Vaccine-Derived Polioviruses VDPVs

1. Vaccine-Derived Polioviruses(VDPVs) Definitions and Properties Olen Kew CDC 7th EMR Polio Laboratory Directors Meeting Amman 25 August 2003

2. Vaccine-related strains Licensed Sabin vaccine strains Everything else (Vaccine-derived) Revertant variants Excreted recipient vaccine strains Vaccine/vaccine recombinants Vaccine/NPEV recombinants Genetically changes (evidence of accumulation of random genetic changes)

3. Vaccine-derived polioviruses (VDPVs) For our program, vaccine-related isolates from clinical samples or the environment have been categorized into two major divisions OPV-like (Sabin-like) <1% divergence in VP1 from respective Sabin strain VDPVs >=1% divergence in VP1 From molecular clock, 1% divergence implies ~1 year of replication or circulation 1% demarcation somewhat arbitrary, but will include nearly all aberrant isolates and exclude most typical isolates Does not predict biological properties of VDPVs, only their replication histories

4. Vaccine-derived polioviruses (VDPVs) Two sub-categories of VDPVs iVDPVs From immunodeficient chronic excretors If recombinant, recombination with other Sabin strain genomes Occur sporadically; independent of OPV coverage cVDPVs Circulating VDPVs Found in areas with gaps in OPV coverage All so far documented have been recombinants with species C enteroviruses

5. Vaccine-derived polioviruses (VDPVs) Both iVDPVs and cVDPVs have been found to be neurovirulent Capacity for sustained circulation demonstrated only for cVDPVs iVDPVs may also have the potential to circulate, but most have been found in areas with high OPV coverage Most are also antigenic variants VDPVs have other properties resembling those of wild polioviruses

7. Developed in 1950s by Albert Sabin before advent of molecular genetics Sabin applied sound principles of genetic selection Sabin OPV strains are spontaneous mutants derived from wild polioviruses by serial passage Sabin strains can revert to wild-type phenotype and (very rarely) cause polio The development of the oral poliovaccines by Albert Sabin was a major medical achievement for its time. The availability of OPV made polio eradication possible because: it is inexpensive easy to deliver uses the natural route of infection OPV infections mimic natural infections intestinal immunity blocks person-to-person spread of poliovirus However, it was recognized early that the inherent genetic instability of polioviruses presented challenges to OPV use. What was not recognized then was the magnitude of the challenge, as it was only later discovered that polioviruses are among the most rapidly evolving viruses in nature.The development of the oral poliovaccines by Albert Sabin was a major medical achievement for its time. The availability of OPV made polio eradication possible because: it is inexpensive easy to deliver uses the natural route of infection OPV infections mimic natural infections intestinal immunity blocks person-to-person spread of poliovirus However, it was recognized early that the inherent genetic instability of polioviruses presented challenges to OPV use. What was not recognized then was the magnitude of the challenge, as it was only later discovered that polioviruses are among the most rapidly evolving viruses in nature.

8. AAA A few critical base substitutions confer the attenuated phenotype to the Sabin strains: Sabin 1: 6 substitutions Sabin 2: 2 substitutions Sabin 3: 3 substitutionsA few critical base substitutions confer the attenuated phenotype to the Sabin strains: Sabin 1: 6 substitutions Sabin 2: 2 substitutions Sabin 3: 3 substitutions

9. Polioviruses evolve very rapidly RNA replicase error rate: ~10-4/cycle Poliovirus evolution rate: 1%/year 1-2 base substitutions/week along any lineage Most substitutions generate synonymous codons Biological properties of wild polioviruses are stable OPV strains are unstable, as attenuating mutations are under negative selection when vaccine virus replicates in humans Polioviruses are among the most rapidly evolving viruses. Like all RNA viruses, the RNA replicase is error prone, because it lacks proofreading capabilities. A high mutation rate is necessary, but not sufficient, for rapid evolution in nature. However, most striking is the rate of evolution in nature: 1 to 2 base substitutions per genome per week along any chain of transmission. This is many orders of magnitude faster than the evolution rate of DNA viruses or cellular genes. This rate is far faster than HIV, influenza A, or hepatitis C viruses, generally considered to be rapidly evolving. Most substitutions generate synonymous codons, and the biological properties of wild polioviruses are very stable. The rapid evolution presents challenges to OPV stability. It also makes high-resolution molecular epidemiology possible.Polioviruses are among the most rapidly evolving viruses. Like all RNA viruses, the RNA replicase is error prone, because it lacks proofreading capabilities. A high mutation rate is necessary, but not sufficient, for rapid evolution in nature. However, most striking is the rate of evolution in nature: 1 to 2 base substitutions per genome per week along any chain of transmission. This is many orders of magnitude faster than the evolution rate of DNA viruses or cellular genes. This rate is far faster than HIV, influenza A, or hepatitis C viruses, generally considered to be rapidly evolving. Most substitutions generate synonymous codons, and the biological properties of wild polioviruses are very stable. The rapid evolution presents challenges to OPV stability. It also makes high-resolution molecular epidemiology possible.

