IPV - The renewal of a classical tool for Polio eradication (Moscow Chumakov Institute Dec 2014) презентация

MD
Medical Affairs
Sanofi Pasteur, Lyon, France

performance of tOPV against PV2
Type 3: no AFP cases since Nov. 2012 (Nigeria): Eradicated?
Type 1: areas of transmission are diminishing
High reduction of the genetic diversity of circulating viruses
Strong reduction in the number of cases
VDPV
No more active cVDPV type 1 and 3 outbreaks
Two active cVDPV type 2 outbreaks
Nigeria (since 2005): declining slowly (the last AFP onset on Aug. 2014)
Pakistan (since 2012): seems to progress (the last AFP onset on June 2014)
In 2014, the total number of AFP cases due to WPV1 (more than 247) will be lower than VAPP cases (several hundreds) and cVDPV cases (more than 39)

Poliomyelitis global epidemiological situation (as of Nov. 2014)

http://www.polioeradication.org/Dataandmonitoring/Poliothisweek.aspx

circulation of polioviruses and control of paralytic poliomyelitis

The by-dose (and cumulated) and by-serotype SC and gut immunity installment in vaccinees is inconsistent and low in many settings and therefore vaccine effectiveness is sub-optimal despite vaccination programs relying on > 10 consecutive OPV administrations up to 5 years of age
Host-related: concomitant viral, bacterial or parasitic enteric co-infections; The gut microbiome; Environmental Enteropathy syndrome; Post-birth short-lived inhibitory factors in some ethnicities / settings
Vaccine-related: intra-vaccine viral interference (type 2 the best replicant +++)
Prevalence of maternally-transmitted Abs
The use of mOPV1, mOPV3 and bOPV1&3 do improve the immune responses against polioviruses types 1 and 3, and therefore do improve their effectiveness

presents more than 1% genomic divergence from the parental Sabin poliovirus in their VP1 sequence (0.6% for type 2)
Accumulation of mutations (1% nucleotide change / yr) or recombination with other enteroviruses of the replicating and/or inter-human circulating Sabin virus within the vaccinee’s guts or within vaccinee’s contact’s guts
When detected, prove that such lineage might circulate since at least 1 yr
Reverted to neurovirulence (or paralyticogenicity) and transmissibility

cVDPV is a VDPV which finds adequate conditions for a sustained transmission in a human community and responsible for at least >2 AFP cases
Low vaccination coverage
Poor sanitation conditions
High population density
Lack of competition from WPV circulation
Tropical conditions

3 type 3) have been responsible for ~ 700 AFP cases - 2 outbreaks still active in 2014 -

CHINA
2004
cVDPV1

NIGERIA
2005-14
cVDPV2

SOMALIA
2008-13
cVDPV2

INDIA
2009-10
cVDPV2

MADAGASCAR
2001-02
cVDPV2

YEMEN
2011
cVDPV2

AFGHANISTAN
2010-13
cVDPV2

MADAGASCAR
2005
cVDPV2

NIGER
2006
2009-11
2013
cVDPV2

YEMEN
2012
cVDPV3

PAKISTAN
2013-14
cVDPV2

KENYA
2012
cVDPV2

http://www.polioeradication.org/Dataandmonitoring/Poliothisweek.aspx

CAMEROON
2013
cVDPV2

with neurologic deficit 60 days after onset caused by a vaccine-related virus
Diffusion from the gut of a mutant virus having re-acquired the neurovirulence phenotype & clinically indistinguishable from AFP induced by WPVs
May affect both OPV vaccinees & contacts of recent OPV recipients
Most of the time occur in primo-infected
Risk factors
First-dose recipients, as progressive immunity decreases the risk (except birth)
Contact to OPV recipients
Level of exposure to WPVs
Protective factors: Maternally transmitted Abs and birth OPV vaccination
Type 3 (50%) > Type 2 (40%) > Type 1 (10%)
Incidence
One case (in recipients and contacts of recipients) per 2,9 - 3,3 Mdose distributed
2 to 4 cases per million birth cohorts
One case per 1,4 M 1st-time recipients (US) or 2,8 M 1st-time recipients (India)
Leads to 250 to 500 of VAPP cases per year on a global basis (estimation)

the same panel of immune responses

OPV due to the local (mucosal) multiplication of the virus and of its derived “mutants”, is able to induce mucosal immunity (mucosally-secreted sIgA & mucosal immune cells) and a large panel of circulating IgG exhibiting PV neutralizing activities

