Poliovirus vaccines: Their development and use, now and in the future

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1 Karl Landsteiner Poliovirus vaccines: Their development and use, now and in the future Jeffrey Almond Vice President Discovery Research and External R&D sanofi pasteur Outline Briefly revisit OPV and IPV history Summarize the OPV experience and progress on global eradication Summarize IPV experience and recent developments Conclude on future requirements and options available 2

2 Significant progress to control polio made over the past 20 years thanks to the Global Polio Eradication Initiative Polio Eradication Progress, / 350,000 cases estimated 2008 / 1,655 cases Certified Polio-free regions (114 countries) Not Certified but non-endemic (73 countries) Endemic with wild polio virus (4 Countries) Thanks Thanks to to GPEI, GPEI, >5 >5 million million people people healthy healthy today, today, who who would would have have been been paralyzed, paralyzed, had had they they not not received received polio polio vaccines vaccines Adapted from WHO GPEI communication 3 Despite sustained investment, Global Polio Eradication Initiative is facing significant challenges Global Polio case count [ *] GPEI Annual Expenditure [ ] *As of October 20 th Financial Resource Requirements, Contributions and Funding Gap * >1,500 >1,500 cases/year cases/year reported reported since since leading leading to to iterative iterative GPEI GPEI timelines timelines shift shift Adapted from WHO GPEI communication 4

3 Polio is still endemic in 4 countries, reflecting both vaccination failure and failure to vaccinate West UP Bihar Rest of country Polio Endemic countries in % 80% INDIA 60% 40% Polio cases despite high vaccination coverage Vaccine Failure (Poor OPV efficacy) 20% 0% % 0 dose 1-3 doses 4-6 doses 7+ doses High risk Medium risk Rest of country 80% NIGERIA 60% Failure to vaccinate While While awareness/program awareness/program aspects aspects and and political political buy-in buy-in are are at at stake stake in in AFG, AFG, PAK PAK and and NIG, NIG, immunization immunization strategies strategies could could be be revisited revisited in in India India 5 Adapted from WHO GPEI communication 40% 20% 0% dose 1-3 doses 4-6 doses 7+ doses The Early days Of Polio Vaccines Egyptian stele (stone carving) dating bet and 1350 B.C

4 . Poliovirus Poliovirus was discovered by Karl Landsteiner in 1909 In collaboration with C. Levaditi of Institut Pasteur Paris, the infectious agent was shown to be a filterable virus that could spread along nerves and be transferred between monkeys John F. Enders and his coworkers (Weller and Robbins) discovered in 1949 a method of growing the viruses on tissue in the laboratory 7 Jonas Salk 8

5 1st Salk Polio Vaccine 1/ Salk, Jonas & al., Federation Proc. 11:480, 1952 Immunization of Monkeys with Polioviruses grown in Cultures of Monkey Tissue 2/ Salk, Jonas & al., J.A.M.A., March 28, 1953 Studies in Human Subjects on Active Immunization Against Poliomyelitis Type 1 : Mahoney Type 2 : MEF-1 Type 3 : Saukett Inactivation : 0.4% of a 37% solution of formaldehyde USP. Test of inactivation in cynomologus monkeys by intracerebral inoculation of 0.5ml of fluid in 6 to 10 animal. National Foundation places a $9 million order to six drug companies to start stockpiling. 9 The Francis Field Trial A total of 1,829,916 children in communities from all parts of the US, Canada and Finland participated. The experiment involved vaccinees, observed controls and placebo controls. On April 12, 1955, Jonas Salk, along with his mentor, Dr. Thomas Francis, and the March of Dimes announced : The Salk polio vaccine works. "Safe, effective, and potent." The Salk polio vaccine was 60-90% effective in preventing paralytic polio. On the basis of the results of the trial and the data presented by 6 manufacturers, the Salk Vaccine was licensed within a few days after these results were announced. 10

6 Albert Sabin 11 Sabin live attenuated Oral Poliovirus Vaccine (OPV) Hilary Koprowski had started work on an attenuated oral vaccine in 1948 at Lederle. First clinical trials were in A mass immunization campaign was organized in the Congo in 1957 with a type 1 vaccine, and soon a type 3. By 1959 over 46,000 children had been immunized with the type 1. Efficacy in that tropical setting was 60%. Sabin started working on attenuated strains in Merck Laboratories prepared industrial lots of genetically segregated strains in Sabin convinced the Russians to try the vaccine in the Soviet Union. In 1957 the World Health Organization (WHO) decided Dr. Sabin's vaccine deserved world-wide testing. He was invited to administer the vaccine to large groups of children in parts of Russia, Holland, Mexico, Chile, Sweden, and Japan. 1961/2 monovalent oral poliovirus vaccines (MOPV) licensed; , trivalent oral poliovirus vaccine (OPV) licensed. 12

