Centers for Disease Control and Prevention

Vaccine-Associated Paralytic Poliomyelitis

Concepcion F. Estivariz, MD
Global Immunization Division, Polio Eradication Branch

Project Assessment of VAPP in Nigeria 2022-2023

Surveillance officer's training/sensitization
September 2022
OUTLINE

• VAPP Definition and Epidemiology

• Assessment of VAPP Risk in Nigeria, 2022-23
• Study overview
• Study procedures
• Forms
• VAPP Differential Diagnosis
VAPP: Definition and Epidemiology
Vaccine-Associated Paralytic Polio - VAPP
 Very rare serious Adverse Event Following Immunization
(AEFI) with oral poliovirus vaccine (OPV)
 Paralysis presentation identical to that caused by wild virus
 First identified in early 1960s in the US, but lab testing
available could not distinguish vaccine from wild poliovirus
 Mechanism is rapid mutation in specific sites of Sabin virus
genome that result in reversion of neurovirulence (revertant
virus)
• Reversion occurs in many vaccine recipients, but only rarely causes
VAPP in recipients or close contacts
 VAPP Definition
 Individual presenting Acute Flaccid paralysis (AFP) AND
• Temporal association with OPV use
• Onset of paralysis 4-40 days after an OPV dose or 4-75 days after contact with vaccinee*

• Isolation of Sabin virus in stools but no WPV or VDPV

• Clinical confirmation of paralytic poliomyelitis
• Residual paralysis present at 60 days
• Exclusion of other causes of AFP

 Expert committee evaluation required to confirm VAPP

* Some countries used 4-30 days for recipient VAPP and 4-60 days for contact VAPP.
VAPP Epidemiology Country Period tOPV doses VAPP Incidence per
(million) cases doses
 Variable incidence by country USA1 1980-89 203.50 80 1 per 2.5 mo
Latin America2 1989-91 431.61 139 1 per 2.2 mo
• Differences in surveillance
Romania3 1984-92 12.96 93 1 per 0.2 mo
• Presence of risk factors Hungary4 1961-81 34.67 46 1 per 0.7 mo

 Estimated 400 cases per year in England & Wales5 1985-91 18.4 13 1 per 0.7 mo

OPV-using countries before the India6 1999 733.40 181 1 per 4.1 mo

tOPV-bOPV switch Japan7 1971-00 66.40 33 1 per 2.0 mo

Uganda8 2003-11 NA 11 NA*

* Reported 0 to 3.39 cases per million birth cohort per year

1
Strebel PM, Clin Infect Dis 1992;14(2):568; 2Andrus JK, Bull WHO 1995;73(1):33; 3Strebel PM, American J Epidemiol
1994;140(12):1111; 4 Estivariz CF, Am J Epidemiol 2011;174(3):316; 5Joce R, BMJ 1992;305(6845):79; 6Kohler KA, Bull WHO
2002;80(3):210; 7Hao L, Japanese J Infect Dis 2008;61(2):100; 8 Nanteza MB, J Med Virol 2015, 87(12): 2163
RISK FACTORS for VAPP
• Immunodeficiency
• Much higher risk in immunodeficiencies (B cell primarily)
• Predominant in high-income countries
• First dose vs subsequent doses
• Risk 3-7 times higher in medium/high-income countries; lower risk in India
• Recent intramuscular injection
• Similar mechanism as provocation polio with WPV
• Responsible for high rates in Romania and, possibly, Hungary
• Vaccine serotype
• Type 3 > Type 2 >Type 1
• Type 3 more frequent in recipients; Type 2 in contacts and immunodeficiencies
• IPV administration before OPV protects against VAPP
Vaccine Derived Poliovirus (VDPV)
• Sabin polioviruses with multiple mutations because of
many rounds of replication
• In multiple individuals cVDPVs emerge if low population
• In one individual unable to develop immune immunity
response (immunodeficient)
• VDPV definition is genetic
• Type 1 & 3: ≥ 10 nucleotide changes from Sabin
strain in VP1 genomic region X

• Type 2: ≥ 6 nucleotide changes

• VDPVs have neurovirulence and transmissibility of wild
poliovirus of same serotype
• Types of VDPV Just vaccinated Susceptible
• Circulating (cVDPVs)
Immune
• Immune-deficiency associated VDPVs (iVDPVs)
• Ambiguous VDPVs (aVDPVs)
 VAPP case vs VDPV paralytic case
VAPP case VDPV paralytic case

