replicating
ability and stability
nOPV2
Yeh et al., 2020, Cell host and microbe

32. Modifications of the Sabin2
genome:
Two modifications within the 5′-
untranslated region (UTR) (relocated
cre and S15domV), synonymous
mutations at eight nucleotide
positions in the 2C coding region to
inactivate the internal cre and two
mutations in the 3D polymerase
(D53N and K38R) to limit viral
adaptability.
Yeh et al., 2020, Cell host and microbe

33. • Andersen, N. S. B. et al. Host genetics, innate immune responses, and cellular death pathways
in poliomyelitis patients. Front. Microbiol. 10, 1–13 (2019).
•Aghamohammadi, A. et al. Patients with primary immunodeficiencies are a reservoir of poliovirus
and a risk to polio eradication. Front. Immunol. 8, 1–10 (2017).
•Bowers, J. R., Readler, J. M., Sharma, P. & Excoffon, K. J. D. A. Poliovirus Receptor: More than a
simple viral receptor. Virus Res. 242, 1–6 (2017).
• Dotzauer, A. Innate and adaptive immune responses against picornaviruses and their
counteractions: An overview. World J. Virol. 1, 91 (2012).
•Henry, J. L., Jaikaran, E. S., Davies, J. R., Tomlinson, A. J. H., Mason, P. J., Barnes, J. M.,
andBeale, A. J. A study of poliovaccination in infancy: Excretion following challengewith live virus
by children given killed or living poliovaccine. J. Hyg. 64:105–120. (1966).
KEY REFERENCES

34. •Koopman, F. S., Beelen, A., Gilhus, N. E., de Visser, M., & Nollet, F. Treatment for postpolio
syndrome. Cochrane Database of Systematic Reviews. 6-17. (2015).
•Mohanty, M. C. et al. Natural Clearance of Prolonged VDPV Infection in a Child With Primary
Immunodeficiency Disorder. Front. Immunol. 10, 1–9. (2019).
•Ohka, S., Nihei, C., Yamazaki, M., & Nomoto, A. Poliovirus trafficking toward central nervous
system via human poliovirus receptor-dependent and -independent pathway. Frontiers in
Microbiology, 3. (2012).
•O'Grady M, Bruner PJ. Polio Vaccine. [Updated 2020 Aug 11]. In: StatPearls [Internet]. Treasure
Island (FL): StatPearls Publishing; 2020 Jan-. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK526039/
•Shen, L. et al. Pathogenic Events in a Nonhuman Primate Model of Oral Poliovirus Infection
Leading to Paralytic Poliomyelitis. J. Virol. 91, 1–15. (2017).
•Sutter, R. W., Kew, O. M., Cochi, S. L., & Aylward, R. B.. Poliovirus Vaccine–Live. Plotkin’s
Vaccines, 866–917. (2018)

35. •Yeh, M. T., Bujaki, E., Dolan, P. T., Smith, M., Wahid, R., Konz, J., … Andino, R. Engineering the
Live-Attenuated Polio Vaccine to Prevent Reversion to Virulence. Cell Host & Microbe. 27, 736–
751. (2020).
•Wahid, R., Cannon, M. J. & Chow, M. Dendritic Cells and Macrophages Are Productively Infected
by Poliovirus. J. Virol. 79, 401–409 (2005).
•Wahid, R., Cannon, M. J. & Chow, M. Virus-Specific CD4+ and CD8+ Cytotoxic T-Cell Responses
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(2005).
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36. Thanks for your attention! Any question?