7 13 Effects of vaccination against Poliomyelitis USA Poliomyelitis in the USA [reproduced from Salk, D. Rev. Infect. Dis , 228 by permission of the University Of Chicago Press] 14

8 Significant progress to control polio made over the past 20 years thanks to the Global Polio Eradication Initiative Polio Eradication Progress, / 350,000 cases estimated 2008 / 1,655 cases Certified Polio-free regions (114 countries) Not Certified but non-endemic (73 countries) Endemic with wild polio virus (4 Countries) Thanks Thanks to to GPEI, GPEI, >5 >5 million million people people healthy healthy today, today, who who would would have have been been paralyzed, paralyzed, had had they they not not received received polio polio vaccines vaccines Adapted from WHO GPEI communication 15 VAPP (Vaccine associated paralytic poliomyelitis) VDPV (Vaccine-derived Polio viruses) and Long term excretors

9 17 18

10 19 Table 1 Base at position 472, time of isolation, neurovirulence and temperature Sensitivity of Sabin type 3 vaccine-derived strains of poliovirus Virus Base at position 472 Time of isolation after vaccination Mean histological lesion score Rct marker test Sabin vaccine U 0.36 > 5.5 (rct - ) DM1 U 24 H ND ND DM2 U 31 H (rct - ) DM3 U / C 35 H ND ND DM4 C 47 H (rct - ) DM38 C 18 days ND ND DM119 C 3-4 weeks (rct - ) 20

11 Elizabeth Minor : Recombinant Type 3 viruses 21 Areas with confirmed polio cases- Haiti & Dominican Republic, AFP cases, 21 proven to be due to cvdpv Type 1 22 Weekly Epidemiological Record WHO 2002 ; 13, 77 :

12 Relationship Between Sabin 1-Derived Isolates from Haiti and the Dominican Republic to Type 1 Wild Polioviruses BRAZIL 88 HAITI 85 DOMINICAN REPUBLIC 82 DOMINICAN REPUBLIC 80 GUATEMALA 87 SABIN 1 DOMINICAN REPUBLIC 00 HAITI 00 SUDAN 99 CHAD 99 LIBERIA 99 COLOMBIA 91 PAKISTAN 00 PAKISTAN 00 SOMALIA 00 AFGHANISTAN 99 SIERRA LEONE 99 CHINA 99 BANGLADESH 99 BANGLADESH 99 ANGOLA 99 VP1 (906 nt) 0.1 CENTRAL AFRICAN REPUBLIC 99 CAMEROON 99 LIBERIA 99 GUINEA NIGERIA 99 NIGER 99 Sabin 1-Derived Poliovirus Isolates from Hispaniola Outbreak Recombination Patterns in Non-Capsid Sequences AAA Sabin 1 VP2 VP3 VP1 2A 2B 2C 3A 3C 3D n VP2 VP3 VP1 2A 2B 2C 3A 3C 3D AAA n Haiti (Port-de-Paix) Isolate (n = 1) VP2 VP3 VP1 2A 2B 2C 3A 3C 3D AAA n Dominican Republic/Haiti Isolates (n = 21) VP2 VP3 VP1 2A 2B 2C 3A 3C 3D AAA n Dominican Republic Isolates (n = 3) 24

13 Long Term Excretors: The Case of Birmingham man Hypogammaglobulineamic - requires IV serum globulins for healthy life Detected in 1996 as part of a monitoring programme (he was a control) Poliovirus type 2 in stool appeared vaccine-like but substantially evolved and neurovirulent Monitored up to present day and still infected/shedding (~150 sequential isolates). And having children. Last vaccinated (from memory) with OPV around Comparison of type 2 poliovirus sequences through VP1/2A junction 7079ind ind ind pak9 5896vtn vtn cae isr yug wse col per geo egy egy Sabin els Order of isolation of patient samples Patient isolates 25 % difference between sequences 0 26

14 Molecular clock for poliovirus evolution 6 Percentage of changes % changes/year Time post-vaccination (days) 27 Neurovirulence test Clinical Score Mean Lesion Score Sabin 2 attenuated 0/ neurovirulent 8/ /98 neurovirulent 4/ virus isolated from a fatal case. 28