Clinical presentation AFP AFP

60-day follow up Persistent paralysis May persistent or not

h/o OPV exposure 4-40 days before paralysis Not relevant (may or may
or contact with vaccinee 4- not have been exposed)
75 days before paralysis
Virus in stools Vaccine-like (Sabin, nOPV2) VDPV (iVDPV, cVDPV)

Rule out other causes of Necessary in order to Not necessary

AFP establish OPV causality
instead of coincidental OPV
presence in stools

VDPV – Vaccine Derived Poliovirus , immunodeficiency-associated VDPV (iVDPV), circulating VDPV (cVDPV)
Assessment of VAPP Risk in Nigeria 2022-23
Study overview
 Background
• In response to expanding outbreaks of type 2 cVDPV throughout Africa, the GPEI supported the
development and roll-out of novel type 2 OPV
• nOPV2 contains Sabin 2 poliovirus genetically modified to reduce its ability to mutate and revert to
neurovirulence, thus expected to have lower risk of causing VAPP and VDPV emergences

Global Number of Polio Cases by Year, 2011-2021

1400

1200

1000

800

600

400

200

0
2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021

cVDPV WPV1 WPV3

Data as of 16 Aug 2022, GPEI
Background
• The WHO approved use of nOPV2 for outbreak control
under Emergence Use Listing in November 2020 requiring Vaccination campaigns with
close monitoring of safety and performance type 2 OPV, January 21-July 22
• Surveillance for AEFIs during and after campaigns
• AEFIs reviewed by independent global expert committee
(GACVS sub-committee)
• Since March 2021, more than 600 million of nOPV2 doses
have been released for use in 24 countries.
• No increase in AEFI above expectations for Sabin OPV
• However
• GAVCS had concerns about limitations in data quality and
diagnosis processes to provide a robust assessment of
causality in March 2022
• Public data on VAPP risk with Sabin OPV in Africa is nOPV2 mOPV2 tOPV
limited and comparison with nOPV2 will be difficult
Data as of 16 Aug 2022, GPEI
Rationale and objectives for the study
• To improve our knowledge about VAPP risk with nOPV2, we need more data about
VAPP with other Sabin OPV in Africa using standardized methods
• We propose a prospective study to assess VAPP risk with any OPV distributed
through campaigns or routine immunization.
• Specific objectives:
1) To support the Nigeria polio program in the identification of VAPP cases using
AFP surveillance and surveillance for nOPV2 Adverse Events of Special Interest.
2) To describe the clinical and epidemiological characteristics of VAPP cases in
Nigeria.
3) To estimate the risk of VAPP for different types of OPV used in routine
immunization and campaigns in Nigeria.
Project Collaborators

•US CDC, Nigeria CDC

•NEOC/NPHCDA
•AFENETPHO, APHO, LGAF)
•WHO
•Ministry of Health State Epidemiologists
•NEC AEFI/NPEC
•Independent Neurologist/Pediatrician
Methods
• Study design
• Prospective study from September 2022 – August 2023.
• Study population
• All cases with suspect VAPP detected through AFP surveillance or AEFI
surveillance during the study period
• All 36 states and federal capital territory FCT of Nigeria
• Case detection and verification process
1. Detect and confirm AFP case
2. Detect “suspect” VAPP case
3. Confirm (or discard) VAPP case
Case definitions for Nigeria assessment
• AFP case
• Sudden or recent onset of floppy paralysis or muscle weakness due to
any cause in a child less than 15 years old, or paralytic illness in any
person regardless of age if a clinician suspects poliomyelitis.
• Suspect VAPP case
• AFP cases WITH laboratory result positive for Sabin/nOPV2 but negative
for WPV/VDPV  from a WHO certified polio laboratory,
• AND potential exposure to OPV (oral poliovirus vaccine) before paralysis
onset,
• AND residual paralysis at 60 days follow-up examination.
• AFP cases for whom 60-day follow-up was not possible because of death
or lost to follow up will also be considered suspect VAPP case
Case definitions for Nigeria assessment

•Confirmed VAPP case: clinical presentation compatible with poliomyelitis and demonstration of
causal association with OPV exposure
a. Recipient VAPP: vaccine received 4 – 40 days before the onset of weakness/paralysis.
b. Contact VAPP: known contact with a vaccine recipient or campaign conducted in the area of
residence within 4 - 75  days before development of paralysis.
• Discarded VAPP case: Inconsistent causal association with OPV immunization because an
underlying and or emerging condition (s) can explain the weakness/paralysis, and vaccine
detection was coincidental.
• Possible VAPP case: For patients who died or lost to follow-up, clinical presentation compatible
with poliomyelitis, exposure to OPV and absence of other cause for AFP.
Procedures for case identification and classification
Suspect
1. AFP case detection by facility/community focal personAFP case

