1. Approaches to modeling, parameter estimation, and policy guidance during the endgame Dr Isobel BlakeDr Kath O’Reilly Research FellowMRC Research Fellow Vaccine Epidemiology Research Group MRC Centre for Outbreak Analysis and Modelling Imperial College London

2. Policy guidance For modelling to be useful it must be In collaboration with experts, policy makers, program managers, field staff Timely Appropriate Interpretable Examples provided: Age and geographic targeting vaccination during outbreaks Global risk assessment Role of tOPV in cVDPV emergence Papers with other examples provided at the end

4. Targeting immunisation campaigns Are there benefits from increasing the upper age-limit of vaccination campaigns even in the absence of cases in older ages? What is the impact of campaigns in accessible areas in stopping transmission in inaccessible areas? Need to understand contribution to transmission by different groups

5. Dynamic transmission model and parameter estimation Based on stochastic SEIR framework Realistic incubation period of 16 days (Erlang distribution) Random process of case detection (1:200) Allow different transmission rates between ages (+ geographic areas) Incubation period (16 d) Latent period (4 d) Infectious period (? d) SEI R 1:200 reported polio cases Parameter estimation: Maximum likelihood through iterated particle filtering Ionides et al. 2006 PNAS 103(49) R package ‘pomp’ (Partially observed Markov process) Fit of different patterns of mixing by age compared using the likelihood (AIC)

6. Tajikistan and Republic of Congo model fit bOPV outbreak suspected by local physicians Blake IM, Martin R, Goel A, Khetsuriani N, Everts J, et al. (2014) PNAS 111: 10604- 10609

7. Contribution to transmission by age ParameterTajikistanRepublic of Congo Reproduction number for children 0-5 years old at the start of the outbreak 2.18 (2.06 – 2.45)1.57 (1.53 – 3.39) Reproduction number for older children and adults at the start of the outbreak 0.46 (0.42-0.52)1.85(1.83 – 4.00) Blake et al, 2014 PNAS

8. Policy guidance Contribution of adults and older children to transmission is likely to depend on setting No support for expanding age range for vaccination campaigns in absence of adult cases Late detection of outbreak, limited impact of response, need to enhance surveillance to detect earlier

9. Impact of SIAs on inaccessible areas: Somalia 199 confirmed cases 96% cases in Southern and Central Somalia 90% of these in children <5 yrs Estimate Effective reproduction for Banadir 5.9 (4.8 – 8.3) Effective reproduction number for Accessible and inaccessible areas 2.1 (1.8 – 2.8) Duration of infectiousness (days) 9.6 (6.4 – 12.1) Reported case to infection ratio in inaccessible areas 1:902 (1:1538 – 1:606) Divide Southern and Central Somalia into 3 areas (meta-population model) Evidence for a higher transmission rate within Banadir over homogeneous mixing ΔAIC = 105

10. Somalia outbreak: Impact of response tOPV campaign bOPV campaign + Date outbreak confirmed Best fit model Prediction in absence of response Prediction of impact if first early campaign missed Campaigns prevented 345 (67%) cases Strong herd effect inaccessible areas – 60 (58%) cases prevented Early response important

11. Preventing VDPV emergence after OPV withdrawal -There is a trade-off between OPV use and risk of VDPV outbreak -The risk is greatest at low to intermediate levels of SIA coverage or when the number of SIA is small Model without routine immunisation Sabin-R 0 =0.5, VDPV-R 0 =5, OPV-take=55% In a setting with low RI, how many OPV campaigns are needed to reduce the risk of VDPV outbreak? 1 or 2 SIA could increase the risk compared to doing nothing Marga Pons Salort

12. Risk factors for VDPV2 emergence in Nigeria (2004-2014) 29 emergence events Case-control analysis of risk of VDPV2 emergence comparing districts where first VDPV2 detected within a genetic cluster (cases) with districts with no emergence (controls) for data in 6 month periods Matching on time-period (6 months) & zone (NE, NW, NC, SE, SW, SC) Strategy for tOPV SIA preceding serotype 2 OPV withdrawal: sufficient number to achieve high serotype 2 population immunity and high coverage Marga Pons Salort

13. Global risk assessment of outbreak risk Outbreak RA important for immunization planning Analysis of risk in collaboration with WHO HQ began in 2009 Regional RA also being made RATT initiated in 2012 CDC, WHO, Unicef, IDM and (recently) Imperial Feeds into SIA options and immunisation planning Joint WHO/Imperial model

14. A rapid assessment of risk, based on data Rather than include everything in RA, test everything Output must be easily interpretable Flexible enough to include expert assessment Risk assessment made from data on; Population immunity Previous importations in <4 years Migrants from polio affected countries % in-country population displaced ModelPredictive ability (%) Full WHO score model77.8 Reduced WHO score model80.0 Regression model81.5 Regression model (+refugees+mig) 83.3 Comparing 6 month ahead predictions

15. Note: VDPVs in South Sudan and Madagascar not included in the colour-scheme

16. Other examples OPV & IPV vaccination efficacy (not complete list) Jafari H, Deshpande JM, Sutter RW, Bahl S, Verma H, Ahmad M, Kunwar A, Vishwakarma R, Agarwal A, Jain S, Estivariz C, Sethi R, Molodecky NA, Grassly NC, Pallansch MA, Chatterjee A, Aylward RB. Polio eradication. Efficacy of inactivated poliovirus vaccine in India. Science. 2014 Aug 22;345(6199):922-5. O'Reilly KM, Durry E, ul Islam O, Quddus A, Abid N, Mir TP, Tangermann RH, Aylward RB, Grassly NC. The effect of mass immunisation campaigns and new oral poliovirus vaccines on the incidence of poliomyelitis in Pakistan and Afghanistan, 2001-11: a retrospective analysis. Lancet. 2012 Aug 4;380(9840):491-8. Silent transmission Mangal TD, Aylward RB, Grassly NC. The potential impact of routine immunization with inactivated poliovirus vaccine on wild-type or vaccine-derived poliovirus outbreaks in a posteradication setting. Am J Epidemiol. 2013 Nov 15;178(10):1579-87. Waning immunity Grassly NC, Jafari H, Bahl S, Sethi R, Deshpande JM, Wolff C, Sutter RW, Aylward RB. Waning intestinal immunity after vaccination with oral poliovirus vaccines in India. J Infect Dis. 2012 May 15;205(10):1554- 61.

17. Acknowledgements Imperial College Nick Grassly, Marga Pons Salort, Tara Mangal, George Sherriff, Lucy Li, Natalia Molodecky, Ed Parker GPEI staff involved in recent polio outbreak investigations WHO Ajay Goel, (Chris Wolff), Bruce Aylward, Ravi Shankar, Paul Chenoweth CDC Rebecca Martin, Nino Khetsuriani, Steve Wassilak, Abdirahman Mahamud, Cara Burns, Steve Oberste BMGF Ananda Bandyopadhyay, Chris Wolff Funding