15 Excretion of poliovirus type 2 by an immunodeficient patient 6 1st dose of immunoglobulin 2nd dose of immunoglobulin Titre of virus pfu/ml (log) Jan Feb Mar- Mar- Mar- Mar- Apr- Apr Apr Apr Apr- Apr- Apr- Apr- Apr- Aug- Jan- Mar-Aug- Jan- Apr Date of Sample Effect of Pleconaril on SK isolates µg/ml Concentration of pleconaril 0.001µg/ml 0.01µg/ml 0.1µg/ml 1µg/ml Log difference in virus titre Sabin 2 10/01/01 22/08/

16 Titre of virus excreted during treatment with Breast milk End of first round End of second round Breast milk batch number Virus excreted (log pfu/g of faeces) Days after commencement of treatment 31 Birmingham man : The type 2 paradox OPV use has lead to the eradication of polio type 2 BUT OPV has caused the persistence of polio type 2 in a form that (to date) cannot be eradicated 32

17 Genetically stabilised Sabin type 3 strains S15 & S16 C C C A A G A C C G A U G C C G C 490 A A S15 S16 C G G C 510 U A or G C A U A U 480 C G G U A C U A C C A U G G A G C G G U G C C U U U G C G A 530 A U G A A A C G C G CA A A A Courtesy of A. Macadam 33 Conclusions on OPV OPV trivalent and recently monovalent have been paramount in driving the GPEI and has brought use to the brink of eradication. BUT OPV strains can : Through replication in the gut of the vaccinees - revert directly to a virulent phenotype, causing VAPP in vaccinee (type 3) and contacts (type 2) Recombine with other enteroviruses to give neurotropic viruses of unpredictable fitness that can spread in a partially vaccinated community and cause disease (Haiti experience). Establish chronic infections in immunodeficient individuals and drift in genotype and phenotype in an unpredictable way. Bottom line : OPV strains are live polioviruses and ultimately become part of the eradication problem. Disseminating them in a post-eradication environment (global or regional) no longer makes sense. Disseminating them in the pre-eradication environment risks the events above and should be phased out as soon as alternatives are available. 34

18 What Role for IPV in the End Game and beyond? 35 Pre-eradication will be extended as Wild Polio Virus cases continue to be reported Today WPV Containment & Certification VAPP/VDPV Elim. & Verification 'Post OPV' Era Fill mopv stockpile Stop topv Stockpile maintenance IPV? Last WPV case WHO s WHO sstrategic Advisory Advisory Group Group of of Experts Experts [SAGE] [SAGE] on on IPV IPV immunization immunization will will issue issue revised revised guidelines guidelines on on IPV IPV use use in in Pre-eradication Pre-eradication period period (expected (expected April April 2010) 2010) Adapted from WHO GPEI communication 36

19 9 month-old Ivory Coast Children Seronegative after 3 Doses of OPV and Then Given 1 Dose of OPV or IPV Morinier, Lancet 1993 OPV IPV Type 1 4/28 (14%) 22/27 (81%) Type 2 4/15 (27%) 12/12 (100%) Type 3 2/43 (5%) 28/42 (67%) 37 Seroconversion rates for poliovirus types 1,2,3 after 3 doses of inactivated poliovirus vaccine, Puerto Rico Dayan GH, et al. JID 195:12-20,

20 WHO is now foreseeing universal use of IPV in the posterdication era and is pushing for affordable IPV options Today WPV Containment & Certification VAPP/VDPV Elim. & Verification 'Post OPV' Era Fill mopv stockpile Stop topv Stockpile maintenance Last WPV case Refine options for IPV use Optimize IPV use Pursue IPV use In In addition addition to to its its use use in in pre-eradication pre-eradication setting, setting, IPV IPV is is to to become become the the polio polio immunization immunization pillar pillar once once WPV WPV circulation circulation is is controlled controlled 39 Adapted from WHO GPEI communication Sabin IPV? Can Sabin IPV allow new manufacturers to enter in the field of IPV manufacturing with minimal containment risk? The manufacturing facility escape of Sabin virus leading to emergence of virulent cvdpvs still remains a risk 40