IPV is able to induce high levels of poliovirus neutralizing circulating Abs able to neutralize circulating viruses and also to transude onto mucosal (intestinal and oro-pharyngeal) surfaces (with variable half-life) allowing a certain degree of mucosal protection (better at the oro-pharyngeal level than at the intestinal level)

of the same magnitude

OPV- and IPV-vaccinees cannot resist to a poliovirus infection but OPV-vaccinees will be infected for much shorter durations than IPV-vaccinees
The epidemiological consequences of this vary according to the ecological conditions prevailing in the affected communities
In many situations, an IPV-based program do have no effect on preventing the installation of a silent sustained PV transmission: Israel, Q2-3 2013
Whereas in other situations, it does: France 2000-2014: no isolation of WPV in environmental samples, regular isolations of imported Sabin-PV and no AFP cases and no evidence of spread within communities

Duintjer-Tebbens RJ & al. Risk Analysis 2014; 33: 544-605
Shulman LM & al. Euro Surveill. 2014; 19: pii=20709
Antona D & al. Eur J Microbiol Infect Dis 2007; 26: 403-412and Antona D & al. BEH 2010; 48: 489-493

at least end of 2015

future milestones

Six months of silence for the cVDPV2 outbreaks in Pakistan and Nigeria
March 2015
All countries having introduced IPV in their routine NIP
End of 2015
tOPV to bOPV1&3 switch
April 2016

work done at RIVM, Ch.Mérieux at the Mérieux Institute drove the large-scale industrialization of the modern IPV (eIPV)

In the early 1970s
Safety of OPV in question
Efficacy in routine immunization with OPV SC sub-optimal in the tropics
Very limited IPV industrial capacity
The challenges
To really scale up the industrial IPV production
To improve and standardize potency (in vitro antigenicity assay)
To demonstrate immunogenicity and efficacy both in developed and developing countries
To license products as broadly as possible

and the RIVM scientist A. van Wezel

times with a long interval (6 month) in developing countries

Several dose-response (using 2- or 4-fold increase incremental antigen contents) clinical trials conducted in 1977-80 with IPV antigens combined or not with DTwP vaccine
Ags and vaccines prepared by RIVM (PMKC) and Mérieux Institute (PMKC from wild monkeys, then tertiary MKC from captive-bred monkeys and then Vero)

been demonstrated several times through field studies

Melnick calculated an efficacy of 96% through two polio seasons in Houston
In Senegal, two doses of a DTwP-IPV combination vaccine were given in the Kolda area, which subsequently suffered an outbreak of WPV1
A case-control analysis revealed an efficacy for one dose of 36% (95% CI: 0% to 67%) and for two doses of 89% (95% CI: 62% to 97%)
In the North Arcot region of India, J. John compared OPV in one district with IPV vaccination in two other districts
Vaccination coverage with three doses rose to 85% to 90% in the OPV districts and 75% to 80% in the IPV districts
Case-control analysis revealed an efficacy of 92% for IPV and 66% for OPV
During the introduction of IPV into Canada, efficacy of the vaccine was calculated at more than 90%

Melnick JL & al. JAMA 1961; 175: 1159-1162; Stoeckel P & al. Rev Infect Dis 1984; 6(S2): S463-S466; CDC. MMWR 1988; 37: 257-259; John T. 1992. World Conference on Poliomyelitis and Measles, New Delhi. Varughese PV & al. Can J Public Health 1989; 80: 363-368

after 1st dose, public health impact not yet known

One single IM IPV dose in naive 4-month old infants seroconverts 32%-63% (all types)
97%-98% of infants who didn't seroconvert after single IPV dose evidenced immunological priming (against all types)

Resik S & al. NEJM 2013

P1

P2

P3

subjects after two doses

Vidor E & al. PIDJ 1997; 16: 312-322

prevalence and duration (intensity?) of PV intestinal excretion (all types) following tOPV challenge compared to 1st time tOPV-recipients

Rennels & al. PIDJ 2000; 19: 417-23; Laassri M & al. JID 2005; 92: 2092-8; Laassri M & al. 2006; 193: 1344-9

1st time tOPV-recipients

76% of 2-dose IPV-primed excreted PV vs 92% of 1st time tOPV recipents at 1 week

37% of 2-dose IPV-primed excreted PV vs 81% of 1st time tOPV recipents at 1 week

16: 312-322

infant primary immunization

Number of primary series injections (3 > 2 > 1)
Age at first injection (older [3 months or later] > younger [6 weeks of age] > birth)
Interval between doses (more than 2 months > 2 mo > 1 mo)
Ecological context (presence of passively transmitted Abs from mother)
Presence of an aluminium salt adjuvant in the vaccine formulation (IPV-containing adjuvanted multivalent combination products > standalone un-adsorbed IPV)