10. Recombination Any poliovirus that circulates will recombine with other NPEVs or polioviruses New recombination will usually occur within three years of preceding recombination Recombination is easily recognized by non-homologous sequences in one or more non-capsid regions of the genome Recombination may also occur in 5�-UTR, but frequency is much lower

14. Vaccine-Derived Polioviruses Most infections with OPV last ~4 weeks Infections are normally restricted to OPV recipients and their close contacts High levels of population immunity block spread Evolution of vaccine virus by base substitution is generally limited The recent discovery of circulating vaccine-derived polioviruses have had important implications to the strategy of polio eradication. It was initially assumed that the only challenge was to eliminate circulating wild polioviruses. WHO is now engaged in a two-front war against polio. The main front is to knock out wild polioviruses in the remaining reservoirs The second front is to prevent emergence of circulating vaccine-derived polioviruses (cVDPVs), where wild poliovirus circulation has been eliminated, and the only source of polio immunity is from immunization. If OPV coverage rates fall, immunity gaps open up, and the OPV virus can, under suitable conditions, spread widely among susceptible unimmunized children.The recent discovery of circulating vaccine-derived polioviruses have had important implications to the strategy of polio eradication. It was initially assumed that the only challenge was to eliminate circulating wild polioviruses. WHO is now engaged in a two-front war against polio. The main front is to knock out wild polioviruses in the remaining reservoirs The second front is to prevent emergence of circulating vaccine-derived polioviruses (cVDPVs), where wild poliovirus circulation has been eliminated, and the only source of polio immunity is from immunization. If OPV coverage rates fall, immunity gaps open up, and the OPV virus can, under suitable conditions, spread widely among susceptible unimmunized children.

15. Circulating Vaccine-Derived Poliovirus (cVDPV) Four examples of prolonged circulation of VDPV associated with polio outbreaks Egypt: 1988 � 1993; Type 2 30 confirmed cases Hispaniola: 2000 � 01; Type 1 21 confirmed cases; 2 deaths Philippines: 2001; Type 1 3 confirmed cases Madagascar: 2002; Type 2 4 cases This shift in poliovirus epidemiology in the new ecological setting has been conclusively found in four areas.This shift in poliovirus epidemiology in the new ecological setting has been conclusively found in four areas.

16. Circulating Vaccine-Derived Poliovirus Outbreaks In each of these areas, spread of cVDPVs followed the elimination of the corresponding serotype of indigenous wild poliovirus, but with continued introduction of OPV into communities with growing immunity gaps. All of the cVDPV outbreaks were detected first by the laboratory, using sequence data and evolutionary analyses.In each of these areas, spread of cVDPVs followed the elimination of the corresponding serotype of indigenous wild poliovirus, but with continued introduction of OPV into communities with growing immunity gaps. All of the cVDPV outbreaks were detected first by the laboratory, using sequence data and evolutionary analyses.

17. Egypt cVDPV 30 polio cases during 1988-1993 in Egypt Associated with poliovirus type 2 93%-97% VP1 identity to Sabin 2 OPV < 82% identity to other wild type 2 Suggested single OPV infection founder A 2000-2001 outbreak in Hispaniola (Haiti and the Dominican Republic) brought attention to the problem of cVDPVs. But the finding of endemic type 2 cVDPV transmission for over 10 years in Egypt underscored the importance of this public health challenge.A 2000-2001 outbreak in Hispaniola (Haiti and the Dominican Republic) brought attention to the problem of cVDPVs. But the finding of endemic type 2 cVDPV transmission for over 10 years in Egypt underscored the importance of this public health challenge.

18. Egypt cVDPV Estimated date initiating OPV dose ~ August 1983 Progeny of OPV dose circulated for ~ 10 years along several independent chains of transmission cVDPVs caused polio cVDPVs biologically indistinguishable from wild poliovirus Existence of cVDPVs have important implications for polio eradication exit strategy These findings have shaped much of the discussion within WHO about the current and future strategies to maintain a polio-free status after all wild poliovirus circulation has been stopped. So, as you can see, the principles of evolutionary biology are deeply woven into the fabric of global polio eradication from the tracking of pathways of transmission to the establishment of environmental conditions that select against the emergence of cVDPVs.These findings have shaped much of the discussion within WHO about the current and future strategies to maintain a polio-free status after all wild poliovirus circulation has been stopped. So, as you can see, the principles of evolutionary biology are deeply woven into the fabric of global polio eradication from the tracking of pathways of transmission to the establishment of environmental conditions that select against the emergence of cVDPVs.

25. Similarities to Wild Polioviruses Capacity for sustained person-to-person transmission Significant paralytic attack rate Critical attenuating sites reverted/recombined out Highly neurovirulent in transgenic mouse model �Non-vaccine-like� antigenic properties Replicates at 39.5 C Undergoes recombination with NPEVs during circulation

26. Features of cVDPV More than 1% change from parent Sabin strains Evidence of recombination with NPEV Outbreaks occur in areas with low vaccine coverage Outbreaks occur in areas where indigenous wilds strains of the same serotype have been eliminated

27. Patterns of Type 2 Poliovirus Circulation in Egypt

28. Areas with Confirmed Polio Cases on Hispaniola Island, 2000 - 2001*

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38. iVDPVs Can appear anywhere where OPV is used Children with defects in Ab production may be chronic excretors (up to 10+ years) Several iVDPV cases reported worldwide A recent VDPV case in EMR (Syria) is an ambiguous VDPV, some indications that it might be an iVDPV

39. Type 2 VDPV in Syria Type 2 VDPV found in northwestern and (eastern) Syria in late 2001 Isolates ~1% divergent from Sabin 2 No recombination with NPEV Preliminary results suggest that genetic properties resemble iVDPVs Complete genomic sequencing in progress

41. Summary VDPVs have important implications for our Program Higher demands placed upon laboratory proficiency and appropiate screening methods Has immediate implications for maintaining high poliovaccine coverage rates Has important implications for end-game strategy Much of the critical information is coming from our LabNet