2. AFP case verification and investigation by SO/PHO/APHO/DSNO

AFP case Non-AFP

Vaccine
3. Results of stool testing communicated to WHO WPV/VDPV or
negative

No VDPV/WPV
Lost to Residual
4. 60 day follow up by WHO SO/PHO/APHO/LGAF residual case or non-
F/U or paralysis =
Suspect VAPP paralysis polio AFP
Death

Possible Confirmed examDiscarded Discarded

VAPP or 5 .Neurological
VAPP VAPP VAPP
discarded6. NPEC/NEC evaluation
VAPP
 Data Analysis plan
• Data collection
• Clinical, vaccination and epi
information from cases available
in CIF, DCIF, NCEP/NCE report
• Type of vaccine virus isolated in
stools
• No. rounds and type of OPV
distributed in campaigns by
district
• Coverage for routine
immunization
• Analysis
• Epidemiological and clinical
characteristics of confirmed and
discarded VAPP cases
• Risk of VAPP per million OPV doses
distributed during the assessment
period
• Overall for all OPV used
• Per type of vaccine (mOPV2, bOPV,
nOPV2)
• Risk of VAPP per million birth cohort (by
number of surviving infants according to
UN population estimates)
Assessment of VAPP Risk in Nigeria 2022-23
Study procedures
1. AFP case detection and report

• AFP surveillance focal persons in health facilities and community informants

will detect suspect AFP cases
Detect

• And report the case to the disease surveillance and notification officer
(DSNO) of the local government area (LGA) using established process in the
surveillance network.
Report
 2. AFP case verification and investigation
For AFP cases, DSNO and/or assistant DSNO will do the following per WHO guidelines

• A Surveillance Officer, PHO, APHO, or LGAF from WHO will examine the case and
confirm:
• AFP case - < 15 years with flaccid paralysis of acute/recent onset or older
AFP person if clinician suspects polio
verification • Non-AFP case - h/o trauma, h/o chronic weakness/paralysis,…..

The DSNO/ADSNO will investigate the AFP case per WHO guidelines
1.Fill Case Investigation Form: Demographics, clinical symptoms, travel and
vaccination history
AFP 2.Organize stool collection and shipment to a WHO polio laboratory within 72
hours of collection
investigation

Public health officer =PHO), assistant public health officer =APHO; Local government facilitator=LGAF, SNO.
3. Laboratory testing
• Stool samples from all AFP cases will be tested for the presence of poliovirus in
a WHO accredited laboratory with standard methods
1. Poliovirus isolation through cell culture
2. Intratypic differentiation and genetic sequencing by RT-PCR
• Results available within 45 days of collection

Vaccine virus Negative Negative

(SL1, SL2, (inadequate (adequate WPV or VDPV
SL3,nOPV2) sample) sample)

60-day follow 60-day follow Non-polio AFP WPV or VDPV

up exam up exam case case

For this assessment Standard procedures for AFP surveillance

4. 60-day Follow up exam
• The PHO or APHO from WHO will visit all AFP cases (inadequate and adequate
samples) with vaccine virus (Sabin types 1, 2 or 3, or nOPV2) isolated in stools.
• The PHO/APHO will conduct a physical exam of the child using detailed case
investigation form (DCIF)

Residual Residual
Lost or Died weakness/paralysis weakness/paralysis
before follow-up present absent

Suspect VAPP Discarded VAPP

Submit to NEC/NPEC Continue Submit form and enter

investigation information in database
5. Neurological assessment of “suspect VAPP case”

• A neurologist/pediatrician will review all AFP cases with positive Sabin/nOPV2

Isolate AND residual paralysis at 60 days.
Neurologist • Within 7 days of the 60-day follow up
assessment • Use checklist to collect relevant clinical information and suspected diagnosis

The study coordinator will prepare a dossier with all relevant information:
• CIF, laboratory results, DCIF
Preparation • Neurologist report
of dossier • Other clinical documents and tests results
6. Causality assessment and classification
• The dossiers of all “suspected” VAPP cases and those without a 60-day follow-
up (lost/died) will be presented to the NEC and NPEC at a joint meeting
• The NPEC/NEC will review information and classify cases using a checklist for
causality assessment and the VAPP definitions.