+

-

-

vaccines in 7 countries since 1986
USA (5), China (3), UK, Brazil, Mexico, Taiwan & Guatemala
1 or 2 IPV followed by 1 or 2 OPV administered as « 2+1 », « 3+1 » or « 3+0 » regimen
No OPV given at birth in all cases
Several types of study design
Non-randomized descriptive-only licensing or launch studies or RCTs between sequential schedules and IPV-only and / or OPV-only schedules
Some trials have investigated prevalence, intensity, duration and genetics of PV intestinal excretion after OPV vaccination / challenge
Several types of IPV-containing vaccines
IPV stand-alone (Vero-IPV or MRC5-IPV)
wP-based combinations
aP-based combinations

in still-at-risk communities

Address most (if not all) VAPP cases
Combine the full benefit of both vaccines in terms of breath of individual responses (mucosal and humoral)
The incorporation of at least one dose of IPV at the start of the immunization schedule increase post-primary series Ab levels compared to OPV-only schedules
I-I-O primary series during the first year of life schedule is the best performer in terms of absolute post-primary series antibody levels (versus OPV-only)
≥ 2 doses of IPV during the first year of life seems able to reduce prevalence and duration (intensity?) of PV intestinal excretion (all types) following PV infection compared to 1st time tOPV-recipients
Much stronger effect on oro-pharyngeal excretion
The use of OPV in populations around the "uncovered" will allow their "indirect vaccination" if environmental / ecological conditions are adequate

by multiples variables and could target variable objectives (more or less compatible)

If high, maintain OPV use

Early IPV administration is less immunogenic

If low, maintain OPV use through Routine Immunization or through SIAs

Start polio immunization with IPV as early as possible (birth OPV not a risk factor)

An aP-IPV combo will drive for a “3+1” regimen

Risk level of polioviruses importation

Performance of routine NIP (by-dose coverage and uncovered)

Desire to eliminate VAPP occurrence

Prevalence of PV Abs in pregnant women

Nature of IPV-containing vaccines available for the NIP

Desire to eliminate VDPV risks

Total cessation of OPV use or >98% OPV coverage

Desire to ensure long term protection

Budget

Will drive Nb of doses in the regimen & Nb of campaigns

Introduce toddler and / or pre-school booster(s)

The polio immunization regimen best suited to a country/region depends on the importance of each of the above drivers and objectives

Sutter R, Kew O, Cochi S. Poliovirus vaccine - Live. Vaccines 6th edition. 2013: 631-686
Vidor E, Plotkin.S. Poliovirus vaccine - Inactivated. Vaccines 6th edition. 2013: 605-630
WHO. WER 2014; 89: 73-92

their routine publicly funded infant National Immunization Programs (and much more countries in their private markets)

IPV-only (46 countries)

Sutter R & al. Poliovirus vaccine-Live. Plotkin SA, Orenstein WA, Offit P (eds), 6th edition, in Vaccines. W.B. Saunders Company, Philadelphia, PA, 2012
Vidor E & al. Poliovirus vaccine-Inactivated. Plotkin SA, Orenstein WA, Offit P (eds), 6th edition, in Vaccines. W.B. Saunders Company, Philadelphia, PA, 2012

- IPV-only supplemented with OPV SIAs
- IPV-followed-by-OPV Sequential (24 countries)
- Mixed / Combined IPV / OPV

programs and routine use of IPV-containing vaccines over 35 years, it is Sanofi Pasteur’s conviction that …

A “2-dose IPV IM-dosing regimen” should be the backbone of all polio immunization regimen
All IPV dosing(s) done on the top of this backbone IPV regimen will improve duration of immunity and maximize mucosal protection
Every opportunity of catching 0 to 2 years old infants living in LICs and LMICs should be used to administer as early as possible this backbone regimen whatever the number and type of OPV administered before, during or after these IPV dosing opportunities
All OPV dosing(s) done on the top of this backbone IPV regimen will re-enforce the quality of the intestinal immunity at the individual level and at the community level (if ecological conditions permit) and therefore will decrease the chain of poliovirus transmission

has been accumulated with IPV-containing vaccines
A 2-dose IPV IM-dosing regimen should be the backbone of all polio immunization regimens
Multiples drivers govern the choice of the polio immunization regimen to be used in each situation
The most medically- and epidemiologically-sounded regimen in polio-afflicted communities is the IPV-followed-by-OPV sequential schedule made of I – I – O – O given as a “3+1”
Many countries have already adopted IPV with different approaches in terms of immunization regimen each one adapted to specific country situation and objectives