21 IPV-Containing Combinations for Infants sp (only) Product Portfolio : complexity... pentavalent 2I//A WI//A 5mI A5I Td5I tetravalent 5mI//A hexavalent 2I AR2I WI OPV I monovalent mi DTmI TdmI 17 Formulations bivalent T Polio DT Polio Td Polio trivalent pentavalent Product Portfolio WI//A 5mI 30 Filled Products 2I//A A5I 5mI//A hexavalent AR2I IPV OPV OPV I pentavalent monovalent WI//A 5mI Td5I 5mI//A A5I 2I//A tetravalent hexavalent 2I AR2I WI OPV T mi Polio DT Polio TdmI DTmI Td Polio bivalent trivalent 450 Finished Products I monovalent Td5I tetravalent 2I WI mi T Polio DT Polio bivalent Td Polio TdmI DTmI 41 ti l t OPV IPV vero IPV mrc5 IPV reduced schedule is promoted by WHO as a way to implement more easily IM-based vaccination programs There is no doubt that the concept is valid from a clinical standpoint «modern» IPV has been developed (Ag content) with the objective of having a vaccine working with 2 doses given six month apart in tropical settings Implementing such an approach would necessitate the use of two separate vaccines Penta (IPV-free) and hexa products to be used in mixed hexapenta schedules Penta (IPV-free) and IPV standalone products to be used in coadministration mode While While this this approach approach is is relevant, relevant, the the programmatic programmatic constrains constrains might might be be difficult difficult versus versus a hexa-based hexa-based program program 42

22 Supply and cost 43 Single layer of Vero cells on micro beads Electronic microscopy J. Tektoff, IM *VERO chosen with J. Salk, J. Petricciani (NIH, P. Albrecht lab.) and P. Stœckel as part of a FAIR assessment of continuously cell lines candidates for vaccine production; see Cell Substrates for Biologics Production : factors affecting acceptability in Cell Substrates, John Petricciani, BOB, FDA (Plenum Publ. 1979). 44

23 Recent third party assessment suggests that IPV capacity will be adequate to meet demand IPV demand will raise from 80 to 425 million annual doses in the post eradication era IPV capacity has the potential to expand to ~ 400 million doses if demand materializes Salk Salk IPV IPV remains remains the the most most viable viable option option and and capacity capacity will will meet meet the the post post eradication eradication worldwide worldwide demand demand 45 Source : O.WYMAN report Break-even IPV prices Polio vaccine alternative 2 doses IPV in a 10-dose vial 3 doses IPV in single-dose vial 3 doses IPV in 10-dose vial 3 doses IPV-DTPa-Hib 3 doses IPV-DTPa-Hib-hepB 4 doses IPV in single dose vial 4 doses IPV in a 10 dose vial Source: Department of Health, South Africa Griffiths UK, et al. Vaccine 24: , Break-even price per dose

24 VAPP Cases in USA IPV use increasing IPV/OPV recommended IPV alone recommended When seeking for an affordable IPV option, 6 in 1 combination seems the most logical solution Hib initiative benchmarck (as of May 2008) Birth cohort vaccinated (excluding India) 70% % 50% 40% 30% 20% 10% 0% Currently, the vast majority of IPV is delivered through combination vaccines Ease acceptability of additional injections Minimize the impact on price IPV universal immunization via combination vaccines would provide significant benefits Programmatic sustainability, in countries already using 5 in 1 Coverage enhancement for all diseases The success of the Hib Initiative reinforces the value of combination vaccines 42 GAVI eligible countries received support for Hib introduction with pentavalent combos More than 30 millions children will be vaccinated representing 2/3 of GAVI eligible countries birth cohort Availability Availability of of an an affordable affordable hexavalent hexavalent IPV IPV solution solution will will be be critical critical to to ensure ensure that that polio polio is is contained contained 48

25 Conclusions on IPV IPV is very safe and highly effective. In some highly endemic areas IPV provides protection superior to that provided by OPV Global supply can meet global demand Schedule changes could be accommodated if really needed Other new developments such as Sabin IPV, ID administration and adjuvantation are late, less effective and probably not required. Although more expensive than OPV can be readily incorporated into pediatric combination vaccines (Hexavalent) where increased cost would be modest. IPV use does not risk VAPP, cvdpv, or establishing chronic excretors. Can be used in post eradication setting without risking the return of virulent derivative polio strains 49 Acknowledgements For slides: E. Vidor G.Galy, F.Sandre P.Morgon Stanley Plotkin Andrew Macadam Phil Minor For Early work on Polio genetics: Phil Minor et al. Geoffrey Schild Andrew Macadam Rudi Hauptmann et al. And many others 50