Lost to follow-up Suspect VAPP

Possible VAPP Discarded VAPP Confirmed VAPP: Discarded VAPP

Recipient or
contact
Roles and responsibilities
Agency Role
US CDC, Atlanta • Funding,
• Technical support for design and implementation, writing protocol, analysis and
interpretation of data, report writing and development of manuscript
US CDC, Nigeria • Technical support for design and implementation of assessment, analysis and
interpretation of data, report writing and development of manuscript
NEOC/NPHCDA • Approval of assessment

AFENET • Coordination of study

• Development of study protocol
• Stakeholder’s sensitization and training/orientation data collectors
• Data management
• Writing report and manuscript
 Roles and responsibilities
Agency Role
WHO (Surveillance Officer • Support routine AFP surveillance Polio laboratory functions/activities
(Lead), PHO, APHO, LGAF) • Conduct 60 days follow-up exam of AFP cases with vaccine virus isolated in stools
• Arrange neurologist review of cases with persistent paralysis;
• Share forms of suspect VAPP cases with study coordinator

State Ministry of Health State • Coordination and supervision of AFP cases detection and investigation
Epidemiologist/ DSNO • Monitoring shipment of specimen to the National laboratory
DSNO/ADSNO • Investigation of AFP cases including specimen collection and transportation
• Referral of cases with residual paralysis and vaccine virus for neurologist review
Neurologist/Pediatrician • Detailed examination and neurological review of AFP cases with vaccine isolated in
stools and residual paralysis at 60 days

NEC AEFI/NPEC • Assessment of suspect VAPP cases for classification into confirmed / discarded
VAPP
Assessment of VAPP Risk in Nigeria 2022-23
Study Forms
Forms to use in the project

1. Case Investigation Form - Acute Flaccid Paralysis

2. Detailed case investigation form (for 60 days follow-up)
3. Neurologist Report
4. Causality Assessment checklist
Differential Diagnosis of VAPP
Neurologist / NPEC
 Clinical presentation of poliomyelitis
• Similar presentation if caused by vaccine or wild poliovirus
• Spinal paralysis - Typical presentation
• Progresses to the maximum extent within a few days
• Descending: starts proximally and progresses distally in extremities.

• Flaccid (in contrast to upper motoneuron source)

• Asymmetric: one extremity more affected; proximal muscles more
affected than distal muscles
• Frequent pain in muscles affected, backache
• Sensation not affected
• Diminished or absent deep tendon reflexes
• Individual is alert
• Usually fever present with paralysis development
Clinical presentation of poliomyelitis
• Other presentations
• Bulbar or bulbospinal (~ 20%) – depending on the anatomic location
of damage in the spinal cord or brainstem
• Affects cranial nerves and respiratory nerves
• Responsible for most of the deaths
• Severity is higher in adults than in children
Evolution

• Long term paralysis

• Partial or total recovery may happen within the first 6 months
through compensation from other muscles
• Paralysis/weakness after 60 days is required for VAPP classification
• Atrophy, muscle contractures and deformities observed long-term
• Post-polio syndrome: pain, worsening of residual weakness or
new weakness/paralysis 15-40 years after infection
• Observed in 25-40%
• Case fatality rate
• About 2-5% in children and 15-30% in adults
• Certain outbreaks of wild poliovirus associated with fatality rates
>30% (Namibia 2006, Congo 2010)
• Young adults and adolescent mostly affected
Elements to look to confirm VAPP
DNSO/ADSNO –
confirmed by
• Ascertain timing of last OPV dose – before or after paralysis onset neurologist,
• Ask the family and check card/registries for all OPV doses received
• Confirm with family that child did not receive additional doses after paralysis
• child found during a campaign
• HCW gave the child OPV after paralysis “to cure/protect” against polio
• Child received OPV during AFP case ascertainment
• Record most accurate date possible in the case investigation form
• Investigate exposure to vaccinated contacts
• Timing of last SIA in the area Neurologist,
• Presence of children below target for SIA in household NCP/NCEP
• Presence of children receiving RI in household – time of vaccination
• Rule out other causes of AFP using thorough clinical exam and available tests
 Causes of Acute Flaccid Paralysis
Site of lesion Condition, factor, agent
Anterior horn cells of Poliovirus, Non-polio enterovirus (EV 70, 71 and 68, Coxsackie A and B, echovirus)
spinal cord
Other neurotropic virus: Japanese encephalitis, Rabies, West Nile
Guillain-Barre Acute inflammatory polyradiculoneuropathy , Cytomegalovirus polyradiculomyelopathy
Syndrome Acute motor axonal neuropathy
Diseases of Myasthenia gravis, Lamber-Eaton myasthenic syndrome
neuromuscular Toxins from clostridium botulinum or clostridium tetani
junction
Venoms from snakes, frogs, poisonous fish, shellfish and crabs and arthropods
Pesticides: Organophosphates
Adulterated food products: cooking oil, mustard oil, Jamaican ginger tonic, flour
Peripheral Bacterial toxins: diphtheria, tetanus (cephalic form), Moraxella
neuropathies Viral infections: AIDS, rabies, cytomegalovirus, Epstein Barr, hepatitis B
Insects: Tick bite paralysis, spider venom, wasp venom, Lyme disease
Metals (lead, arsenic, thallium), antimicrobial or chemotherapeutic drugs, pesticides.
Plants and plant toxins: buckthorn, cycas, gloriosa superba (lily), Fungal mycotoxins
Causes of Acute Flaccid Paralysis
Site of lesion Condition, factor, agent
Spinal cord Space-occupying lesions such as abscesses, tumor or hematoma,
compression or
injury Trauma, postoperative spinal cord damage
Traumatic neuritis Intramuscular gluteal injection
Transverse myelitis M. pneumonia, Schistosoma, Cysticercus and other parasitic infections, enteroviruses
herpesviridae, rabies virus, unknown causes.
Muscle disorders Polymyositis: neoplasm, autoimmune disorder, viral, parasitic or bacterial infection
Hereditary disorders such as Werdnig-Hoffman disease, Wohlfart-Kugelberg-Welander
disease
Toxic myopathy
Metabolic and Acute hypokalemic periodic paralysis, Hypophosphatemia
nutritional disorders
Thyrotoxic periodic paralysis
Vitamin B deficiencies, cassava consumption, lathyrism from ingestion of certain peas
Other clinical Post-ictal hemiparesis (Todd’s paralyisi)
syndromes Bell’s palsy
 Differential Diagnosis (most common diagnosis)
Feature Poliomyelitis Guillain-Barré Syndrome Traumatic Neuritis Transverse Myelitis
(After Injection)
Time between onset 24- to 48-hours hours to 10 days hours to 4 days hours to 4 days
of paralysis and full
paralysis
Fever at onset High; present during onset Not common Commonly present Rarely present
and progression of paralysis before, during, and
only after flaccid paralysis
Flaccid paralysis Descending Ascending    
Muscle tone Reduced or absent in Global hypotonia Reduced or absent in Hypotonia in affected
affected affected limbs
Deep tendon reflexes Decreased or absent Globally absent Decreased or absent Absent early;
hyperreflexia late
Sensation Myalgia & backache; no Cramps; tingling; hypoesthesia Pain in gluteus; Anesthesia of lower
sensory changes of palms and soles hypothermia limbs with sensory
level
Cranial nerve When bulbar involvement Often present affecting VII, IX, Absent Absent
involvement present X, XI, XII
Respiratory When bulbar involvement In severe cases, enhanced by Absent Sometimes
insufficiency present bacterial pneumonia
 Differential Diagnosis (most common diagnosis)
Feature Poliomyelitis Guillain-Barré Syndrome Traumatic Neuritis Transverse Myelitis
(After Injection)
Autonomic signs and Rare Frequent blood pressure Hypothermia in Present
symptoms alterations; sweating; affected limb
blushing; body
temperature fluctuations
Cerebrospinal fluid Inflammatory Albumin-cytologic Normal Normal or mild
dissociation elevation in cells
Bladder dysfunction Rare Transient Never Present
Nerve conduction Abnormal: anterior horn cell Abnormal: slowed Abnormal: axonal Normal or abnormal;
velocity, third week disease (normal during first conduction; decreased damage no diagnostic value
2 weeks) motor amplitudes
Electromyography at Abnormal Normal Normal Normal
3 weeks
Sequelae at 3 months Severe, asymmetric atrophy; Symmetric atrophy of distal Moderate atrophy; Flaccid diplegia;
skeletal deformities muscles only in affected limbs atrophy after years
developing later
Questions
For more information, contact CDC
1-800-CDC-INFO (232-4636)
TTY: 1-888-232-6348 www.cdc.gov

The findings and conclusions in this report are those of the authors and do not necessarily represent
the official position of the Centers for Disease Control and Prevention.